CARDIAC NEXT-GENERATION SEQUENCING PANELS

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TABLE OF CONTENTS

GENETIC TESTING FOR INHERITED CARDIOVASCULAR CONDITIONS 6

GENETICS AND INDICATIONS 6 TESTING METHODS, SENSITIVITY, AND LIMITATIONS 7 TURNAROUND TIME 9 SPECIMEN AND SHIPPING REQUIREMENTS 9 CUSTOMER SERVICES AND GENETIC COUNSELING 10

THE COMPREHENSIVE PANEL 11

DILATED CARDIOMYOPATHY (DCM) SUBPANEL 23

ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY (ARVC) SUBPANEL 28

HYPERTROPHIC CARDIOMYOPATHY (HCM) SUBPANEL 30

LEFT VENTRICULAR NON-COMPACTION CARDIOMYOPATHY (LVNC) SUBPANEL 33

THE COMPREHENSIVE ARRHYTHMIAS PANEL 35

BRUGADA SYNDROME (BRS) SUBPANEL 40

CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT) SUBPANEL 42

LONG / SHORT QT SYNDROME (LQTS / SQTS) SUBPANEL 43

AORTOPATHIES PANEL 45

CONGENITAL HEART DISEASE (CHD) PANEL 47

FAMILIAL HYPERCHOLESTEROLEMIA (FH) PANEL 51

PULMONARY HYPERTENSION (PAH) PANEL 52

METABOLIC CARDIOMYOPATHY PANEL 53

NOONAN SPECTRUM DISORDERS PANEL 55

HEREDITARY HEMORRHAGIC PANEL 57

REFERENCES 58

DISCLAIMER 67

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Genetic Testing for INHERITED CARDIOVASCULAR CONDITIONS

Many cardiovascular diseases have a genetic background and can be inherited from parents to their offspring. Controlling for risk factors such as smoking, hypertension, high cholesterol, and , researchers have established genetic etiology’s significant contribution in cardiovascular disease through twin studies and investigations of families with early onset cardiac complications. For example, a monozygotic twin has a marked increase in risk of early cardiovascular mortality when the first twin has died due to cardiac complications. This in turn supports genetic testing of families in order to identify changes in and pathways whose altered functions affect cardiovascular outcomes. Further, genetic testing can improve diagnostic accuracy and refine family management by identifying the molecular etiology of disease.

Next-generation sequencing (NGS) technology is ideal for diagnostic testing of families and index cases with cardiovascular complications due to the extreme heterogeneity and phenotypic overlap between the genes involved. Sema4 utilizes Agilent SureSelectQXT target enrichment library prep with Illumina NovaSeq sequencing to detect pathogenic variants in genes involved in cardiovascular disease. A comprehensive menu of heritable cardiovascular conditions was curated by experts and relevant genes were selected based on literature review, clinical actionability scores, and comparison with commercially available assays. The Cardiac Panel includes 241 genes with the following subpanels: Comprehensive Cardiomyopathy (190), (DCM; 57), Hypertrophic Cardiomyopathy (HCM; 40), Left Ventricular Non-Compaction Cardiomyopathy (LVNC; 20), Comprehensive Arrhythmias (54), Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC; 8), Brugada Syndrome (BrS; 20), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT; 8), Long / Short QT Syndrome (19), Aortopathies (33), Congenital Heart Disease (CHD; 44), Familial Hypercholesterolemia (FH; 4), Pulmonary Hypertension (10), Metabolic Cardiomyopathy (24), Noonan Spectrum Disorders (19), and Hereditary Hemorrhagic Telangiectasia Panel (5).

Customizable testing of the cardiac panel is available along with targeted familial testing. Genetic testing can help clarify the underlying cause of a cardiac complication, provide information on the likelihood of related health issues, and establish risk to other family members and future generations.

Genetics

The disorders included in this panel may be inherited in an autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), or isolated cases (IC) manner. For genes displaying an AD mode of inheritance, an affected parent carrying the mutated has a 50% chance of passing the variant on to an offspring, regardless of gender. Some of these genes are not fully penetrant, meaning that an individual may have a mutated gene but not display any of the signs/symptoms of the disorder. Additionally, these disorders may have variable expressivity indicating that individuals carrying the same pathogenic variant may display differing features and/or differing severity. For diseases with AR inheritance, the risk for a couple who are both carriers to have a child affected with the disease is 25% for each pregnancy. The parents of an affected child are most often obligate carriers (heterozygotes) and each carry one mutant allele (unless a de novo mutation occurs). An X-linked inheritance means that the risk of a male offspring with the disorder will be 50% if the mother carries an XL mutation. Depending on the X-inactivation pattern of the gene, a mother and her daughters may rarely be affected. Although X-linked diseases are normally transmitted from mother to son, transmission of an X-linked mutation will occur from an affected father to each daughter, but will not occur from father to son. An IC mode of inheritance indicates no prior family history.

Indications

1. Clinical status: to confirm a clinical diagnosis in an affected patient, in an individual with unknown status (no screening/evaluation), or in unaffected relatives of an affected patient (all screening/evaluations(s) normal). The purpose of the test may be diagnostic, carrier testing, familial follow-up on a known family variant, or prenatal testing for known variant(s).

2. Treatment: to clarify the cause of an individual’s cardiovascular disease, provide information on the likelihood of related health issues, and guide treatment.

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3. Family risk: to establish risk to other family members and future generations.

For patients with a suspected syndrome or disorder, please consider single gene sequencing or associated subpanels prior to ordering the comprehensive panel.

Testing Methods, Sensitivity, and Limitations

Next Generation Sequencing (NGS) (Analytical Detection Rate >95%)

Agilent SureSelectTM QXT technology is used with a custom capture library to target the exonic regions and intron/exon splice junctions of the relevant genes, as well as a number of UTR, intronic or promoter regions that contain previously reported mutations. Samples are pooled and sequenced on the Illumina NovaSeq platform in the Xp workflow, using 100 bp paired-end reads. The sequencing data are analyzed using a custom bioinformatics algorithm designed and validated in-house. In our validation, average coverage was greater than 200X per sample with >99.9% of regions covered at greater than 20X.

The coding exons and splice junctions of the known -coding RefSeq genes are assessed for the average depth of coverage (minimum of 20X) and data quality threshold values. Most exons not meeting a minimum of >20X read depth across the exon are further analyzed by Sanger sequencing. Please note that several genomic regions present difficulties in mapping or obtaining read depth >20X. These regions include, but are not limited to, UTRs, promoters, and deep intronic areas. In addition, a mutation(s) in a gene not included on the panel could be present in this patient. The following regions (hg19 coordinates) have been excluded due to lack of amenability to NGS or Sanger sequencing, high GC content, high homology, lack of known clinically significant variants, or overlap with repetitive regions: ATP7A chrX:77269723-77269729, ATP7A chrX:77278955-77279156, DMD chrX:31897426-31897627, DMD chrX:32668999-32669253, DMD chrX:32644476-32644680, DMD chrX:31627637-31627838, DMD chrX:32460213-32460334, DMD chrX:31219361-31219367, DMD chrX:31219126-31219287, DMD chrX:32644160-32644321, FKTN chr9:108368751-108368962, FLNC chr7:128498050-128498282, GATA6 chr18:19749269-19749275, GBA chr1:155207120-155207380, GBA chr1:155204774-155204902, GBA chr1:155208296-155208452, LAMP2 chrX:119604075-119604081, LEFTY2 chr1:226127049-226127311, MUT chr6:49404225-49404231, NDUFS7 chr19:1386640-1386646, PGM1 chr1:64124731-64124737, RASA2 chr3:141235158-141235284, SCN1B chr19:35521713-35521775, SDHA chr5:251441-251594, SDHA chr5:251441,251594, SDHA chr5:218459-218544, SGSH chr17:78193967- 78194168, TBX1 chr22:19748416-19748814, TRDN chr6:123851639-123851721, TRDN chr6:123576214- 123576281, TTN chr2:179518142-179518245, TTN chr2:179518336-179518439, TTN chr2:179518532- 179518635, TTN chr2:179518727-179518833, TTN chr2:179518923-179519029, TTN chr2:179519160- 179519272, TTN chr2:179519460-179519566, TTN chr2:179519627-179519733, TTN chr2:179522213- 179522319, TTN chr2:179522402-179522505, TTN chr2:179522596:179522699, TTN chr2:179522792- 179522895, TTN chr2:179522987-179523093, TTN chr2:179523183-179523289, TTN chr2:179523420- 179523532, TTN chr2:179523720-179523826, TTN chr2:179523887-179523993, TTN chr2:179526474- 179526580, TTN chr2:179526663-179526766, TTN chr2:179526857-179526960, TTN chr2:179527053- 179527156, TTN chr2:179527248-179527354, TTN chr2:179527444-179527550, TTN chr2:179527681- 179527793, TTN chr2:179527981-179528087, and TTN chr2:179528148-179528254. The exons contained within these regions will not be reflexed to Sanger sequencing if the mapping quality or coverage is poor due to high . Any variants identified during testing in these regions are confirmed by a second method and reported.

This test will detect variants within the exons and the intron-exon boundaries of the target regions. Variants outside these regions may not be detected, including, but not limited to, UTRs, promoters, and deep intronic areas, or regions that fall into the exceptions mentioned above. This technology may not detect all small insertion/deletions and is not diagnostic for repeat expansions and structural genomic variation. In addition, a mutation(s) in a gene not included on the panel could be present in this patient.

Copy Number Variant Analysis (Analytical Detection Rate >90%)

Large duplications and deletions were called from the relative read depths on an exon-by-exon basis using a custom Exome Hidden Markov Model (XHMM) algorithm. This algorithm is designed to pick up deletions and

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duplications of two or more exons/probed regions in length. For deletions (≥2 exons/probed regions), the analytical sensitivity and analytical specificity are >99%. For duplications (≥2 exons/probed regions), the analytical sensitivity is >80% and analytical specificity is >99%. All reported pathogenic or likely pathogenic deletions and/or duplications were confirmed by a custom aCGH platform, quantitative PCR, and/or MLPA, depending on CNV size and gene content.

Multiplex Ligation-Dependent Probe Amplification (MLPA) (Analytical Detection Rate >99%)

MLPA probe sets and reagents from MRC-Holland are used for copy number analysis of specific targets versus known control samples. False positive or negative results may occur due to rare sequence variants in target regions detected by MLPA probes. Analytical sensitivity and specificity of the MLPA method are both 99%. MLPA for Duchenne muscular dystrophy disease (DMD) will only be performed if indicated. For Duchenne muscular dystrophy, the copy numbers of all DMD exons are analyzed. Potentially pathogenic single exon deletions and duplications are confirmed by a second method. Analysis of DMD is performed in association with sequencing of the coding regions.

Exon Array (Confirmation method) (Accuracy >99%)

The customized oligonucleotide microarray (Oxford Gene Technology) is a highly-targeted exon-focused array capable of detecting medically relevant microdeletions and microduplications at a much higher resolution than traditional aCGH methods. Each array matrix has approximately one hundred and eighty thousand 60-mer oligonucleotide probes that cover the entire gene panel. This platform is designed based on NCBI Build 37 (hg19) and the CGH probes are selected to target the exonic regions of 222 genes. This test does not include analysis of ALPK3, CALM2, EIF2AK4, GDF2, LZTR1, MAT2A, MEIS2, MFAP5, MIB1, PET100, PLEKHM2, PPP1CB, PRKG1, RASA2, SLMAP, and SOS2. For the majority of genes there are a minimum of 4 probes per exon. For very large exons, probes are distributed evenly along the exon with 1 probe every 125 bp. In the untargeted backbone regions, this array has one probe every 42kb. All genomic coordinates are reported using human genome NCBI Build 37 (hg19). Copy number aberrations are identified using the Aberration Detection Method-2 (ADM2) algorithm with a sensitivity threshold of 6.0 (Agilent Technologies). The log2 ratio threshold values to detect aberrations are < -0.25 for copy number losses and > 0.25 for copy number gains. Please note that any inconsistencies in the reported biological familial relationships could significantly change the interpretation of these results. For reported CNVs with uncertain clinical significance, continued surveillance of the medical literature for new information is recommended.

The sensitivity of this assay is estimated to be greater than 99% for microdeletions and microduplications in the exonic regions of 224 medically-relevant genes. Variant interpretation and classification is performed based on the American College of standards and guidelines for the interpretation of sequence variants (Richards et al, 2015). Frequency in control populations is evaluated based on the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/), the Database of Genomic Variants (http://dgv.tcag.ca/dgv/app/home), and 1000 genomes (http://www.1000genomes.org/) databases. Any benign polymorphisms identified during this analysis will not be reported. Variant interpretations, based on current knowledge, may change over time as more information arises.

The following aberrations will NOT be reported and parental studies will NOT be performed: • CNVs that are considered benign based on coverage in the Database of Genomic Variants (DGV; ) and/or our internal laboratory CNV database • Gains or losses of <500 kb that do not include any known genes () • Gains or losses with no known clinical significance (based on gene content and/or coverage in the DGV) • Copy number variation of ALPK3, CALM2, EIF2AK4, GDF2, LZTR1, MAT2A, MEIS2, MFAP5, MIB1, PET100, PLEKHM2, PPP1CB, PRKG1, RASA2, SLMAP, and SOS2. • Copy number gains and losses associated with genetic susceptibility, quantitative trait loci, pharmacogenetic alleles, and cancer predisposition • Copy number gains and losses that are < 1.0 Mb in size and that appear to be mosaic by aCGH due to atypical log2 ratios, unless the affected region is determined to be clinically significant based on gene content and/or coverage in the DGV

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The aCGH technology cannot detect balanced rearrangements, such as reciprocal translocations, Robertsonian translocations, inversions and balanced insertions, or imbalances that are below the resolution of this array. This technology will also not detect point mutations or small insertion/deletions below this array’s resolution that cause frameshifts, imprinting defects or other epigenetic mutations, and may not detect low level mosaicism. The failure to detect an alteration at any locus does not exclude the diagnosis of any of the disorders represented on the microarray.

The aCGH technology cannot detect balanced rearrangements, such as reciprocal translocations, Robertsonian translocations, inversions and balanced insertions, or imbalances that are below the resolution of this array. This technology will also not detect point mutations or small insertion/deletions below this array’s resolution that cause frameshifts, imprinting defects or other epigenetic mutations, and may not detect low level mosaicism. The failure to detect an alteration at any locus does not exclude the diagnosis of any of the disorders represented on the microarray.

Quantitative PCR (Confirmation method) (Accuracy >99%)

The relative quantification PCR is utilized on a Roche Universal Library Probe (UPL) system, which relates the PCR signal of the target region in one group to another. To test for genomic imbalances, both sample DNA and reference DNA is amplified with primer/probe sets that specific to the target region and a control region with known genomic copy number. Relative genomic copy numbers are calculated based on the standard ∆∆Ct formula.

Sanger Sequencing (Confirmation method) (Accuracy >99%)

Sanger sequencing, as indicated, is performed using BigDye Terminator chemistry with the ABI 3730 DNA analyzer with target specific amplicons. It also may be used to supplement specific guaranteed target regions that fail NGS sequencing due to poor quality or low depth of coverage (<20 reads) or as a confirmatory method for NGS positive results. False negative results may occur if rare variants interfere with amplification or annealing.

Variant Interpretation and Reporting

Variant interpretation and classification was performed based on the American College of Medical Genetics Standards and guidelines for the interpretation of sequence variants (PMID:25741868). Frequency in control populations were evaluated based on the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/) , and Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Potentially pathogenic variants may be confirmed by Sanger sequencing if indicated. Familial samples are only tested for certain variants by Sanger sequencing if indicated. Variants classified as likely benign in the proband were not confirmed by Sanger sequencing. We cannot rule out the possibility that variants classified as uncertain clinical significance may contribute to disease. Any benign polymorphisms identified during this analysis were not reported. Variant interpretations, based on current knowledge, may change over time as more information arises.

Turnaround Time

Results are reported to the referring physician within 10-14 business days (for prenatal samples) and 3-4 weeks (for postnatal samples) from the receipt of the specimen. Please note only targeted analysis is performed for prenatal cases, where the familial gene and mutation(s) are known.

Specimen and Shipping Requirements

Postnatal blood samples: 2 yellow-top (ACD-A or ACD-B) or 2 lavender-top (EDTA) tubes, 5-10 mL of blood from the patient are required. One blood tube from both parents is requested.

Newborn/child: 1 yellow-top (ACD-A or ACD-B) or 1 lavender-top (EDTA) tube, 2 mL of blood from the patient are required. Additionally, 1 yellow-top (ACD-A or ACD-B) or 1 lavender-top (EDTA) 5-10 mL tube of blood from

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both parents is requested.

Prenatal Specimens: 2 confluent T-25 flasks of cultured cells (originating from amniotic fluid or chorionic villi) or more than 4 mg of direct CVS tissue, or 15 mL of direct amniotic fluid (AF) as well as 1 lavender-top (EDTA) 5- 10mL tube of blood from the pregnant patient and her partner are required. Note: parental blood samples are requested for confirmation studies necessary in some cases; maternal blood is also used for maternal cell contamination studies. Please note, prenatal analysis will only be performed for known parental variants.

Extracted DNA samples: We request 20 µL DNA (50-250 ng/µL) or at minimum require 10 µL DNA (50-250 ng/µL). Causes for rejection include impurities in the test or reference DNA samples, including NaCl or KCl (>40 mM) and other salts, phenol, ethanol, heparin, EDTA (>1.5 mM), and Fe, contaminated DNA, and low concentration of DNA (<20 ng/µL).

Saliva samples: We can accept saliva specimens upon request. Saliva samples should be collected in Oragene DNA (OG-500) kits by DNA Genotek. Please contact our laboratory to obtain saliva kits.

Cheek swab: 1 cheek swab specimen collected from ORAGENE kit from the patient is required. 1 cheek swab specimen collected from ORAGENE kit from both parents is requested.

Tubes of blood, cultured cells, direct CVS, and direct AF should be kept and shipped refrigerated or at room temperature (PLEASE DO NOT FREEZE). Please note that additional samples may be required for exon array studies if ordered.

Customer Services and Genetic Counseling

Include the following with each sample: • Completed and signed test requisition form and informed consent • Billing information or payment (include copy of insurance card) • Contact information for referring physician • Testing to be performed • Indication for testing, patient’s family history, ethnic background and prior relevant test results

Send same day or overnight (check for morning delivery) to:

Sema4 62 Southfield Avenue Stamford, CT 06902

Contact: [email protected] Tel: 800.298.6470 Fax: 646.859.6870

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THE COMPREHENSIVE CARDIOMYOPATHY PANEL

Cardiomyopathies refer to diseases of the heart muscle, which can be inherited or acquired. As cardiomyopathy worsens and the heart weakens, signs and symptoms of usually occur. These signs and symptoms can include shortness of breath with physical exertion, , and swelling in the ankles, feet, legs, abdomen, and of the neck. Genetic testing of genes associated with inherited forms should be considered if the presence of cardiomyopathy observed in a patient cannot be explained by an acquired etiology. The Comprehensive Cardiomyopathy Panel contains the following 190 genes with six well-established subpanels: Arrythmias, Arrhythmogenic Right Ventricular Cardiomyopathy, Dilated Cardiomyopathy, Hypertrophic Cardiomyopathy, Metabolic Cardiomyopathy, and Left Ventricular Non-compaction Cardiomyopathy. Further details about these subpanels are provided on subsequent pages.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; Comprehensive 614050: AD Atrial fibrillation, familial, 12 ABCC9 601439 Cardiomyopathy; Comprehensive Arrythmias; 608569: Cardiomyopathy, dilated, 1O AD Dilated Cardiomyopathy; Brugada Syndrome 239850: AD Hypertrichotic osteochondrodysplasia Comprehensive Cardiovascular; Comprehensive ACADVL 609575 201475: AR VLCAD deficiency AR Cardiomyopathy; Metabolic 611788: AD Aortic aneurysm, familial thoracic 6 Comprehensive Cardiovascular; Comprehensive 614042: Moyamoya disease 5 ACTA2 102620 AD Cardiomyopathy; Aortopathies 613834: AD Multisystemic dysfunction syndrome Comprehensive Cardiovascular; Comprehensive 612794: AD Atrial septal defect 5 Cardiomyopathy; Congenital Heart Disease; Dilated 613424: AD Cardiomyopathy, dilated, 1R ACTC1 102540 AD Cardiomyopathy; Hypertrophic Cardiomyopathy; 612098: AD Cardiomyopathy, hypertrophic, 11 Left Ventricular Ncompaction 613424: AD Left ventricular noncompaction 4 Comprehensive Cardiovascular; Comprehensive 612158: AD Cardiomyopathy, dilated, 1AA, with or ACTN2 102573 Cardiomyopathy; Comprehensive Arrythmias; without LVNC AD Dilated Cardiomyopathy; Hypertrophic 612158: AD Cardiomyopathy, hypertrophic, 23,

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Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy with or without LVNC Comprehensive Cardiovascular; Comprehensive 614691: AR Cataract 38, AR AGK 610345 AR Cardiomyopathy 212350: AR Sengers syndrome Comprehensive Cardiovascular; Comprehensive 232400: AR Glycogen storage disease IIIa AGL 610860 Cardiomyopathy; Hypertrophic Cardiomyopathy; AR 232400: AR Glycogen storage disease IIIb Metabolic Cardiomyopathies Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; AKAP9 604001 611820: AD ?Long QT syndrome-11 AD Comprehensive Arrythmias; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 608540: AR Congenital disorder of glycosylation, ALG1 605907 AR Cardiomyopathy; Metabolic Cardiomyopathies type Ik Comprehensive Cardiovascular; Comprehensive 607143: AR Congenital disorder of glycosylation, ALG12 607144 AR Cardiomyopathy; Metabolic Cardiomyopathies type Ig Comprehensive Cardiovascular; Comprehensive ALMS1 606844 203800: AR Alstrom syndrome AR Cardiomyopathy; Congenital Heart Disease Comprehensive Cardiovascular; Comprehensive 618052: AR Cardiomyopathy, familial hypertrophic ALPK3 617608 AR Cardiomyopathy 27 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Catecholaminergic Polymorphic 600919: AD Cardiac arrhythmia, -B-related ANK2 106410 Ventricular Tachycardia; Long / Short Qt Syndrome; AD 600919: AD Long QT syndrome 4 Comprehensive Arrythmias; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive ANKRD1 609599 Cardiomyopathy; Dilated Cardiomyopathy; None None Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 253200: AR type VI ARSB 611542 AR Cardiomyopathy; Metabolic Cardiomyopathies (Maroteaux-Lamy) Comprehensive Cardiovascular; Comprehensive 613881: AD Cardiomyopathy, dilated, 1HH BAG3 603883 Cardiomyopathy; Dilated Cardiomyopathy; AD 612954: AD Myopathy, myofibrillar, 6 Hypertrophic Cardiomyopathy 211980: Adenocarcinoma of , somatic 115150: AD Cardiofaciocutaneous syndrome Comprehensive Cardiovascular; Comprehensive Colorectal cancer, somatic (3) BRAF 164757 Cardiomyopathy; Congenital Heart Disease; Noonan 613707: AD LEOPARD syndrome 3 AD Spectrum Disorders Melanoma, malignant, somatic (3) Nonsmall cell lung cancer, somatic (3) 613706: AD 7 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; 611875: Brugada syndrome 3 CACNA1C 114205 Comprehensive Arrythmias; Dilated AD 601005: AD Timothy syndrome Cardiomyopathy; Hypertrophic Cardiomyopathy; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive CACNA2D1 114204 Cardiomyopathy; Long / Short Qt Syndrome; None None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive CACNB2 600003 Cardiomyopathy; Long / Short Qt Syndrome; 611876: Brugada syndrome 4 None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive 616247: AD Long QT syndrome 14 Cardiomyopathy; Catecholaminergic Polymorphic CALM1 114180 614916: AD Ventricular tachycardia, AD Ventricular Tachycardia; Long / Short Qt Syndrome; catecholaminergic polymorphic, 4 Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Catecholaminergic Polymorphic CALM2 114182 616249: AD Long QT syndrome 15 AD Ventricular Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Catecholaminergic Polymorphic CALM3 114183 None None Ventricular Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive 611938: AR Ventricular tachycardia, CASQ2 114251 Cardiomyopathy; Catecholaminergic Polymorphic AR catecholaminergic polymorphic, 2 Ventricular Tachycardia; Comprehensive Arrythmias

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Gene MIM Disease Category OMIM Phenotype Inheritance 192600: AD Cardiomyopathy, familial hypertrophic Comprehensive Cardiovascular; Comprehensive 123320: AD Creatine phosphokinase, elevated Cardiomyopathy; Long / Short Qt Syndrome; serum CAV3 601253 AD Comprehensive Arrythmias; Dilated 611818: AD Long QT syndrome 9 Cardiomyopathy; Hypertrophic Cardiomyopathy 614321: AD Myopathy, distal, Tateyama type 606072: AD Rippling muscle disease Comprehensive Cardiovascular; Comprehensive CAVIN4 617714 None None Cardiomyopathy; Dilated Cardiomyopathy 607785: AD, SM ?Juvenile myelomonocytic Comprehensive Cardiovascular; Comprehensive leukemia CBL 165360 Cardiomyopathy; Congenital Heart Disease; Noonan AD, SM 613563: AD Noonan syndrome-like disorder with or Spectrum Disorders without juvenile myelomonocytic leukemia 236200: AR Homocystinuria, B6-responsive and Comprehensive Cardiovascular; Comprehensive CBS 613381 nonresponsive types AR Cardiomyopathy; Aortopathies 236200: AR Thrombosis, hyperhomocysteinemic Comprehensive Cardiovascular; Comprehensive CHRM2 118493 None None Cardiomyopathy Comprehensive Cardiovascular; Comprehensive COL3A1 120180 130050: AD Ehlers-Danlos syndrome, vascular type AD Cardiomyopathy; Aortopathies Comprehensive Cardiovascular; Comprehensive COL5A1 120215 130000: AD Ehlers-Danlos syndrome, classic type, 1 AD Cardiomyopathy; Aortopathies Comprehensive Cardiovascular; Comprehensive COL5A2 120190 130010: AD Ehlers-Danlos syndrome, classic type, 2 AD Cardiomyopathy; Aortopathies 256000: AR, Mitochondrial Leigh syndrome due to Comprehensive Cardiovascular; Comprehensive mitochondrial COX4 deficiency COX10 602125 AR Cardiomyopathy 220110: AR, Mitochondrial Mitochondrial complex IV deficiency 615119: AR Cardioencephalomyopathy, fatal Comprehensive Cardiovascular; Comprehensive infantile, due to cytochrome c oxidase deficiency 2 COX15 603646 AR Cardiomyopathy 256000: AR, Mitochondrial Leigh syndrome due to cytochrome c oxidase deficiency 600649: AR CPT II deficiency, infantile 608836: AR CPT II deficiency, lethal neonatal Comprehensive Cardiovascular; Comprehensive 255110: AR, AD CPT II deficiency, myopathic, stress- CPT2 600650 Cardiomyopathy; Hypertrophic Cardiomyopathy; AD, AR induced Metabolic Cardiomyopathies 614212: AR, AD {Encephalopathy, acute, infection- induced, 4, susceptibility to} 615184: AD Cardiomyopathy, dilated, 1II 613763: AR, AD Cataract 16, multiple types Comprehensive Cardiovascular; Comprehensive CRYAB 123590 608810: AD Myopathy, myofibrillar, 2 AD, AR Cardiomyopathy; Dilated Cardiomyopathy 613869: AR Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related Comprehensive Cardiovascular; Comprehensive 607482: ?Cardiomyopathy, dilated, 1M CSRP3 600824 Cardiomyopathy; Dilated Cardiomyopathy; AD 612124: AD Cardiomyopathy, hypertrophic, 12 Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 615616: AD Arrhythmogenic right ventricular CTNNA3 607667 AD Cardiomyopathy; Comprehensive Arrythmias dysplasia, familial, 13 Comprehensive Cardiovascular; Comprehensive 604765: Cardiomyopathy, dilated, 1I Cardiomyopathy; Comprehensive Arrythmias; 601419: AR, AD Myopathy, myofibrillar, 1 DES 125660 AD, AR Dilated Cardiomyopathy; Hypertrophic 181400: AD Scapuloperoneal syndrome, Cardiomyopathy neurogenic, Kaeser type Comprehensive Cardiovascular; Comprehensive 300376: XLR Becker muscular dystrophy DMD 300377 Cardiomyopathy; Dilated Cardiomyopathy; 302045: XL Cardiomyopathy, dilated, 3B XLR, XL Hypertrophic Cardiomyopathy 310200: XLR Duchenne muscular dystrophy Comprehensive Cardiovascular; Comprehensive 610768: AR Congenital disorder of glycosylation, DOLK 610746 Cardiomyopathy; Dilated Cardiomyopathy; AR type Im Metabolic Cardiomyopathies 610476: AR, AD Arrhythmogenic right ventricular Comprehensive Cardiovascular; Comprehensive dysplasia 11 Cardiomyopathy; Arrythmogenic Right Ventricular DSC2 125645 610476: AR, AD Arrhythmogenic right ventricular AD, AR Cardiomyopathy; Comprehensive Arrythmias; dysplasia 11 with mild palmoplantar Dilated Cardiomyopathy and woolly hair Comprehensive Cardiovascular; Comprehensive 610193: AD Arrhythmogenic right ventricular DSG2 125671 AD Cardiomyopathy; Arrythmogenic Right Ventricular dysplasia 10

62 Southfield Ave. Stamford, CT 06902 13 P: 800-298-6470 Branford CT Lic#: CL-0830 F: 646-859-6870 Stamford CT Lic#: CL-1016 www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Comprehensive Arrythmias; 612877: Cardiomyopathy, dilated, 1BB Dilated Cardiomyopathy 607450: AD Arrhythmogenic right ventricular dysplasia 8 605676: AR Cardiomyopathy, dilated, with woolly Comprehensive Cardiovascular; Comprehensive hair and keratoderma Cardiomyopathy; Arrythmogenic Right Ventricular 615821: AD Dilated cardiomyopathy with woolly DSP 125647 Cardiomyopathy; Comprehensive Arrythmias; AD, AR hair, keratoderma, and tooth agenesis Dilated Cardiomyopathy; Left Ventricular 609638: AR Epidermolysis bullosa, lethal Ncompaction acantholytic 612908: AD palmoplantaris striata II 607655: AR Skin fragility-woolly hair syndrome Comprehensive Cardiovascular; Comprehensive 604169: AD Left ventricular noncompaction 1, with DTNA 601239 AD Cardiomyopathy; Left Ventricular Ncompaction or without congenital heart defects 615440: AR Combined oxidative phosphorylation Comprehensive Cardiovascular; Comprehensive deficiency 17 ELAC2 605367 AR Cardiomyopathy; Dilated Cardiomyopathy 614731: {Prostate cancer, hereditary, 2, susceptibility to} Comprehensive Cardiovascular; Comprehensive 310300: XLR Emery-Dreifuss muscular dystrophy 1, EMD 300384 Cardiomyopathy; Comprehensive Arrythmias; XLR, XL XL Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 605362: AD ?Cardiomyopathy, dilated, 1J EYA4 603550 AD Cardiomyopathy; Dilated Cardiomyopathy 601316: AD Deafness, AD 10 102370: AD 129600: AD , familial 614185: AD Geleophysic dysplasia 2

604308: MASS syndrome Comprehensive Cardiovascular; Comprehensive FBN1 134797 616914: AD Marfan lipodystrophy syndrome AD Cardiomyopathy; Aortopathies 154700: AD 184900: AD 608328: AD Weill-Marchesani syndrome 2, dominant 121050: AD Contractural , Comprehensive Cardiovascular; Comprehensive FBN2 612570 congenital AD Cardiomyopathy; Aortopathies 616118: AD Macular degeneration, early-onset 300696: XLR Emery-Dreifuss muscular dystrophy 6, XL 300696: XLR Myopathy, XL, with postural muscle atrophy

300717: XLD Reducing body myopathy, XL 1a, Comprehensive Cardiovascular; Comprehensive FHL1 300163 severe, infantile or early childhood onset XLD, XLR, XL Cardiomyopathy; Hypertrophic Cardiomyopathy 300718: XL Reducing body myopathy, XL 1b, with late childhood or adult onset 300695: XLD Scapuloperoneal myopathy, XLD 300280: XLR ?Uruguay faciocardiomusculoskeletal syndrome 613153: AR Muscular dystrophy- dystroglycanopathy (congenital with brain and eye anomalies), type A, 5

Comprehensive Cardiovascular; Comprehensive 606612: AR Muscular dystrophy- FKRP 606596 AR Cardiomyopathy; Metabolic Cardiomyopathies dystroglycanopathy (congenital with or without mental retardation), type B, 5 607155: AR Muscular dystrophy- dystroglycanopathy (limb-girdle), type C, 5 611615: AR Cardiomyopathy, dilated, 1X 253800: AR Muscular dystrophy- dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Comprehensive Cardiovascular; Comprehensive FKTN 607440 613152: AR Muscular dystrophy- AR Cardiomyopathy; Dilated Cardiomyopathy dystroglycanopathy (congenital without mental retardation), type B, 4 611588: AR Muscular dystrophy- dystroglycanopathy (limb-girdle), type C, 4 FLNA 300017 Comprehensive Cardiovascular; Comprehensive 314400: XLR Cardiac valvular dysplasia, XL XLD, XLR, XL

62 Southfield Ave. Stamford, CT 06902 14 P: 800-298-6470 Branford CT Lic#: CL-0830 F: 646-859-6870 Stamford CT Lic#: CL-1016 www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Aortopathies 300048: XLR Congenital short bowel syndrome 300321: XL ?FG syndrome 2 305620: XLR Frontometaphyseal dysplasia 1 300049: XLD Heterotopia, periventricular 300048: XLR Intestinal pseudoobstruction, neuronal 309350: XLD Melnick-Needles syndrome 311300: XLD Otopalatodigital syndrome, type I 304120: XLD Otopalatodigital syndrome, type II 300244: XLD Terminal osseous dysplasia Cardiomyopathy, familial hypertrophic, 26 (3) Comprehensive Cardiovascular; Comprehensive 617047: AD Cardiomyopathy, familial restrictive 5 FLNC 102565 Cardiomyopathy; Dilated Cardiomyopathy; AD 614065: AD Myopathy, distal, 4 Hypertrophic Cardiomyopathy 609524: AD Myopathy, myofibrillar, 5 Comprehensive Cardiovascular; Comprehensive GAA 606800 Cardiomyopathy; Hypertrophic Cardiomyopathy; 232300: AR Glycogen storage disease II AR Metabolic Cardiomyopathies 607941: AD Atrial septal defect 2 614430: AD Atrioventricular septal defect 4 Comprehensive Cardiovascular; Comprehensive 615542: AD ?Testicular anomalies with or without GATA4 600576 AD Cardiomyopathy; Congenital Heart Disease congenital heart disease 187500: AD Tetralogy of Fallot 614429: AD Ventricular septal defect 1 614475: AD Atrial septal defect 9 614474: AD Atrioventricular septal defect 5 Comprehensive Cardiovascular; Comprehensive 600001: AD Pancreatic agenesis and congenital GATA6 601656 AD Cardiomyopathy; Congenital Heart Disease heart defects 217095: Persistent truncus arteriosus 187500: AD Tetralogy of Fallot Comprehensive Cardiovascular; Comprehensive GATAD1 614518 614672: AR ?Cardiomyopathy, dilated, 2B AR Cardiomyopathy; Dilated Cardiomyopathy 608013: AR Gaucher disease, perinatal lethal 230800: AR Gaucher disease, type I 230900: AR Gaucher disease, type II

Comprehensive Cardiovascular; Comprehensive 231000: AR Gaucher disease, type III AD, AR, IC, GBA 606463 Cardiomyopathy; Metabolic Cardiomyopathies 231005: AR Gaucher disease, type IIIC MF 127750: AD {Lewy body dementia, susceptibility to} 168600: IC, MF {Parkinson disease, late-onset, susceptibility to} Comprehensive Cardiovascular; Comprehensive 232500: AR Glycogen storage disease IV GBE1 607839 AR Cardiomyopathy; Metabolic Cardiomyopathies 263570: AR Polyglucosan body disease, adult form Comprehensive Cardiovascular; Comprehensive 614049: AD Atrial fibrillation, familial, 11 GJA5 121013 AD Cardiomyopathy; Comprehensive Arrythmias 108770: AD Atrial standstill, digenic (GJA5/SCN5A) Comprehensive Cardiovascular; Comprehensive 301500: XL GLA 300644 Cardiomyopathy; Hypertrophic Cardiomyopathy; XL 301500: XL Fabry disease, cardiac variant Metabolic Cardiomyopathies 230500: AR GM1-gangliosidosis, type I 230600: AR GM1-gangliosidosis, type II Comprehensive Cardiovascular; Comprehensive GLB1 611458 230650: AR GM1-gangliosidosis, type III AR Cardiomyopathy; Metabolic Cardiomyopathies 253010: AR Mucopolysaccharidosis type IVB (Morquio) Comprehensive Cardiovascular; Comprehensive GPD1L 611778 Cardiomyopathy; Comprehensive Arrythmias; 611777: Brugada syndrome 2 None Brugada Syndrome Comprehensive Cardiovascular; Comprehensive GUSB 611499 253220: AR Mucopolysaccharidosis VII AR Cardiomyopathy; Metabolic Cardiomyopathies 609016: AR Fatty liver, acute, of pregnancy 609016: AR HELLP syndrome, maternal, of Comprehensive Cardiovascular; Comprehensive HADHA 600890 pregnancy AR Cardiomyopathy; Metabolic Cardiomyopathies 609016: AR LCHAD deficiency 609015: AR Trifunctional protein deficiency Comprehensive Cardiovascular; Comprehensive 613123: Brugada syndrome 8 HCN4 605206 Cardiomyopathy; Comprehensive Arrythmias; Left AD 163800: AD Sick sinus syndrome 2 Ventricular Ncompaction; Brugada Syndrome HEXB 606873 Comprehensive Cardiovascular; Comprehensive 268800: AR Sandhoff disease, infantile, juvenile, AR

62 Southfield Ave. Stamford, CT 06902 15 P: 800-298-6470 Branford CT Lic#: CL-0830 F: 646-859-6870 Stamford CT Lic#: CL-1016 www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Metabolic Cardiomyopathies and adult forms 109800: {Bladder cancer, somatic} 218040: AD, IC Congenital myopathy with excess of muscle spindles

218040: AD, IC Comprehensive Cardiovascular; Comprehensive 162900: {Nevus sebaceous or woolly hair nevus, HRAS 190020 Cardiomyopathy; Congenital Heart Disease; Noonan AD, IC somatic} Spectrum Disorders 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 137550: {Spitz nevus or nevus spilus, somatic} 188470: {Thyroid carcinoma, follicular, somatic} 607014: AR Mucopolysaccharidosis Ih Comprehensive Cardiovascular; Comprehensive IDUA 252800 607015: AR Mucopolysaccharidosis Ih/s AR Cardiomyopathy; Metabolic Cardiomyopathies 607016: AR Mucopolysaccharidosis Is Comprehensive Cardiovascular; Comprehensive ILK 602366 None None Cardiomyopathy; Dilated Cardiomyopathy 118450: AD Alagille syndrome 1 Comprehensive Cardiovascular; Comprehensive 617992: ?Deafness, congenital heart defects, and JAG1 601920 AD Cardiomyopathy; Congenital Heart Disease posterior embryotoxon 187500: AD Tetralogy of Fallot Comprehensive Cardiovascular; Comprehensive JPH2 605267 613873: AD Cardiomyopathy, hypertrophic, 17 AD Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 611528: AD Arrhythmogenic right ventricular Cardiomyopathy; Arrythmogenic Right Ventricular JUP 173325 dysplasia 12 AD, AR Cardiomyopathy; Comprehensive Arrythmias; 601214: AR Naxos disease Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive KCNA5 176267 Cardiomyopathy; Comprehensive Arrythmias; 612240: AD Atrial fibrillation, familial, 7 AD Pulmonary Hypertension Comprehensive Cardiovascular; Comprehensive 616399: AD Brugada syndrome 9 KCND3 605411 Cardiomyopathy; Comprehensive Arrythmias; AD 607346: AD 19 Brugada Syndrome Comprehensive Cardiovascular; Comprehensive 612347: AR Jervell and Lange-Nielsen syndrome 2 KCNE1 176261 Cardiomyopathy; Long / Short Qt Syndrome; AD, AR 613695: AD Long QT syndrome 5 Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive 611493: Atrial fibrillation, familial, 4 KCNE2 603796 Cardiomyopathy; Long / Short Qt Syndrome; AD 613693: AD Long QT syndrome 6 Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive KCNE3 604433 Cardiomyopathy; Comprehensive Arrythmias; 613119: Brugada syndrome 6 None Brugada Syndrome Comprehensive Cardiovascular; Comprehensive KCNE5 300328 Cardiomyopathy; Comprehensive Arrythmias; None None Brugada Syndrome 613688: AD Long QT syndrome 2 Comprehensive Cardiovascular; Comprehensive 613688: AD {Long QT syndrome 2, acquired, KCNH2 152427 Cardiomyopathy; Long / Short Qt Syndrome; AD susceptibility to} Comprehensive Arrythmias; Brugada Syndrome 609620: Short QT syndrome 1 Comprehensive Cardiovascular; Comprehensive 170390: AD Andersen syndrome Cardiomyopathy; Catecholaminergic Polymorphic KCNJ2 600681 613980: AD Atrial fibrillation, familial, 9 AD Ventricular Tachycardia; Long / Short Qt Syndrome; 609622: Short QT syndrome 3 Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive 613677: AD Hyperaldosteronism, familial, type III KCNJ5 600734 Cardiomyopathy; Long / Short Qt Syndrome; AD 613485: AD Long QT syndrome 13 Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive KCNJ8 600935 Cardiomyopathy; Comprehensive Arrythmias; None None Brugada Syndrome 607554: AD Atrial fibrillation, familial, 3 220400: AR Jervell and Lange-Nielsen syndrome Comprehensive Cardiovascular; Comprehensive 192500: AD Long QT syndrome 1 KCNQ1 607542 Cardiomyopathy; Long / Short Qt Syndrome; AD, AR 192500: AD {Long QT syndrome 1, acquired, Comprehensive Arrythmias susceptibility to} 609621: AD Short QT syndrome 2

62 Southfield Ave. Stamford, CT 06902 16 P: 800-298-6470 Branford CT Lic#: CL-0830 F: 646-859-6870 Stamford CT Lic#: CL-1016 www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance 108010: Arteriovenous malformation of the brain, somatic 109800: Bladder cancer, somatic 114480: Breast cancer, somatic 615278: Cardiofaciocutaneous syndrome 2 137215: Gastric cancer, somatic Comprehensive Cardiovascular; Comprehensive 601626: AD Leukemia, acute myeloid KRAS 190070 Cardiomyopathy; Congenital Heart Disease; Noonan AD 211980: Lung cancer, somatic Spectrum Disorders 609942: AD Noonan syndrome 3 260350: Pancreatic carcinoma, somatic 614470: AD RAS-associated autoimmune leukoproliferative disorder 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic Comprehensive Cardiovascular; Comprehensive LAMA4 600133 615235: AD Cardiomyopathy, dilated, 1JJ AD Cardiomyopathy; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; LAMP2 309060 300257: XLD XLD Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathies 601493: AD Cardiomyopathy, dilated, 1C, with or Comprehensive Cardiovascular; Comprehensive without LVNC Cardiomyopathy; Comprehensive Arrythmias; LDB3 605906 601493: AD Cardiomyopathy, hypertrophic, 24 AD Dilated Cardiomyopathy; Hypertrophic 601493: AD Left ventricular noncompaction 3 Cardiomyopathy; Left Ventricular Ncompaction 609452: AD Myopathy, myofibrillar, 4 115200: AD Cardiomyopathy, dilated, 1A 605588: AR Charcot-Marie-Tooth disease, type 2B1 181350: AD Emery-Dreifuss muscular dystrophy 2, AD

616516: AR Emery-Dreifuss muscular dystrophy 3, Comprehensive Cardiovascular; Comprehensive AR Cardiomyopathy; Comprehensive Arrythmias; LMNA 150330 610140: AD Heart-hand syndrome, Slovenian type AD, AR Dilated Cardiomyopathy; Left Ventricular 176670: AR, AD Hutchinson-Gilford Ncompaction 151660: AD Lipodystrophy, familial partial, type 2 212112: AD Malouf syndrome 248370: AR 613205: AD Muscular dystrophy, congenital 275210: AR Restrictive dermopathy, lethal Comprehensive Cardiovascular; Comprehensive MAP2K1 176872 Cardiomyopathy; Congenital Heart Disease; Noonan 615279: Cardiofaciocutaneous syndrome 3 None Spectrum Disorders Comprehensive Cardiovascular; Comprehensive MAP2K2 601263 Cardiomyopathy; Congenital Heart Disease; Noonan 615280: Cardiofaciocutaneous syndrome 4 None Spectrum Disorders 309520: XLR Lujan-Fryns syndrome Comprehensive Cardiovascular; Comprehensive MED12 300188 300895: XLR Ohdo syndrome, XL XLR, XL Cardiomyopathy; Aortopathies 305450: XLR Opitz-Kaveggia syndrome Comprehensive Cardiovascular; Comprehensive MIB1 608677 615092: AD Left ventricular noncompaction 7 AD Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; Comprehensive MLYCD 606761 248360: AR Malonyl-CoA decarboxylase deficiency AR Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 614702: AR Combined oxidative phosphorylation MTO1 614667 AR Cardiomyopathy; Metabolic Cardiomyopathies deficiency 10 Comprehensive Cardiovascular; Comprehensive MUT 609058 251000: AR Methylmalonic aciduria, mut(0) type AR Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 615396: AD Cardiomyopathy, dilated, 1MM Cardiomyopathy; Dilated Cardiomyopathy; MYBPC3 600958 115197: AD Cardiomyopathy, hypertrophic, 4 AD Hypertrophic Cardiomyopathy; Left Ventricular 615396: AD Left ventricular noncompaction 10 Ncompaction Comprehensive Cardiovascular; Comprehensive MYH11 160745 132900: AD Aortic aneurysm, familial thoracic 4 AD Cardiomyopathy; Aortopathies Comprehensive Cardiovascular; Comprehensive 614089: Atrial septal defect 3 MYH6 160710 Cardiomyopathy; Congenital Heart Disease; Dilated 613252: Cardiomyopathy, dilated, 1EE AD Cardiomyopathy; Hypertrophic Cardiomyopathy 613251: AD Cardiomyopathy, hypertrophic, 14

62 Southfield Ave. Stamford, CT 06902 17 P: 800-298-6470 Branford CT Lic#: CL-0830 F: 646-859-6870 Stamford CT Lic#: CL-1016 www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance 614090: {Sick sinus syndrome 3} 613426: AD Cardiomyopathy, dilated, 1S 192600: AD Cardiomyopathy, hypertrophic, 1 Comprehensive Cardiovascular; Comprehensive 160500: AD Laing distal myopathy

Cardiomyopathy; Dilated Cardiomyopathy; 613426: AD Left ventricular noncompaction 5 MYH7 160760 AD, AR Hypertrophic Cardiomyopathy; Left Ventricular 608358: AD Myopathy, storage, AD Ncompaction 255160: AR Myopathy, myosin storage, AR 181430: AD Scapuloperoneal syndrome, myopathic type Comprehensive Cardiovascular; Comprehensive MYL2 160781 608758: AD Cardiomyopathy, hypertrophic, 10 AD Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive MYL3 160790 608751: AR, AD Cardiomyopathy, hypertrophic, 8 AD, AR Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive MYLK 600922 613780: AD Aortic aneurysm, familial thoracic 7 AD Cardiomyopathy; Aortopathies Comprehensive Cardiovascular; Comprehensive 192600: AD Cardiomyopathy, hypertrophic, 1, MYLK2 606566 AD Cardiomyopathy; Hypertrophic Cardiomyopathy digenic Comprehensive Cardiovascular; Comprehensive MYOM1 603508 None None Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive MYOZ2 605602 613838: AD Cardiomyopathy, hypertrophic, 16 AD Cardiomyopathy; Hypertrophic Cardiomyopathy 615248: AD Cardiomyopathy, dilated, 1KK Comprehensive Cardiovascular; Comprehensive 615248: AD Cardiomyopathy, familial restrictive, 4 MYPN 608517 Cardiomyopathy; Dilated Cardiomyopathy; AD, AR 615248: AD Cardiomyopathy, hypertrophic, 22 Hypertrophic Cardiomyopathy 617336: AR 11, AR Comprehensive Cardiovascular; Comprehensive NDUFA10 603835 256000: AR, Mitochondrial Leigh syndrome AR Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 256000: AR, Mitochondrial Leigh syndrome due to NDUFA12 614530 AR Cardiomyopathy mitochondrial complex 1 deficiency Comprehensive Cardiovascular; Comprehensive 256000: AR, Mitochondrial Leigh syndrome due to NDUFA2 602137 AR Cardiomyopathy mitochondrial complex I deficiency Comprehensive Cardiovascular; Comprehensive 256000: AR, Mitochondrial Leigh syndrome due to NDUFA9 603834 AR Cardiomyopathy mitochondrial complex I deficiency Comprehensive Cardiovascular; Comprehensive 252010: AR, XLD, Mitochondrial Mitochondrial NDUFAF2 609653 AR, XLD Cardiomyopathy complex I deficiency Comprehensive Cardiovascular; Comprehensive 256000: AR, Mitochondrial Leigh syndrome due to NDUFAF6 612392 AR Cardiomyopathy mitochondrial complex I deficiency 256000: AR, Mitochondrial Leigh syndrome due to Comprehensive Cardiovascular; Comprehensive mitochondrial complex I deficiency NDUFS3 603846 AR, XLD Cardiomyopathy 252010: AR, XLD, Mitochondrial Mitochondrial complex I deficiency 256000: AR, Mitochondrial Leigh syndrome Comprehensive Cardiovascular; Comprehensive NDUFS4 602694 252010: AR, XLD, Mitochondrial Mitochondrial AR, XLD Cardiomyopathy complex I deficiency Comprehensive Cardiovascular; Comprehensive NDUFS7 601825 256000: AR, Mitochondrial Leigh syndrome AR Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 256000: AR, Mitochondrial Leigh syndrome due to NDUFS8 602141 AR Cardiomyopathy mitochondrial complex I deficiency Comprehensive Cardiovascular; Comprehensive NEBL 605491 None None Cardiomyopathy; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 613122: AD Cardiomyopathy, dilated, 1CC NEXN 613121 Cardiomyopathy; Dilated Cardiomyopathy; AD 613876: AD Cardiomyopathy, hypertrophic, 20 Hypertrophic Cardiomyopathy 108900: AD Atrial septal defect 7, with or without AV conduction defects 217095: Conotruncal heart malformations, variable Comprehensive Cardiovascular; Comprehensive 614435: AD Hypoplastic left heart syndrome 2 NKX2-5 600584 Cardiomyopathy; Comprehensive Arrythmias; AD 225250: AD Hypothyroidism, congenital Congenital Heart Disease nongoitrous, 5 187500: AD Tetralogy of Fallot 614432: AD Ventricular septal defect 3 Comprehensive Cardiovascular; Comprehensive 616028: AD Adams-Oliver syndrome 5 NOTCH1 190198 Cardiomyopathy; Aortopathies; Congenital Heart AD 109730: AD Aortic valve disease 1 Disease

62 Southfield Ave. Stamford, CT 06902 18 P: 800-298-6470 Branford CT Lic#: CL-0830 F: 646-859-6870 Stamford CT Lic#: CL-1016 www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; Comprehensive 612201: AD Atrial fibrillation, familial, 6 NPPA 108780 AD, AR Cardiomyopathy; Comprehensive Arrythmias 615745: AR Atrial standstill 2 114500: Colorectal cancer, somatic 162900: Epidermal nevus, somatic 137550: Melanocytic nevus syndrome, congenital,

somatic Comprehensive Cardiovascular; Comprehensive 249400: Neurocutaneous melanosis, somatic NRAS 164790 Cardiomyopathy; Congenital Heart Disease; Noonan 613224: AD Noonan syndrome 6 AD Spectrum Disorders 614470: ?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 188470: Thyroid carcinoma, follicular, somatic Comprehensive Cardiovascular; Comprehensive OBSCN Cardiomyopathy; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive PCCA 232000 606054: AR Propionicacidemia AR Cardiomyopathy; Metabolic Cardiomyopathies Comprehensive Cardiovascular; Comprehensive PCCB 232050 606054: AR Propionicacidemia AR Cardiomyopathy; Metabolic Cardiomyopathies Comprehensive Cardiovascular; Comprehensive PDLIM3 605889 None None Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 220110: AR, Mitochondrial Mitochondrial complex PET100 614770 AR Cardiomyopathy IV deficiency Comprehensive Cardiovascular; Comprehensive 614921: AR Congenital disorder of glycosylation, PGM1 171900 AR Cardiomyopathy type It Comprehensive Cardiovascular; Comprehensive PHYH 602026 266500: AR Refsum disease AR Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Arrythmogenic Right Ventricular 609040: AD Arrhythmogenic right ventricular PKP2 602861 AD Cardiomyopathy; Comprehensive Arrythmias; dysplasia 9 Dilated Cardiomyopathy; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive PLEKHM2 609613 None None Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; 609909: Cardiomyopathy, dilated, 1P PLN 172405 AD Dilated Cardiomyopathy; Hypertrophic 613874: AD Cardiomyopathy, hypertrophic, 18 Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; Comprehensive 225400: AR Ehlers-Danlos syndrome, kyphoscoliotic PLOD1 153454 AR Cardiomyopathy; Aortopathies type, 1 Comprehensive Cardiovascular; Comprehensive 212065: AR Congenital disorder of glycosylation, PMM2 601785 AR Cardiomyopathy type Ia Comprehensive Cardiovascular; Comprehensive 615373: AD Cardiomyopathy, dilated, 1LL PRDM16 605557 Cardiomyopathy; Dilated Cardiomyopathy; Left AD 615373: AD Left ventricular noncompaction 8 Ventricular Ncompaction 600858: AD Cardiomyopathy, hypertrophic 6 Comprehensive Cardiovascular; Comprehensive 261740: AD Glycogen storage disease of heart, PRKAG2 602743 Cardiomyopathy; Comprehensive Arrythmias; AD lethal congenital Hypertrophic Cardiomyopathy 194200: ?AD Wolff-Parkinson-White syndrome Comprehensive Cardiovascular; Comprehensive PRKG1 176894 615436: AD Aortic aneurysm, familial thoracic 8 AD Cardiomyopathy; Aortopathies 151100: AD LEOPARD syndrome 1 Comprehensive Cardiovascular; Comprehensive 607785: Leukemia, juvenile myelomonocytic, Cardiomyopathy; Congenital Heart Disease; PTPN11 176876 somatic AD Hypertrophic Cardiomyopathy; Noonan Spectrum 156250: AD Disorders 163950: AD Noonan syndrome 1 Comprehensive Cardiovascular; Comprehensive 615916: AD Cardiomyopathy, dilated, 1NN Cardiomyopathy; Congenital Heart Disease; Dilated RAF1 164760 611554: LEOPARD syndrome 2 AD Cardiomyopathy; Hypertrophic Cardiomyopathy; 611553: AD Noonan syndrome 5 Noonan Spectrum Disorders Comprehensive Cardiovascular; Comprehensive RANGRF 607954 Cardiomyopathy; Comprehensive Arrythmias; None None Brugada Syndrome Comprehensive Cardiovascular; Comprehensive 605462: Basal cell carcinoma, somatic RASA1 139150 AD Cardiomyopathy; Hereditary Hemorrhagic 608354: AD malformation-arteriovenous

62 Southfield Ave. Stamford, CT 06902 19 P: 800-298-6470 Branford CT Lic#: CL-0830 F: 646-859-6870 Stamford CT Lic#: CL-1016 www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Telangiectasia malformation 608355: AD Comprehensive Cardiovascular; Comprehensive RBM20 613171 613172: AD Cardiomyopathy, dilated, 1DD AD Cardiomyopathy; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive RIT1 609591 Cardiomyopathy; Congenital Heart Disease; Noonan 615355: AD Noonan syndrome 8 AD Spectrum Disorders Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Catecholaminergic Polymorphic 600996: AD Arrhythmogenic right ventricular Ventricular Tachycardia; Arrythmogenic Right dysplasia 2 RYR2 180902 AD Ventricular Cardiomyopathy; Comprehensive 604772: AD Ventricular tachycardia, Arrythmias; Dilated Cardiomyopathy; Left catecholaminergic polymorphic, 1 Ventricular Ncompaction Comprehensive Cardiovascular; Comprehensive SCN10A 604427 Cardiomyopathy; Comprehensive Arrythmias; 615551: AD Episodic pain syndrome, familial, 2 AD Brugada Syndrome 615377: AD Atrial fibrillation, familial, 13 612838: Brugada syndrome 5 Comprehensive Cardiovascular; Comprehensive 612838: Cardiac conduction defect, nonspecific SCN1B 600235 Cardiomyopathy; Comprehensive Arrythmias; 604233: AD Epilepsy, generalized, with febrile AD, AR Brugada Syndrome seizures plus, type 1 617350: AR Epileptic encephalopathy, early infantile, 52 Comprehensive Cardiovascular; Comprehensive SCN2B 601327 Cardiomyopathy; Comprehensive Arrythmias; 615378: AD Atrial fibrillation, familial, 14 AD Brugada Syndrome Comprehensive Cardiovascular; Comprehensive 613120: AD Atrial fibrillation, familial, 16 SCN3B 608214 Cardiomyopathy; Comprehensive Arrythmias; AD 613120: AD Brugada syndrome 7 Brugada Syndrome Comprehensive Cardiovascular; Comprehensive 611819: AD Atrial fibrillation, familial, 17 SCN4B 608256 Cardiomyopathy; Long / Short Qt Syndrome; AD 611819: AD Long QT syndrome-10 Comprehensive Arrythmias 614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E Comprehensive Cardiovascular; Comprehensive 113900: AD Heart block, nonprogressive Cardiomyopathy; Long / Short Qt Syndrome; 113900: AD Heart block, progressive, type IA SCN5A 600163 Comprehensive Arrythmias; Dilated AD, AR 603830: AD Long QT syndrome-3 Cardiomyopathy; Left Ventricular Ncompaction; 608567: AR Sick sinus syndrome 1 Brugada Syndrome 272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1 Comprehensive Cardiovascular; Comprehensive 220110: AR, Mitochondrial Mitochondrial complex SCO1 603644 AR Cardiomyopathy IV deficiency 613642: Cardiomyopathy, dilated, 1GG 256000: AR, Mitochondrial Leigh syndrome Comprehensive Cardiovascular; Comprehensive SDHA 600857 252011: AR Mitochondrial respiratory chain AD, AR Cardiomyopathy complex II deficiency 614165: AD Paragangliomas 5 Comprehensive Cardiovascular; Comprehensive SDHAF1 612848 252011: AR Mitochondrial complex II deficiency AR Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 606685: Cardiomyopathy, dilated, 1L SGCD 601411 AR Cardiomyopathy; Dilated Cardiomyopathy 601287: AR Muscular dystrophy, limb-girdle, AR 6 Comprehensive Cardiovascular; Comprehensive 252900: AR Mucopolysaccharidosis type IIIA SGSH 605270 AR Cardiomyopathy (Sanfilippo A) Comprehensive Cardiovascular; Comprehensive 607721: AD Noonan-like syndrome with loose SHOC2 602775 Cardiomyopathy; Congenital Heart Disease; Noonan AD anagen hair Spectrum Disorders Comprehensive Cardiovascular; Comprehensive SKI 164780 182212: AD Shprintzen-Goldberg syndrome AD Cardiomyopathy; Aortopathies Comprehensive Cardiovascular; Comprehensive SLC22A5 603377 Cardiomyopathy; Dilated Cardiomyopathy; 212140: AR Carnitine deficiency, systemic primary AR Metabolic Cardiomyopathies SLC25A20 613698 Comprehensive Cardiovascular; Comprehensive 212138: AR Carnitine-acylcarnitine AR

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Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Metabolic Cardiomyopathies deficiency Comprehensive Cardiovascular; Comprehensive SLC2A10 606145 208050: AR Arterial tortuosity syndrome AR Cardiomyopathy; Aortopathies Comprehensive Cardiovascular; Comprehensive SLMAP 602701 Cardiomyopathy; Comprehensive Arrythmias; None None Brugada Syndrome Comprehensive Cardiovascular; Comprehensive SMAD3 603109 613795: AD Loeys-Dietz syndrome 3 AD Cardiomyopathy; Aortopathies 175050: AD Juvenile polyposis/hereditary Comprehensive Cardiovascular; Comprehensive hemorrhagic telangiectasia syndrome SMAD4 600993 Cardiomyopathy; Aortopathies; Hereditary 139210: AD Myhre syndrome AD Hemorrhagic Telangiectasia 260350: Pancreatic cancer, somatic 174900: AD Polyposis, juvenile intestinal Comprehensive Cardiovascular; Comprehensive SNTA1 601017 Cardiomyopathy; Long / Short Qt Syndrome; 612955: AD Long QT syndrome 12 AD Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive 135300: AD ?Fibromatosis, gingival, 1 SOS1 182530 Cardiomyopathy; Congenital Heart Disease; Noonan AD 610733: AD Noonan syndrome 4 Spectrum Disorders 616684: AR Charcot-Marie-Tooth disease, type 4K Comprehensive Cardiovascular; Comprehensive SURF1 185620 256000: AR, Mitochondrial Leigh syndrome, due to AR Cardiomyopathy COX IV deficiency Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Left TAZ 300394 302060: XLR XLR Ventricular Ncompaction; Metabolic Cardiomyopathies 217095: Conotruncal anomaly face syndrome Comprehensive Cardiovascular; Comprehensive 188400: AD DiGeorge syndrome TBX1 602054 AD Cardiomyopathy; Congenital Heart Disease 187500: AD Tetralogy of Fallot 192430: AD Velocardiofacial syndrome Comprehensive Cardiovascular; Comprehensive TBX5 601620 142900: AD Holt-Oram syndrome AD Cardiomyopathy; Congenital Heart Disease Comprehensive Cardiovascular; Comprehensive 607487: AD Cardiomyopathy, hypertrophic, 25 TCAP 604488 Cardiomyopathy; Dilated Cardiomyopathy; AD, AR 601954: AR Muscular dystrophy, limb-girdle, AR 7 Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive TGFB2 190220 614816: AD Loeys-Dietz syndrome 4 AD Cardiomyopathy; Aortopathies Comprehensive Cardiovascular; Comprehensive 107970: AD Arrhythmogenic right ventricular Cardiomyopathy; Arrythmogenic Right Ventricular TGFB3 190230 dysplasia 1 AD Cardiomyopathy; Aortopathies; Comprehensive 615582: AD Loeys-Dietz syndrome 5 Arrythmias 609192: AD Loeys-Dietz syndrome 1 Comprehensive Cardiovascular; Comprehensive TGFBR1 190181 132800: AD {Multiple self-healing squamous AD Cardiomyopathy; Aortopathies epithelioma, susceptibility to} 614331: Colorectal cancer, hereditary Comprehensive Cardiovascular; Comprehensive nonpolyposis, type 6 TGFBR2 190182 AD Cardiomyopathy; Aortopathies 133239: Esophageal cancer, somatic 610168: AD Loeys-Dietz syndrome 2 Comprehensive Cardiovascular; Comprehensive 604400: AD Arrhythmogenic right ventricular Cardiomyopathy; Arrythmogenic Right Ventricular dysplasia 5 TMEM43 612048 AD Cardiomyopathy; Comprehensive Arrythmias; 614302: AD Emery-Dreifuss muscular dystrophy 7, Dilated Cardiomyopathy AD Comprehensive Cardiovascular; Comprehensive 614052: AR Mitochondrial complex V (ATP TMEM70 612418 AR Cardiomyopathy synthase) deficiency, nuclear type 2 Comprehensive Cardiovascular; Comprehensive TMPO 188380 None None Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 611879: Cardiomyopathy, dilated, 1Z TNNC1 191040 Cardiomyopathy; Dilated Cardiomyopathy; AD 613243: AD Cardiomyopathy, hypertrophic, 13 Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive 613286: Cardiomyopathy, dilated, 1FF Cardiomyopathy; Dilated Cardiomyopathy; 611880: AR ?Cardiomyopathy, dilated, 2A TNNI3 191044 AD, AR Hypertrophic Cardiomyopathy; Left Ventricular 115210: AD Cardiomyopathy, familial restrictive, 1 Ncompaction 613690: AD Cardiomyopathy, hypertrophic, 7 TNNT2 191045 Comprehensive Cardiovascular; Comprehensive 601494: AD Cardiomyopathy, dilated, 1D AD

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Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Dilated Cardiomyopathy; 612422: AD Cardiomyopathy, familial restrictive, 3 Hypertrophic Cardiomyopathy; Left Ventricular 115195: AD Cardiomyopathy, hypertrophic, 2 Ncompaction 601494: AD Left ventricular noncompaction 6 Comprehensive Cardiovascular; Comprehensive 611878: AD Cardiomyopathy, dilated, 1Y Cardiomyopathy; Dilated Cardiomyopathy; TPM1 191010 115196: AD Cardiomyopathy, hypertrophic, 3 AD Hypertrophic Cardiomyopathy; Left Ventricular 611878: AD Left ventricular noncompaction 9 Ncompaction Comprehensive Cardiovascular; Comprehensive 615441: AR Ventricular tachycardia, Cardiomyopathy; Catecholaminergic Polymorphic TRDN 603283 catecholaminergic polymorphic, 5, with or without AR Ventricular Tachycardia; Long / Short Qt Syndrome; muscle weakness Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive TRPM4 606936 Cardiomyopathy; Comprehensive Arrythmias; 604559: AD Progressive familial heart block, type IB AD Brugada Syndrome 604145: Cardiomyopathy, dilated, 1G 613765: AD Cardiomyopathy, familial hypertrophic, 9

Comprehensive Cardiovascular; Comprehensive 608807: AR Muscular dystrophy, limb-girdle, AR 10 TTN 188840 AD, AR Cardiomyopathy; Dilated Cardiomyopathy 603689: Myopathy, proximal, with early respiratory muscle involvement 611705: AR Salih myopathy 600334: AD Tibial muscular dystrophy, tardive 105210: AD Amyloidosis, hereditary, transthyretin- Comprehensive Cardiovascular; Comprehensive related TTR 176300 Cardiomyopathy; Dilated Cardiomyopathy; 115430: AD Carpal tunnel syndrome, familial AD Hypertrophic Cardiomyopathy 145680: AD [Dystransthyretinemic hyperthyroxinemia] Comprehensive Cardiovascular; Comprehensive TXNRD2 606448 617825: AR ?Glucocorticoid deficiency 5 AR Cardiomyopathy; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; 611407: Cardiomyopathy, dilated, 1W VCL 193065 AD Hypertrophic Cardiomyopathy; Left Ventricular 613255: AD Cardiomyopathy, hypertrophic, 15 Ncompaction

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. DMD: The following DMD hg19 coordinates have been excluded from this assay: chrX:31897426-31897627, chrX:32668999-32669253, chrX:32644476-32644680, chrX:31627637-31627838, chrX:32460213-32460334, chrX:31219361-31219367, chrX:31219126-31219287, chrX:32644160-32644321 3. FKTN: The following FKTN hg19 coordinates have been excluded from this assay: chr9:108368751-108368962 4. FLNC: The following FLNC hg19 coordinates have been excluded from this assay: chr7:128498050-128498282 5. GATA6: The following GATA6 hg19 coordinates have been excluded from this assay: chr18:19749269-19749275 6. GBA: The following GBA hg19 coordinates have been excluded from this assay: chr1:155207120-155207380, chr1:155204774- 155204902, chr1:155208296-155208452 7. LAMP2: The following LAMP2 hg19 coordinates have been excluded from this assay: chrX:119604075-119604081 8. MUT: The following MUT hg19 coordinates have been excluded from this assay: chr6:49404225-49404231 9. NDUFS7: The following NDUFS7 hg19 coordinates have been excluded from this assay: chr19:1386640-1386646 10. PGM1: The following PGM1 hg19 coordinates have been excluded from this assay: chr1:64124731-64124737 11. SCN1B: The following SCN1B hg19 coordinates have been excluded from this assay: chr19:35521713-35521775 12. SDHA: The following SDHA hg19 coordinates have been excluded from this assay: chr5:251441-251594, chr5:254496-254632, chr5:218459-218544 13. SGSH: The following SGSH hg19 coordinates have been excluded from this assay: chr17:78193967-78194168 14. TBX1: The following TBX1 hg19 coordinates have been excluded from this assay: chr22:19748416-19748814 15. TRDN: The following TRDN hg19 coordinates have been excluded from this assay: chr6:123851639-123851721, chr6:123576214- 123576281

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DILATED CARDIOMYOPATHY (DCM) SUBPANEL

Dilated cardiomyopathy (DCM) is characterized by the presence of left ventricular dilation and left ventricular systolic dysfunction in the absence of abnormal loading conditions or coronary disease. DCM usually presents with heart failure with symptoms of congestion, reduced , arrhythmias, and/or thromboembolic disease. Right ventricular dilation may be present but is not necessary for the diagnosis. The most prevalent cause of DCMs is ischemic injury due to prior myocardial infarction from .

The Dilated Cardiomyopathy (DCM) Subpanel contains the following 57 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; 614050: AD Atrial fibrillation, familial, 12 Comprehensive Cardiomyopathy; 608569: Cardiomyopathy, dilated, 1O ABCC9 601439 AD Comprehensive Arrythmias; Dilated 239850: AD Hypertrichotic Cardiomyopathy; Brugada Syndrome osteochondrodysplasia Comprehensive Cardiovascular; 612794: AD Atrial septal defect 5 Comprehensive Cardiomyopathy; Congenital 613424: AD Cardiomyopathy, dilated, 1R ACTC1 102540 Heart Disease; Dilated Cardiomyopathy; AD 612098: AD Cardiomyopathy, hypertrophic, 11 Hypertrophic Cardiomyopathy; Left Ventricular 613424: AD Left ventricular noncompaction 4 Ncompaction Comprehensive Cardiovascular; 612158: AD Cardiomyopathy, dilated, 1AA, with Comprehensive Cardiomyopathy; or without LVNC ACTN2 102573 AD Comprehensive Arrythmias; Dilated 612158: AD Cardiomyopathy, hypertrophic, 23, Cardiomyopathy; Hypertrophic Cardiomyopathy with or without LVNC Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short AKAP9 604001 611820: AD ?Long QT syndrome-11 AD Qt Syndrome; Comprehensive Arrythmias; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 600919: AD Cardiac arrhythmia, ankyrin-B- Catecholaminergic Polymorphic Ventricular ANK2 106410 related AD Tachycardia; Long / Short Qt Syndrome; 600919: AD Long QT syndrome 4 Comprehensive Arrythmias; Dilated Cardiomyopathy Comprehensive Cardiovascular; ANKRD1 609599 Comprehensive Cardiomyopathy; Dilated None None Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; 613881: AD Cardiomyopathy, dilated, 1HH BAG3 603883 Comprehensive Cardiomyopathy; Dilated AD 612954: AD Myopathy, myofibrillar, 6 Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short 611875: Brugada syndrome 3 CACNA1C 114205 Qt Syndrome; Comprehensive Arrythmias; AD 601005: AD Timothy syndrome Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Brugada Syndrome 192600: AD Cardiomyopathy, familial Comprehensive Cardiovascular; hypertrophic Comprehensive Cardiomyopathy; Long / Short 123320: AD Creatine phosphokinase, elevated CAV3 601253 Qt Syndrome; Comprehensive Arrythmias; serum AD Dilated Cardiomyopathy; Hypertrophic 611818: AD Long QT syndrome 9 Cardiomyopathy 614321: AD Myopathy, distal, Tateyama type 606072: AD Rippling muscle disease Comprehensive Cardiovascular; CAVIN4 617714 Comprehensive Cardiomyopathy; Dilated None None Cardiomyopathy 615184: AD Cardiomyopathy, dilated, 1II Comprehensive Cardiovascular; 613763: AR, AD Cataract 16, multiple types CRYAB 123590 Comprehensive Cardiomyopathy; Dilated 608810: AD Myopathy, myofibrillar, 2 AD, AR Cardiomyopathy 613869: AR Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related Comprehensive Cardiovascular; 607482: ?Cardiomyopathy, dilated, 1M CSRP3 600824 Comprehensive Cardiomyopathy; Dilated AD Cardiomyopathy; Hypertrophic Cardiomyopathy 612124: AD Cardiomyopathy, hypertrophic, 12 Comprehensive Cardiovascular; 604765: Cardiomyopathy, dilated, 1I DES 125660 Comprehensive Cardiomyopathy; 601419: AR, AD Myopathy, myofibrillar, 1 AD, AR Comprehensive Arrythmias; Dilated 181400: AD Scapuloperoneal syndrome,

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Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Hypertrophic Cardiomyopathy neurogenic, Kaeser type Comprehensive Cardiovascular; 300376: XLR Becker muscular dystrophy DMD 300377 Comprehensive Cardiomyopathy; Dilated 302045: XL Cardiomyopathy, dilated, 3B XLR, XL Cardiomyopathy; Hypertrophic Cardiomyopathy 310200: XLR Duchenne muscular dystrophy Comprehensive Cardiovascular; 610768: AR Congenital disorder of DOLK 610746 Comprehensive Cardiomyopathy; Dilated AR glycosylation, type Im Cardiomyopathy; Metabolic Cardiomyopathy Comprehensive Cardiovascular; 610476: AR, AD Arrhythmogenic right Comprehensive Cardiomyopathy; ventricular dysplasia 11 DSC2 125645 Arrythmogenic Right Ventricular 610476: AR, AD Arrhythmogenic right AD, AR Cardiomyopathy; Comprehensive Arrythmias; ventricular dysplasia 11 with mild palmoplantar Dilated Cardiomyopathy keratoderma and woolly hair Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 610193: AD Arrhythmogenic right ventricular DSG2 125671 Arrythmogenic Right Ventricular dysplasia 10 AD Cardiomyopathy; Comprehensive Arrythmias; 612877: Cardiomyopathy, dilated, 1BB Dilated Cardiomyopathy 607450: AD Arrhythmogenic right ventricular dysplasia 8 Comprehensive Cardiovascular; 605676: AR Cardiomyopathy, dilated, with Comprehensive Cardiomyopathy; woolly hair and keratoderma Arrythmogenic Right Ventricular 615821: AD Dilated cardiomyopathy with woolly DSP 125647 AD, AR Cardiomyopathy; Comprehensive Arrythmias; hair, keratoderma, and tooth agenesis Dilated Cardiomyopathy; Left Ventricular 609638: AR Epidermolysis bullosa, lethal Ncompaction acantholytic 612908: AD Keratosis palmoplantaris striata II 607655: AR Skin fragility-woolly hair syndrome 615440: AR Combined oxidative Comprehensive Cardiovascular; phosphorylation deficiency 17 ELAC2 605367 Comprehensive Cardiomyopathy; Dilated AR 614731: {Prostate cancer, hereditary, 2, Cardiomyopathy susceptibility to} Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 310300: XLR Emery-Dreifuss muscular EMD 300384 XLR, XL Comprehensive Arrythmias; Dilated dystrophy 1, XL Cardiomyopathy Comprehensive Cardiovascular; 605362: AD ?Cardiomyopathy, dilated, 1J EYA4 603550 Comprehensive Cardiomyopathy; Dilated AD Cardiomyopathy 601316: AD Deafness, AD 10 611615: AR Cardiomyopathy, dilated, 1X 253800: AR Muscular dystrophy- dystroglycanopathy (congenital with brain and Comprehensive Cardiovascular; eye anomalies), type A, 4 FKTN 607440 Comprehensive Cardiomyopathy; Dilated 613152: AR Muscular dystrophy- AR Cardiomyopathy dystroglycanopathy (congenital without mental retardation), type B, 4 611588: AR Muscular dystrophy- dystroglycanopathy (limb-girdle), type C, 4 Cardiomyopathy, familial hypertrophic, 26 (3) Comprehensive Cardiovascular; 617047: AD Cardiomyopathy, familial restrictive FLNC 102565 Comprehensive Cardiomyopathy; Dilated 5 AD Cardiomyopathy; Hypertrophic Cardiomyopathy 614065: AD Myopathy, distal, 4 609524: AD Myopathy, myofibrillar, 5 Comprehensive Cardiovascular; GATAD1 614518 Comprehensive Cardiomyopathy; Dilated 614672: AR ?Cardiomyopathy, dilated, 2B AR Cardiomyopathy Comprehensive Cardiovascular; ILK 602366 Comprehensive Cardiomyopathy; Dilated None None Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 611528: AD Arrhythmogenic right ventricular JUP 173325 Arrythmogenic Right Ventricular dysplasia 12 AD, AR Cardiomyopathy; Comprehensive Arrythmias; 601214: AR Naxos disease Dilated Cardiomyopathy Comprehensive Cardiovascular; LAMA4 600133 Comprehensive Cardiomyopathy; Dilated 615235: AD Cardiomyopathy, dilated, 1JJ AD Cardiomyopathy Comprehensive Cardiovascular; LAMP2 309060 300257: XLD Danon disease XLD Comprehensive Cardiomyopathy; Dilated

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Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathy Comprehensive Cardiovascular; 601493: AD Cardiomyopathy, dilated, 1C, with Comprehensive Cardiomyopathy; or without LVNC LDB3 605906 Comprehensive Arrythmias; Dilated 601493: AD Cardiomyopathy, hypertrophic, 24 AD Cardiomyopathy; Hypertrophic 601493: AD Left ventricular noncompaction 3 Cardiomyopathy; Left Ventricular Ncompaction 609452: AD Myopathy, myofibrillar, 4 115200: AD Cardiomyopathy, dilated, 1A 605588: AR Charcot-Marie-Tooth disease, type 2B1 181350: AD Emery-Dreifuss muscular dystrophy 2, AD 616516: AR Emery-Dreifuss muscular Comprehensive Cardiovascular; dystrophy 3, AR Comprehensive Cardiomyopathy; 610140: AD Heart-hand syndrome, Slovenian LMNA 150330 AD, AR Comprehensive Arrythmias; Dilated type Cardiomyopathy; Left Ventricular Ncompaction 176670: AR, AD Hutchinson-Gilford progeria 151660: AD Lipodystrophy, familial partial, type 2 212112: AD Malouf syndrome 248370: AR Mandibuloacral dysplasia 613205: AD Muscular dystrophy, congenital 275210: AR Restrictive dermopathy, lethal Comprehensive Cardiovascular; 615396: AD Cardiomyopathy, dilated, 1MM Comprehensive Cardiomyopathy; Dilated MYBPC3 600958 115197: AD Cardiomyopathy, hypertrophic, 4 AD Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction 615396: AD Left ventricular noncompaction 10 Comprehensive Cardiovascular; 614089: Atrial septal defect 3 Comprehensive Cardiomyopathy; Congenital 613252: Cardiomyopathy, dilated, 1EE MYH6 160710 AD Heart Disease; Dilated Cardiomyopathy; 613251: AD Cardiomyopathy, hypertrophic, 14 Hypertrophic Cardiomyopathy 614090: {Sick sinus syndrome 3} 613426: AD Cardiomyopathy, dilated, 1S 192600: AD Cardiomyopathy, hypertrophic, 1 Comprehensive Cardiovascular; 160500: AD Laing distal myopathy Comprehensive Cardiomyopathy; Dilated 613426: AD Left ventricular noncompaction 5 MYH7 160760 AD, AR Cardiomyopathy; Hypertrophic 608358: AD Myopathy, myosin storage, AD Cardiomyopathy; Left Ventricular Ncompaction 255160: AR Myopathy, myosin storage, AR 181430: AD Scapuloperoneal syndrome, myopathic type 615248: AD Cardiomyopathy, dilated, 1KK Comprehensive Cardiovascular; 615248: AD Cardiomyopathy, familial MYPN 608517 Comprehensive Cardiomyopathy; Dilated restrictive, 4 AD, AR Cardiomyopathy; Hypertrophic Cardiomyopathy 615248: AD Cardiomyopathy, hypertrophic, 22 617336: AR Nemaline myopathy 11, AR Comprehensive Cardiovascular; NEBL 605491 Comprehensive Cardiomyopathy; Dilated None None Cardiomyopathy Comprehensive Cardiovascular; 613122: AD Cardiomyopathy, dilated, 1CC NEXN 613121 Comprehensive Cardiomyopathy; Dilated AD 613876: AD Cardiomyopathy, hypertrophic, 20 Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; OBSCN Comprehensive Cardiomyopathy; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 609040: AD Arrhythmogenic right ventricular PKP2 602861 Arrythmogenic Right Ventricular AD dysplasia 9 Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 609909: Cardiomyopathy, dilated, 1P PLN 172405 Comprehensive Arrythmias; Dilated AD 613874: AD Cardiomyopathy, hypertrophic, 18 Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; 615373: AD Cardiomyopathy, dilated, 1LL PRDM16 605557 Comprehensive Cardiomyopathy; Dilated AD Cardiomyopathy; Left Ventricular Ncompaction 615373: AD Left ventricular noncompaction 8 RAF1 164760 Comprehensive Cardiovascular; 615916: AD Cardiomyopathy, dilated, 1NN AD

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Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiomyopathy; Congenital 611554: LEOPARD syndrome 2 Heart Disease; Dilated Cardiomyopathy; 611553: AD Noonan syndrome 5 Hypertrophic Cardiomyopathy; Noonan Spectrum Disorders Comprehensive Cardiovascular; RBM20 613171 Comprehensive Cardiomyopathy; Dilated 613172: AD Cardiomyopathy, dilated, 1DD AD Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 600996: AD Arrhythmogenic right ventricular Catecholaminergic Polymorphic Ventricular dysplasia 2 RYR2 180902 Tachycardia; Arrythmogenic Right Ventricular AD 604772: AD Ventricular tachycardia, Cardiomyopathy; Comprehensive Arrythmias; catecholaminergic polymorphic, 1 Dilated Cardiomyopathy; Left Ventricular Ncompaction 614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E Comprehensive Cardiovascular; 113900: AD Heart block, nonprogressive Comprehensive Cardiomyopathy; Long / Short 113900: AD Heart block, progressive, type IA SCN5A 600163 Qt Syndrome; Comprehensive Arrythmias; AD, AR 603830: AD Long QT syndrome-3 Dilated Cardiomyopathy; Left Ventricular 608567: AR Sick sinus syndrome 1 Ncompaction; Brugada Syndrome 272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1 Comprehensive Cardiovascular; 606685: Cardiomyopathy, dilated, 1L SGCD 601411 Comprehensive Cardiomyopathy; Dilated 601287: AR Muscular dystrophy, limb-girdle, AR Cardiomyopathy AR 6 Comprehensive Cardiovascular; 212140: AR Carnitine deficiency, systemic SLC22A5 603377 Comprehensive Cardiomyopathy; Dilated AR primary Cardiomyopathy; Metabolic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated TAZ 300394 302060: XLR Barth syndrome XLR Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathy Comprehensive Cardiovascular; 607487: AD Cardiomyopathy, hypertrophic, 25 TCAP 604488 Comprehensive Cardiomyopathy; Dilated 601954: AR Muscular dystrophy, limb-girdle, AD, AR Cardiomyopathy; Hypertrophic Cardiomyopathy AR 7 Comprehensive Cardiovascular; 604400: AD Arrhythmogenic right ventricular Comprehensive Cardiomyopathy; dysplasia 5 TMEM43 612048 Arrythmogenic Right Ventricular AD 614302: AD Emery-Dreifuss muscular Cardiomyopathy; Comprehensive Arrythmias; dystrophy 7, AD Dilated Cardiomyopathy Comprehensive Cardiovascular; 611879: Cardiomyopathy, dilated, 1Z TNNC1 191040 Comprehensive Cardiomyopathy; Dilated AD 613243: AD Cardiomyopathy, hypertrophic, 13 Cardiomyopathy; Hypertrophic Cardiomyopathy 613286: Cardiomyopathy, dilated, 1FF Comprehensive Cardiovascular; 611880: AR ?Cardiomyopathy, dilated, 2A Comprehensive Cardiomyopathy; Dilated TNNI3 191044 115210: AD Cardiomyopathy, familial AD, AR Cardiomyopathy; Hypertrophic restrictive, 1 Cardiomyopathy; Left Ventricular Ncompaction 613690: AD Cardiomyopathy, hypertrophic, 7 601494: AD Cardiomyopathy, dilated, 1D Comprehensive Cardiovascular; 612422: AD Cardiomyopathy, familial Comprehensive Cardiomyopathy; Dilated TNNT2 191045 restrictive, 3 AD Cardiomyopathy; Hypertrophic 115195: AD Cardiomyopathy, hypertrophic, 2 Cardiomyopathy; Left Ventricular Ncompaction 601494: AD Left ventricular noncompaction 6 Comprehensive Cardiovascular; 611878: AD Cardiomyopathy, dilated, 1Y Comprehensive Cardiomyopathy; Dilated TPM1 191010 115196: AD Cardiomyopathy, hypertrophic, 3 AD Cardiomyopathy; Hypertrophic 611878: AD Left ventricular noncompaction 9 Cardiomyopathy; Left Ventricular Ncompaction 604145: Cardiomyopathy, dilated, 1G 613765: AD Cardiomyopathy, familial hypertrophic, 9 Comprehensive Cardiovascular; 608807: AR Muscular dystrophy, limb-girdle, TTN 188840 Comprehensive Cardiomyopathy; Dilated AR 10 AD, AR Cardiomyopathy 603689: Myopathy, proximal, with early respiratory muscle involvement 611705: AR Salih myopathy 600334: AD Tibial muscular dystrophy, tardive

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Gene MIM Disease Category OMIM Phenotype Inheritance 105210: AD Amyloidosis, hereditary, Comprehensive Cardiovascular; transthyretin-related TTR 176300 Comprehensive Cardiomyopathy; Dilated 115430: AD Carpal tunnel syndrome, familial AD Cardiomyopathy; Hypertrophic Cardiomyopathy 145680: AD [Dystransthyretinemic hyperthyroxinemia] Comprehensive Cardiovascular; TXNRD2 606448 Comprehensive Cardiomyopathy; Dilated 617825: AR ?Glucocorticoid deficiency 5 AR Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated 611407: Cardiomyopathy, dilated, 1W VCL 193065 AD Cardiomyopathy; Hypertrophic 613255: AD Cardiomyopathy, hypertrophic, 15 Cardiomyopathy; Left Ventricular Ncompaction

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. DMD: The following DMD hg19 coordinates have been excluded from this assay: chrX:31897426-31897627, chrX:32668999-32669253, chrX:32644476-32644680, chrX:31627637-31627838, chrX:32460213-32460334, chrX:31219361-31219367, chrX:31219126-31219287, chrX:32644160-32644321 3. FKTN: The following FKTN hg19 coordinates have been excluded from this assay: chr9:108368751-108368962 4. FLNC: The following FLNC hg19 coordinates have been excluded from this assay: chr7:128498050-128498282 5. LAMP2: The following LAMP2 hg19 coordinates have been excluded from this assay: chrX:119604075-119604081

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ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY (ARVC) SUBPANEL

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by right ventricular dysfunction, ventricular arrhythmias, and progressive fibrofatty replacement of the myocardium resulting in an increased risk of sudden death in young individuals and athletes. In particular, the arrhythmias in ARVC, which arise from the right ventricle, have left bundle branch block morphology, which can be seen with an electrocardiogram. Cardiac MRI studies have also identified regional left ventricular dysfunction among individuals with ARVC. Overall, ARVC is marked by age-dependent penetrance with most patients presenting in the second to fourth decade of life. Of note, males were more likely to have arrhythmia events in analyses of individuals with genetically confirmed ARVC. Since many forms of cardiomyopathy can mimic aspects of ARVC, clinical and genetic testing is recommended for proper management.

The Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Subpanel contains the following 8 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; 610476: AR, AD Arrhythmogenic right Comprehensive Cardiomyopathy; ventricular dysplasia 11 DSC2 125645 Arrythmogenic Right Ventricular 610476: AR, AD Arrhythmogenic right AD, AR Cardiomyopathy; Comprehensive Arrythmias; ventricular dysplasia 11 with mild palmoplantar Dilated Cardiomyopathy keratoderma and woolly hair Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 610193: AD Arrhythmogenic right ventricular DSG2 125671 Arrythmogenic Right Ventricular dysplasia 10 AD Cardiomyopathy; Comprehensive Arrythmias; 612877: Cardiomyopathy, dilated, 1BB Dilated Cardiomyopathy 607450: AD Arrhythmogenic right ventricular dysplasia 8 Comprehensive Cardiovascular; 605676: AR Cardiomyopathy, dilated, with Comprehensive Cardiomyopathy; woolly hair and keratoderma

Arrythmogenic Right Ventricular 615821: AD Dilated cardiomyopathy with woolly DSP 125647 AD, AR Cardiomyopathy; Comprehensive Arrythmias; hair, keratoderma, and tooth agenesis Dilated Cardiomyopathy; Left Ventricular 609638: AR Epidermolysis bullosa, lethal Ncompaction acantholytic 612908: AD Keratosis palmoplantaris striata II 607655: AR Skin fragility-woolly hair syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 611528: AD Arrhythmogenic right ventricular JUP 173325 Arrythmogenic Right Ventricular dysplasia 12 AD, AR Cardiomyopathy; Comprehensive Arrythmias; 601214: AR Naxos disease Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 609040: AD Arrhythmogenic right ventricular PKP2 602861 Arrythmogenic Right Ventricular AD dysplasia 9 Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 600996: AD Arrhythmogenic right ventricular Catecholaminergic Polymorphic Ventricular dysplasia 2 RYR2 180902 Tachycardia; Arrythmogenic Right Ventricular AD 604772: AD Ventricular tachycardia, Cardiomyopathy; Comprehensive Arrythmias; catecholaminergic polymorphic, 1 Dilated Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 107970: AD Arrhythmogenic right ventricular TGFB3 190230 Arrythmogenic Right Ventricular dysplasia 1 AD Cardiomyopathy; Aortopathies; Comprehensive 615582: AD Loeys-Dietz syndrome 5 Arrythmias Comprehensive Cardiovascular; 604400: AD Arrhythmogenic right ventricular Comprehensive Cardiomyopathy; dysplasia 5 TMEM43 612048 Arrythmogenic Right Ventricular AD 614302: AD Emery-Dreifuss muscular Cardiomyopathy; Comprehensive Arrythmias; dystrophy 7, AD Dilated Cardiomyopathy

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1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive).

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HYPERTROPHIC CARDIOMYOPATHY (HCM) SUBPANEL

Hypertrophic Cardiomyopathy (HCM) is a commonly inherited monogenic cardiac disease with variable expression and age-related penetrance. HCM is a condition in which the myocardium is enlarged (hypertrophied) without an obvious cause. This hypertrophy is generally asymmetric and can be associated with obstruction of ventricular outflow. The most prevalent mutations in HCM occur among genes encoding sarcomere . The clinical manifestations are highly variable, ranging from asymptomatic left ventricular hypertrophy to arrhythmias with atrial fibrillation, which is the most common sustained arrhythmia in HCM.

The Hypertrophic Cardiomyopathy (HCM) Subpanel contains the following 40 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; 612794: AD Atrial septal defect 5 Comprehensive Cardiomyopathy; Congenital 613424: AD Cardiomyopathy, dilated, 1R ACTC1 102540 Heart Disease; Dilated Cardiomyopathy; AD 612098: AD Cardiomyopathy, hypertrophic, 11 Hypertrophic Cardiomyopathy; Left Ventricular 613424: AD Left ventricular noncompaction 4 Ncompaction Comprehensive Cardiovascular; 612158: AD Cardiomyopathy, dilated, 1AA, with Comprehensive Cardiomyopathy; or without LVNC ACTN2 102573 AD Comprehensive Arrythmias; Dilated 612158: AD Cardiomyopathy, hypertrophic, 23, Cardiomyopathy; Hypertrophic Cardiomyopathy with or without LVNC Comprehensive Cardiovascular; 232400: AR Glycogen storage disease IIIa AGL 610860 Comprehensive Cardiomyopathy; Hypertrophic AR Cardiomyopathy; Metabolic Cardiomyopathy 232400: AR Glycogen storage disease IIIb Comprehensive Cardiovascular; ANKRD1 609599 Comprehensive Cardiomyopathy; Dilated None None Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; 613881: AD Cardiomyopathy, dilated, 1HH BAG3 603883 Comprehensive Cardiomyopathy; Dilated AD 612954: AD Myopathy, myofibrillar, 6 Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short 611875: Brugada syndrome 3 CACNA1C 114205 AD Qt Syndrome; Comprehensive Arrythmias; 601005: AD Timothy syndrome Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Brugada Syndrome 192600: AD Cardiomyopathy, familial Comprehensive Cardiovascular; hypertrophic Comprehensive Cardiomyopathy; Long / Short 123320: AD Creatine phosphokinase, elevated CAV3 601253 Qt Syndrome; Comprehensive Arrythmias; serum AD Dilated Cardiomyopathy; Hypertrophic 611818: AD Long QT syndrome 9 Cardiomyopathy 614321: AD Myopathy, distal, Tateyama type 606072: AD Rippling muscle disease 600649: AR CPT II deficiency, infantile 608836: AR CPT II deficiency, lethal neonatal Comprehensive Cardiovascular; 255110: AR, AD CPT II deficiency, myopathic, CPT2 600650 Comprehensive Cardiomyopathy; Hypertrophic AD, AR stress-induced Cardiomyopathy; Metabolic Cardiomyopathy 614212: AR, AD {Encephalopathy, acute, infection-induced, 4, susceptibility to} Comprehensive Cardiovascular; 607482: ?Cardiomyopathy, dilated, 1M CSRP3 600824 Comprehensive Cardiomyopathy; Dilated AD 612124: AD Cardiomyopathy, hypertrophic, 12 Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; 604765: Cardiomyopathy, dilated, 1I Comprehensive Cardiomyopathy; 601419: AR, AD Myopathy, myofibrillar, 1 DES 125660 AD, AR Comprehensive Arrythmias; Dilated 181400: AD Scapuloperoneal syndrome, Cardiomyopathy; Hypertrophic Cardiomyopathy neurogenic, Kaeser type Comprehensive Cardiovascular; 300376: XLR Becker muscular dystrophy DMD 300377 Comprehensive Cardiomyopathy; Dilated 302045: XL Cardiomyopathy, dilated, 3B XLR, XL Cardiomyopathy; Hypertrophic Cardiomyopathy 310200: XLR Duchenne muscular dystrophy 300696: XLR Emery-Dreifuss muscular dystrophy 6, XL 300696: XLR Myopathy, XL, with postural Comprehensive Cardiovascular; muscle atrophy XLD, XLR, FHL1 300163 Comprehensive Cardiomyopathy; Hypertrophic 300717: XLD Reducing body myopathy, XL 1a, XL Cardiomyopathy severe, infantile or early childhood onset 300718: XL Reducing body myopathy, XL 1b, with late childhood or adult onset

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Gene MIM Disease Category OMIM Phenotype Inheritance 300695: XLD Scapuloperoneal myopathy, XLD 300280: XLR ?Uruguay faciocardiomusculoskeletal syndrome Cardiomyopathy, familial hypertrophic, 26 (3) Comprehensive Cardiovascular; 617047: AD Cardiomyopathy, familial restrictive FLNC 102565 Comprehensive Cardiomyopathy; Dilated 5 AD Cardiomyopathy; Hypertrophic Cardiomyopathy 614065: AD Myopathy, distal, 4 609524: AD Myopathy, myofibrillar, 5 Comprehensive Cardiovascular; GAA 606800 Comprehensive Cardiomyopathy; Hypertrophic 232300: AR Glycogen storage disease II AR Cardiomyopathy; Metabolic Cardiomyopathy Comprehensive Cardiovascular; 301500: XL Fabry disease GLA 300644 Comprehensive Cardiomyopathy; Hypertrophic XL 301500: XL Fabry disease, cardiac variant Cardiomyopathy; Metabolic Cardiomyopathy Comprehensive Cardiovascular; JPH2 605267 Comprehensive Cardiomyopathy; Hypertrophic 613873: AD Cardiomyopathy, hypertrophic, 17 AD Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated LAMP2 309060 Cardiomyopathy; Hypertrophic 300257: XLD Danon disease XLD Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathy Comprehensive Cardiovascular; 601493: AD Cardiomyopathy, dilated, 1C, with Comprehensive Cardiomyopathy; or without LVNC LDB3 605906 Comprehensive Arrythmias; Dilated 601493: AD Cardiomyopathy, hypertrophic, 24 AD Cardiomyopathy; Hypertrophic 601493: AD Left ventricular noncompaction 3 Cardiomyopathy; Left Ventricular Ncompaction 609452: AD Myopathy, myofibrillar, 4 Comprehensive Cardiovascular; 615396: AD Cardiomyopathy, dilated, 1MM Comprehensive Cardiomyopathy; Dilated MYBPC3 600958 115197: AD Cardiomyopathy, hypertrophic, 4 AD Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction 615396: AD Left ventricular noncompaction 10 Comprehensive Cardiovascular; 614089: Atrial septal defect 3 Comprehensive Cardiomyopathy; Congenital 613252: Cardiomyopathy, dilated, 1EE MYH6 160710 AD Heart Disease; Dilated Cardiomyopathy; 613251: AD Cardiomyopathy, hypertrophic, 14 Hypertrophic Cardiomyopathy 614090: {Sick sinus syndrome 3} 613426: AD Cardiomyopathy, dilated, 1S 192600: AD Cardiomyopathy, hypertrophic, 1 Comprehensive Cardiovascular; 160500: AD Laing distal myopathy Comprehensive Cardiomyopathy; Dilated 613426: AD Left ventricular noncompaction 5 MYH7 160760 AD, AR Cardiomyopathy; Hypertrophic 608358: AD Myopathy, myosin storage, AD Cardiomyopathy; Left Ventricular Ncompaction 255160: AR Myopathy, myosin storage, AR 181430: AD Scapuloperoneal syndrome, myopathic type Comprehensive Cardiovascular; MYL2 160781 Comprehensive Cardiomyopathy; Hypertrophic 608758: AD Cardiomyopathy, hypertrophic, 10 AD Cardiomyopathy Comprehensive Cardiovascular; 608751: AR, AD Cardiomyopathy, hypertrophic, MYL3 160790 Comprehensive Cardiomyopathy; Hypertrophic AD, AR 8 Cardiomyopathy Comprehensive Cardiovascular; 192600: AD Cardiomyopathy, hypertrophic, 1, MYLK2 606566 Comprehensive Cardiomyopathy; Hypertrophic AD Cardiomyopathy digenic Comprehensive Cardiovascular; MYOM1 603508 Comprehensive Cardiomyopathy; Hypertrophic None None Cardiomyopathy Comprehensive Cardiovascular; MYOZ2 605602 Comprehensive Cardiomyopathy; Hypertrophic 613838: AD Cardiomyopathy, hypertrophic, 16 AD Cardiomyopathy 615248: AD Cardiomyopathy, dilated, 1KK Comprehensive Cardiovascular; 615248: AD Cardiomyopathy, familial MYPN 608517 Comprehensive Cardiomyopathy; Dilated restrictive, 4 AD, AR Cardiomyopathy; Hypertrophic Cardiomyopathy 615248: AD Cardiomyopathy, hypertrophic, 22 617336: AR Nemaline myopathy 11, AR Comprehensive Cardiovascular; 613122: AD Cardiomyopathy, dilated, 1CC NEXN 613121 Comprehensive Cardiomyopathy; Dilated AD 613876: AD Cardiomyopathy, hypertrophic, 20 Cardiomyopathy; Hypertrophic Cardiomyopathy Comprehensive Cardiovascular; PDLIM3 605889 None None Comprehensive Cardiomyopathy; Hypertrophic

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Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 609909: Cardiomyopathy, dilated, 1P PLN 172405 AD Comprehensive Arrythmias; Dilated 613874: AD Cardiomyopathy, hypertrophic, 18 Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; 600858: AD Cardiomyopathy, hypertrophic 6 Comprehensive Cardiomyopathy; 261740: AD Glycogen storage disease of heart, PRKAG2 602743 AD Comprehensive Arrythmias; Hypertrophic lethal congenital Cardiomyopathy 194200: ?AD Wolff-Parkinson-White syndrome 151100: AD LEOPARD syndrome 1 Comprehensive Cardiovascular; 607785: Leukemia, juvenile myelomonocytic, Comprehensive Cardiomyopathy; Congenital PTPN11 176876 somatic AD Heart Disease; Hypertrophic Cardiomyopathy; 156250: AD Metachondromatosis Noonan Spectrum Disorders 163950: AD Noonan syndrome 1 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital 615916: AD Cardiomyopathy, dilated, 1NN RAF1 164760 Heart Disease; Dilated Cardiomyopathy; 611554: LEOPARD syndrome 2 AD Hypertrophic Cardiomyopathy; Noonan 611553: AD Noonan syndrome 5 Spectrum Disorders Comprehensive Cardiovascular; 607487: AD Cardiomyopathy, hypertrophic, 25 TCAP 604488 Comprehensive Cardiomyopathy; Dilated 601954: AR Muscular dystrophy, limb-girdle, AD, AR Cardiomyopathy; Hypertrophic Cardiomyopathy AR 7 Comprehensive Cardiovascular; 611879: Cardiomyopathy, dilated, 1Z TNNC1 191040 Comprehensive Cardiomyopathy; Dilated AD 613243: AD Cardiomyopathy, hypertrophic, 13 Cardiomyopathy; Hypertrophic Cardiomyopathy 613286: Cardiomyopathy, dilated, 1FF Comprehensive Cardiovascular; 611880: AR ?Cardiomyopathy, dilated, 2A Comprehensive Cardiomyopathy; Dilated TNNI3 191044 115210: AD Cardiomyopathy, familial AD, AR Cardiomyopathy; Hypertrophic restrictive, 1 Cardiomyopathy; Left Ventricular Ncompaction 613690: AD Cardiomyopathy, hypertrophic, 7 601494: AD Cardiomyopathy, dilated, 1D Comprehensive Cardiovascular; 612422: AD Cardiomyopathy, familial Comprehensive Cardiomyopathy; Dilated TNNT2 191045 restrictive, 3 AD Cardiomyopathy; Hypertrophic 115195: AD Cardiomyopathy, hypertrophic, 2 Cardiomyopathy; Left Ventricular Ncompaction 601494: AD Left ventricular noncompaction 6 Comprehensive Cardiovascular; 611878: AD Cardiomyopathy, dilated, 1Y Comprehensive Cardiomyopathy; Dilated TPM1 191010 115196: AD Cardiomyopathy, hypertrophic, 3 AD Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction 611878: AD Left ventricular noncompaction 9 105210: AD Amyloidosis, hereditary, Comprehensive Cardiovascular; transthyretin-related TTR 176300 Comprehensive Cardiomyopathy; Dilated 115430: AD Carpal tunnel syndrome, familial AD Cardiomyopathy; Hypertrophic Cardiomyopathy 145680: AD [Dystransthyretinemic hyperthyroxinemia] Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated 611407: Cardiomyopathy, dilated, 1W VCL 193065 AD Cardiomyopathy; Hypertrophic 613255: AD Cardiomyopathy, hypertrophic, 15 Cardiomyopathy; Left Ventricular Ncompaction

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. DMD: The following DMD hg19 coordinates have been excluded from this assay: chrX:31897426-31897627, chrX:32668999-32669253, chrX:32644476-32644680, chrX:31627637-31627838, chrX:32460213-32460334, chrX:31219361-31219367, chrX:31219126-31219287, chrX:32644160-32644321 3. FLNC: The following FLNC hg19 coordinates have been excluded from this assay: chr7:128498050-128498282 4. LAMP2: The following LAMP2 hg19 coordinates have been excluded from this assay: chrX:119604075-119604081

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LEFT VENTRICULAR NON-COMPACTION CARDIOMYOPATHY (LVNC) SUBPANEL

Left ventricular noncompaction cardiomyopathy (LVNC) is a congenital abnormality where the left ventricular myocardium fails to compact during embryonic development. The mechanism behind this disorder is thought to be an intrauterine arrest of myocardial development where pieces of muscle (trabeculations) fail to compact. The clinical presentation is variable and is associated with genetic heterogeneity. LVNC can range from asymptomatic to severe heart failure and sudden death. LVNC may occur in isolation or in association with congenital heart disease. LVNC also includes rhythm abnormalities including Wolff-Parkinson-White syndrome, conduction defects, and ventricular tachyarrhythmias. Higher occurrence of familial cases, facial dysmorphism, and congenital arrhythmias is observed in children.

The Left Ventricular Non-Compaction Cardiomyopathy (LVNC) Subpanel contains the following 20 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; 612794: AD Atrial septal defect 5 Comprehensive Cardiomyopathy; Congenital 613424: AD Cardiomyopathy, dilated, 1R ACTC1 102540 Heart Disease; Dilated Cardiomyopathy; AD 612098: AD Cardiomyopathy, hypertrophic, 11 Hypertrophic Cardiomyopathy; Left Ventricular 613424: AD Left ventricular noncompaction 4 Ncompaction 607450: AD Arrhythmogenic right ventricular dysplasia 8 Comprehensive Cardiovascular; 605676: AR Cardiomyopathy, dilated, with Comprehensive Cardiomyopathy; woolly hair and keratoderma

Arrythmogenic Right Ventricular 615821: AD Dilated cardiomyopathy with woolly DSP 125647 AD, AR Cardiomyopathy; Comprehensive Arrythmias; hair, keratoderma, and tooth agenesis Dilated Cardiomyopathy; Left Ventricular 609638: AR Epidermolysis bullosa, lethal Ncompaction acantholytic 612908: AD Keratosis palmoplantaris striata II 607655: AR Skin fragility-woolly hair syndrome Comprehensive Cardiovascular; 604169: AD Left ventricular noncompaction 1, DTNA 601239 Comprehensive Cardiomyopathy; Left AD with or without congenital heart defects Ventricular Ncompaction Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 613123: Brugada syndrome 8 HCN4 605206 AD Comprehensive Arrythmias; Left Ventricular 163800: AD Sick sinus syndrome 2 Ncompaction; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated LAMP2 309060 Cardiomyopathy; Hypertrophic 300257: XLD Danon disease XLD Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathy Comprehensive Cardiovascular; 601493: AD Cardiomyopathy, dilated, 1C, with Comprehensive Cardiomyopathy; or without LVNC LDB3 605906 Comprehensive Arrythmias; Dilated 601493: AD Cardiomyopathy, hypertrophic, 24 AD Cardiomyopathy; Hypertrophic 601493: AD Left ventricular noncompaction 3 Cardiomyopathy; Left Ventricular Ncompaction 609452: AD Myopathy, myofibrillar, 4 115200: AD Cardiomyopathy, dilated, 1A 605588: AR Charcot-Marie-Tooth disease, type 2B1 181350: AD Emery-Dreifuss muscular dystrophy 2, AD 616516: AR Emery-Dreifuss muscular Comprehensive Cardiovascular; dystrophy 3, AR Comprehensive Cardiomyopathy; 610140: AD Heart-hand syndrome, Slovenian LMNA 150330 AD, AR Comprehensive Arrythmias; Dilated type Cardiomyopathy; Left Ventricular Ncompaction 176670: AR, AD Hutchinson-Gilford progeria 151660: AD Lipodystrophy, familial partial, type 2 212112: AD Malouf syndrome 248370: AR Mandibuloacral dysplasia 613205: AD Muscular dystrophy, congenital 275210: AR Restrictive dermopathy, lethal Comprehensive Cardiovascular; MIB1 608677 615092: AD Left ventricular noncompaction 7 AD Comprehensive Cardiomyopathy; Left

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Gene MIM Disease Category OMIM Phenotype Inheritance Ventricular Ncompaction Comprehensive Cardiovascular; 615396: AD Cardiomyopathy, dilated, 1MM Comprehensive Cardiomyopathy; Dilated MYBPC3 600958 115197: AD Cardiomyopathy, hypertrophic, 4 AD Cardiomyopathy; Hypertrophic 615396: AD Left ventricular noncompaction 10 Cardiomyopathy; Left Ventricular Ncompaction 613426: AD Cardiomyopathy, dilated, 1S 192600: AD Cardiomyopathy, hypertrophic, 1 Comprehensive Cardiovascular; 160500: AD Laing distal myopathy Comprehensive Cardiomyopathy; Dilated 613426: AD Left ventricular noncompaction 5 MYH7 160760 AD, AR Cardiomyopathy; Hypertrophic 608358: AD Myopathy, myosin storage, AD Cardiomyopathy; Left Ventricular Ncompaction 255160: AR Myopathy, myosin storage, AR 181430: AD Scapuloperoneal syndrome, myopathic type Comprehensive Cardiovascular; PLEKHM2 609613 Comprehensive Cardiomyopathy; Left None None Ventricular Ncompaction Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 609909: Cardiomyopathy, dilated, 1P PLN 172405 AD Comprehensive Arrythmias; Dilated 613874: AD Cardiomyopathy, hypertrophic, 18 Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; 615373: AD Cardiomyopathy, dilated, 1LL PRDM16 605557 Comprehensive Cardiomyopathy; Dilated AD Cardiomyopathy; Left Ventricular Ncompaction 615373: AD Left ventricular noncompaction 8 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 600996: AD Arrhythmogenic right ventricular Catecholaminergic Polymorphic Ventricular dysplasia 2 RYR2 180902 Tachycardia; Arrythmogenic Right Ventricular AD 604772: AD Ventricular tachycardia, Cardiomyopathy; Comprehensive Arrythmias; catecholaminergic polymorphic, 1 Dilated Cardiomyopathy; Left Ventricular Ncompaction 614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E Comprehensive Cardiovascular; 113900: AD Heart block, nonprogressive Comprehensive Cardiomyopathy; Long / Short 113900: AD Heart block, progressive, type IA SCN5A 600163 Qt Syndrome; Comprehensive Arrythmias; AD, AR 603830: AD Long QT syndrome-3 Dilated Cardiomyopathy; Left Ventricular 608567: AR Sick sinus syndrome 1 Ncompaction; Brugada Syndrome 272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated TAZ 300394 302060: XLR Barth syndrome XLR Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathy 613286: Cardiomyopathy, dilated, 1FF Comprehensive Cardiovascular; 611880: AR ?Cardiomyopathy, dilated, 2A Comprehensive Cardiomyopathy; Dilated TNNI3 191044 115210: AD Cardiomyopathy, familial AD, AR Cardiomyopathy; Hypertrophic restrictive, 1 Cardiomyopathy; Left Ventricular Ncompaction 613690: AD Cardiomyopathy, hypertrophic, 7 601494: AD Cardiomyopathy, dilated, 1D Comprehensive Cardiovascular; 612422: AD Cardiomyopathy, familial Comprehensive Cardiomyopathy; Dilated TNNT2 191045 restrictive, 3 AD Cardiomyopathy; Hypertrophic 115195: AD Cardiomyopathy, hypertrophic, 2 Cardiomyopathy; Left Ventricular Ncompaction 601494: AD Left ventricular noncompaction 6 Comprehensive Cardiovascular; 611878: AD Cardiomyopathy, dilated, 1Y Comprehensive Cardiomyopathy; Dilated TPM1 191010 115196: AD Cardiomyopathy, hypertrophic, 3 AD Cardiomyopathy; Hypertrophic 611878: AD Left ventricular noncompaction 9 Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated 611407: Cardiomyopathy, dilated, 1W VCL 193065 AD Cardiomyopathy; Hypertrophic 613255: AD Cardiomyopathy, hypertrophic, 15 Cardiomyopathy; Left Ventricular Ncompaction

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. LAMP2: The following LAMP2 hg19 coordinates have been excluded from this assay: chrX:119604075-119604081

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THE COMPREHENSIVE ARRHYTHMIAS PANEL

Collectively, arrhythmias are disorders of cardiac ion channels and are commonly referred to as cardiac channelopathies. The maintenance of normal cardiac rhythm depends on the proper movement of ions mediating the action potential in each cardiac compartment. In arrhythmias, abnormalities in ion channel function manifest as electrocardiogram abnormalities and in most studies, individuals who are digenic/biallelic carriers have a more severe arrhythmia phenotype. Pathogenic variants in certain genes, which encode specific ion channels, have been shown to underlie well known heritable arrhythmogenic disorders occurring in the structurally normal heart. These include arrhythmogenic right ventricular cardiomyopathy, long and short QT syndromes, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). The Arrhythmias Panel contains the following 54 genes with four well-established subpanels: Arrythmogenic Right Ventricular Cardiomyopathy (ARVC), Brugada Syndrome (BrS), CPVT, and Long / Short QT Syndrome (LSQT).

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; 614050: AD Atrial fibrillation, familial, 12 Comprehensive Cardiomyopathy; 608569: Cardiomyopathy, dilated, 1O ABCC9 601439 AD Comprehensive Arrythmias; Dilated 239850: AD Hypertrichotic Cardiomyopathy; Brugada Syndrome osteochondrodysplasia Comprehensive Cardiovascular; 612158: AD Cardiomyopathy, dilated, 1AA, with Comprehensive Cardiomyopathy; or without LVNC ACTN2 102573 AD Comprehensive Arrythmias; Dilated 612158: AD Cardiomyopathy, hypertrophic, 23, Cardiomyopathy; Hypertrophic Cardiomyopathy with or without LVNC Comprehensive Cardiovascular; AKAP9 604001 Comprehensive Cardiomyopathy; Long / Short 611820: AD ?Long QT syndrome-11 AD Qt Syndrome; Comprehensive Arrythmias;

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Gene MIM Disease Category OMIM Phenotype Inheritance Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 600919: AD Cardiac arrhythmia, ankyrin-B- Catecholaminergic Polymorphic Ventricular ANK2 106410 related AD Tachycardia; Long / Short Qt Syndrome; 600919: AD Long QT syndrome 4 Comprehensive Arrythmias; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short 611875: Brugada syndrome 3 CACNA1C 114205 Qt Syndrome; Comprehensive Arrythmias; AD 601005: AD Timothy syndrome Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short CACNA2D1 114204 None None Qt Syndrome; Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short CACNB2 600003 611876: Brugada syndrome 4 None Qt Syndrome; Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 616247: AD Long QT syndrome 14 CALM1 114180 Catecholaminergic Polymorphic Ventricular 614916: AD Ventricular tachycardia, AD Tachycardia; Long / Short Qt Syndrome; catecholaminergic polymorphic, 4 Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; CALM2 114182 Catecholaminergic Polymorphic Ventricular 616249: AD Long QT syndrome 15 AD Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; CALM3 114183 Catecholaminergic Polymorphic Ventricular None None Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 611938: AR Ventricular tachycardia, CASQ2 114251 AR Catecholaminergic Polymorphic Ventricular catecholaminergic polymorphic, 2 Tachycardia; Comprehensive Arrythmias 192600: AD Cardiomyopathy, familial Comprehensive Cardiovascular; hypertrophic Comprehensive Cardiomyopathy; Long / Short 123320: AD Creatine phosphokinase, elevated CAV3 601253 Qt Syndrome; Comprehensive Arrythmias; serum AD Dilated Cardiomyopathy; Hypertrophic 611818: AD Long QT syndrome 9 Cardiomyopathy 614321: AD Myopathy, distal, Tateyama type 606072: AD Rippling muscle disease Comprehensive Cardiovascular; 615616: AD Arrhythmogenic right ventricular CTNNA3 607667 Comprehensive Cardiomyopathy; AD dysplasia, familial, 13 Comprehensive Arrythmias Comprehensive Cardiovascular; 604765: Cardiomyopathy, dilated, 1I Comprehensive Cardiomyopathy; 601419: AR, AD Myopathy, myofibrillar, 1 DES 125660 AD, AR Comprehensive Arrythmias; Dilated 181400: AD Scapuloperoneal syndrome, Cardiomyopathy; Hypertrophic Cardiomyopathy neurogenic, Kaeser type Comprehensive Cardiovascular; 610476: AR, AD Arrhythmogenic right Comprehensive Cardiomyopathy; ventricular dysplasia 11 DSC2 125645 Arrythmogenic Right Ventricular 610476: AR, AD Arrhythmogenic right AD, AR Cardiomyopathy; Comprehensive Arrythmias; ventricular dysplasia 11 with mild palmoplantar Dilated Cardiomyopathy keratoderma and woolly hair Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 610193: AD Arrhythmogenic right ventricular DSG2 125671 Arrythmogenic Right Ventricular dysplasia 10 AD Cardiomyopathy; Comprehensive Arrythmias; 612877: Cardiomyopathy, dilated, 1BB Dilated Cardiomyopathy Comprehensive Cardiovascular; 607450: AD Arrhythmogenic right ventricular Comprehensive Cardiomyopathy; dysplasia 8 DSP 125647 Arrythmogenic Right Ventricular 605676: AR Cardiomyopathy, dilated, with AD, AR Cardiomyopathy; Comprehensive Arrythmias; woolly hair and keratoderma Dilated Cardiomyopathy; Left Ventricular 615821: AD Dilated cardiomyopathy with woolly

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Gene MIM Disease Category OMIM Phenotype Inheritance Ncompaction hair, keratoderma, and tooth agenesis 609638: AR Epidermolysis bullosa, lethal acantholytic 612908: AD Keratosis palmoplantaris striata II 607655: AR Skin fragility-woolly hair syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 310300: XLR Emery-Dreifuss muscular EMD 300384 XLR, XL Comprehensive Arrythmias; Dilated dystrophy 1, XL Cardiomyopathy Comprehensive Cardiovascular; 614049: AD Atrial fibrillation, familial, 11 GJA5 121013 Comprehensive Cardiomyopathy; 108770: AD Atrial standstill, digenic AD Comprehensive Arrythmias (GJA5/SCN5A) Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; GPD1L 611778 611777: Brugada syndrome 2 None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 613123: Brugada syndrome 8 HCN4 605206 AD Comprehensive Arrythmias; Left Ventricular 163800: AD Sick sinus syndrome 2 Ncompaction; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 611528: AD Arrhythmogenic right ventricular JUP 173325 Arrythmogenic Right Ventricular dysplasia 12 AD, AR Cardiomyopathy; Comprehensive Arrythmias; 601214: AR Naxos disease Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; KCNA5 176267 612240: AD Atrial fibrillation, familial, 7 AD Comprehensive Arrythmias; Pulmonary Hypertension Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 616399: AD Brugada syndrome 9 KCND3 605411 AD Comprehensive Arrythmias; Brugada 607346: AD Spinocerebellar ataxia 19 Syndrome Comprehensive Cardiovascular; 612347: AR Jervell and Lange-Nielsen KCNE1 176261 Comprehensive Cardiomyopathy; Long / Short syndrome 2 AD, AR Qt Syndrome; Comprehensive Arrythmias 613695: AD Long QT syndrome 5 Comprehensive Cardiovascular; 611493: Atrial fibrillation, familial, 4 KCNE2 603796 Comprehensive Cardiomyopathy; Long / Short AD Qt Syndrome; Comprehensive Arrythmias 613693: AD Long QT syndrome 6 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; KCNE3 604433 613119: Brugada syndrome 6 None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; KCNE5 300328 None None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; 613688: AD Long QT syndrome 2 Comprehensive Cardiomyopathy; Long / Short 613688: AD {Long QT syndrome 2, acquired, KCNH2 152427 AD Qt Syndrome; Comprehensive Arrythmias; susceptibility to} Brugada Syndrome 609620: Short QT syndrome 1 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 170390: AD Andersen syndrome KCNJ2 600681 Catecholaminergic Polymorphic Ventricular 613980: AD Atrial fibrillation, familial, 9 AD Tachycardia; Long / Short Qt Syndrome; 609622: Short QT syndrome 3 Comprehensive Arrythmias Comprehensive Cardiovascular; 613677: AD Hyperaldosteronism, familial, type KCNJ5 600734 Comprehensive Cardiomyopathy; Long / Short III AD Qt Syndrome; Comprehensive Arrythmias 613485: AD Long QT syndrome 13 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; KCNJ8 600935 None None Comprehensive Arrythmias; Brugada Syndrome 607554: AD Atrial fibrillation, familial, 3 Comprehensive Cardiovascular; 220400: AR Jervell and Lange-Nielsen KCNQ1 607542 Comprehensive Cardiomyopathy; Long / Short syndrome AD, AR Qt Syndrome; Comprehensive Arrythmias 192500: AD Long QT syndrome 1 192500: AD {Long QT syndrome 1, acquired,

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Gene MIM Disease Category OMIM Phenotype Inheritance susceptibility to} 609621: AD Short QT syndrome 2 Comprehensive Cardiovascular; 601493: AD Cardiomyopathy, dilated, 1C, with Comprehensive Cardiomyopathy; or without LVNC LDB3 605906 Comprehensive Arrythmias; Dilated 601493: AD Cardiomyopathy, hypertrophic, 24 AD Cardiomyopathy; Hypertrophic 601493: AD Left ventricular noncompaction 3 Cardiomyopathy; Left Ventricular Ncompaction 609452: AD Myopathy, myofibrillar, 4 115200: AD Cardiomyopathy, dilated, 1A 605588: AR Charcot-Marie-Tooth disease, type 2B1 181350: AD Emery-Dreifuss muscular dystrophy 2, AD 616516: AR Emery-Dreifuss muscular Comprehensive Cardiovascular; dystrophy 3, AR Comprehensive Cardiomyopathy; 610140: AD Heart-hand syndrome, Slovenian LMNA 150330 AD, AR Comprehensive Arrythmias; Dilated type Cardiomyopathy; Left Ventricular Ncompaction 176670: AR, AD Hutchinson-Gilford progeria 151660: AD Lipodystrophy, familial partial, type 2 212112: AD Malouf syndrome 248370: AR Mandibuloacral dysplasia 613205: AD Muscular dystrophy, congenital 275210: AR Restrictive dermopathy, lethal 108900: AD Atrial septal defect 7, with or without AV conduction defects 217095: Conotruncal heart malformations, Comprehensive Cardiovascular; variable Comprehensive Cardiomyopathy; NKX2-5 600584 614435: AD Hypoplastic left heart syndrome 2 AD Comprehensive Arrythmias; Congenital Heart 225250: AD Hypothyroidism, congenital Disease nongoitrous, 5 187500: AD Tetralogy of Fallot 614432: AD Ventricular septal defect 3 Comprehensive Cardiovascular; 612201: AD Atrial fibrillation, familial, 6 NPPA 108780 Comprehensive Cardiomyopathy; AD, AR 615745: AR Atrial standstill 2 Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 609040: AD Arrhythmogenic right ventricular PKP2 602861 AD Arrythmogenic Right Ventricular dysplasia 9 Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 609909: Cardiomyopathy, dilated, 1P PLN 172405 Comprehensive Arrythmias; Dilated AD 613874: AD Cardiomyopathy, hypertrophic, 18 Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; 600858: AD Cardiomyopathy, hypertrophic 6 Comprehensive Cardiomyopathy; 261740: AD Glycogen storage disease of heart, PRKAG2 602743 AD Comprehensive Arrythmias; Hypertrophic lethal congenital Cardiomyopathy 194200: ?AD Wolff-Parkinson-White syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; RANGRF 607954 None None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 600996: AD Arrhythmogenic right ventricular Catecholaminergic Polymorphic Ventricular dysplasia 2 RYR2 180902 Tachycardia; Arrythmogenic Right Ventricular AD 604772: AD Ventricular tachycardia, Cardiomyopathy; Comprehensive Arrythmias; catecholaminergic polymorphic, 1 Dilated Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; SCN10A 604427 615551: AD Episodic pain syndrome, familial, 2 AD Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; 615377: AD Atrial fibrillation, familial, 13 Comprehensive Cardiomyopathy; 612838: Brugada syndrome 5 SCN1B 600235 AD, AR Comprehensive Arrythmias; Brugada 612838: Cardiac conduction defect, nonspecific Syndrome 604233: AD Epilepsy, generalized, with febrile

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Gene MIM Disease Category OMIM Phenotype Inheritance seizures plus, type 1 617350: AR Epileptic encephalopathy, early infantile, 52 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; SCN2B 601327 615378: AD Atrial fibrillation, familial, 14 AD Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 613120: AD Atrial fibrillation, familial, 16 SCN3B 608214 AD Comprehensive Arrythmias; Brugada 613120: AD Brugada syndrome 7 Syndrome Comprehensive Cardiovascular; 611819: AD Atrial fibrillation, familial, 17 SCN4B 608256 Comprehensive Cardiomyopathy; Long / Short AD 611819: AD Long QT syndrome-10 Qt Syndrome; Comprehensive Arrythmias 614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E Comprehensive Cardiovascular; 113900: AD Heart block, nonprogressive Comprehensive Cardiomyopathy; Long / Short 113900: AD Heart block, progressive, type IA SCN5A 600163 Qt Syndrome; Comprehensive Arrythmias; AD, AR 603830: AD Long QT syndrome-3 Dilated Cardiomyopathy; Left Ventricular 608567: AR Sick sinus syndrome 1 Ncompaction; Brugada Syndrome 272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; SLMAP 602701 None None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; SNTA1 601017 Comprehensive Cardiomyopathy; Long / Short 612955: AD Long QT syndrome 12 AD Qt Syndrome; Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 107970: AD Arrhythmogenic right ventricular TGFB3 190230 Arrythmogenic Right Ventricular dysplasia 1 AD Cardiomyopathy; Aortopathies; Comprehensive 615582: AD Loeys-Dietz syndrome 5 Arrythmias Comprehensive Cardiovascular; 604400: AD Arrhythmogenic right ventricular Comprehensive Cardiomyopathy; dysplasia 5 TMEM43 612048 Arrythmogenic Right Ventricular AD 614302: AD Emery-Dreifuss muscular Cardiomyopathy; Comprehensive Arrythmias; dystrophy 7, AD Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 615441: AR Ventricular tachycardia, TRDN 603283 Catecholaminergic Polymorphic Ventricular catecholaminergic polymorphic, 5, with or AR Tachycardia; Long / Short Qt Syndrome; without muscle weakness Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 604559: AD Progressive familial heart block, TRPM4 606936 AD Comprehensive Arrythmias; Brugada type IB Syndrome

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. SCN1B: The following SCN1B hg19 coordinates have been excluded from this assay: chr19:35521713-35521775 3. TRDN: The following TRDN hg19 coordinates have been excluded from this assay: chr6:123851639-123851721, chr6:123576214- 123576281

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BRUGADA SYNDROME (BrS) SUBPANEL

Brugada syndrome (BrS) is a channelopathy caused by genetic changes in transmembrane ion channels and cardiac conduction abnormalities that can result in sudden death. BrS is typically associated with a distinctive electrocardiogram (ECG) pattern in the absence of structural heart abnormalities. Of note, malignant arrhythmias and a previous history of syncopal episodes is a common presentation. Specifically, there is a ST-segment elevation in BrS within the right precordial ECG leads. The ST-segment elevation may be transient in nature and can be evoked by pharmacological sodium channel blockade. Other conduction defects can manifest as first- degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome. Loss-of- function mutations in the pore-forming subunit of the cardiac sodium channel have been causally related to the disease in a subset of cases. Although BrS is commonly considered a Mendelian disorder with autosomal dominant transmission, studies in families harboring BrS-related mutations have demonstrated low disease penetrance and, in some instances, absence of a familial mutation in some affected family members. An implantable cardioverter defibrillator is recommended for management of individuals with a history of syncope or cardiac arrest.

The Brugada Syndrome (BrS) Subpanel contains the following 20 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; 614050: AD Atrial fibrillation, familial, 12 Comprehensive Cardiomyopathy; 608569: Cardiomyopathy, dilated, 1O ABCC9 601439 AD Comprehensive Arrythmias; Dilated 239850: AD Hypertrichotic Cardiomyopathy; Brugada Syndrome osteochondrodysplasia Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short 611875: Brugada syndrome 3 CACNA1C 114205 Qt Syndrome; Comprehensive Arrythmias; AD 601005: AD Timothy syndrome Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short CACNA2D1 114204 None None Qt Syndrome; Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short CACNB2 600003 611876: Brugada syndrome 4 None Qt Syndrome; Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; GPD1L 611778 611777: Brugada syndrome 2 None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 613123: Brugada syndrome 8 HCN4 605206 AD Comprehensive Arrythmias; Left Ventricular 163800: AD Sick sinus syndrome 2 Ncompaction; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 616399: AD Brugada syndrome 9 KCND3 605411 AD Comprehensive Arrythmias; Brugada 607346: AD Spinocerebellar ataxia 19 Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; KCNE3 604433 613119: Brugada syndrome 6 None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; KCNE5 300328 None None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; 613688: AD Long QT syndrome 2 Comprehensive Cardiomyopathy; Long / Short 613688: AD {Long QT syndrome 2, acquired, KCNH2 152427 AD Qt Syndrome; Comprehensive Arrythmias; susceptibility to} Brugada Syndrome 609620: Short QT syndrome 1 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; KCNJ8 600935 None None Comprehensive Arrythmias; Brugada Syndrome

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Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 609040: AD Arrhythmogenic right ventricular PKP2 602861 Arrythmogenic Right Ventricular AD dysplasia 9 Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; RANGRF 607954 None None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; SCN10A 604427 615551: AD Episodic pain syndrome, familial, 2 AD Comprehensive Arrythmias; Brugada Syndrome 615377: AD Atrial fibrillation, familial, 13 612838: Brugada syndrome 5 Comprehensive Cardiovascular; 612838: Cardiac conduction defect, nonspecific Comprehensive Cardiomyopathy; SCN1B 600235 604233: AD Epilepsy, generalized, with febrile AD, AR Comprehensive Arrythmias; Brugada seizures plus, type 1 Syndrome 617350: AR Epileptic encephalopathy, early infantile, 52 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; SCN2B 601327 615378: AD Atrial fibrillation, familial, 14 AD Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 613120: AD Atrial fibrillation, familial, 16 SCN3B 608214 AD Comprehensive Arrythmias; Brugada 613120: AD Brugada syndrome 7 Syndrome 614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E Comprehensive Cardiovascular; 113900: AD Heart block, nonprogressive Comprehensive Cardiomyopathy; Long / Short 113900: AD Heart block, progressive, type IA SCN5A 600163 Qt Syndrome; Comprehensive Arrythmias; AD, AR 603830: AD Long QT syndrome-3 Dilated Cardiomyopathy; Left Ventricular 608567: AR Sick sinus syndrome 1 Ncompaction; Brugada Syndrome 272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; SLMAP 602701 None None Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 604559: AD Progressive familial heart block, TRPM4 606936 AD Comprehensive Arrythmias; Brugada type IB Syndrome

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. SCN1B: The following SCN1B hg19 coordinates have been excluded from this assay: chr19:35521713-35521775

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CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT) SUBPANEL

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited life‐ threatening arrhythmia leading to syncope and sudden cardiac death at a young age. CPVT patients do not show any detectable cardiac disease and in particular manifest ventricular premature beats and bidirectional or polymorphic ventricular tachycardia in response to emotional or physical stress. Spontaneous recovery may occur when these arrhythmias self- terminate. However, in other instances, the ventricular tachycardia can degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation (CPR) is not performed. The common genetic form of CPVT is associated with autosomal dominant mutations in the cardiac , however there is also a very rare form linked to recessive mutations in . Current clinical management of CPVT is based on treatment with β‐ blockers to reduce the frequency of arrhythmias and the implantation of automated defibrillators to terminate fatal arrhythmias.

The Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Subpanel contains the following 8 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 600919: AD Cardiac arrhythmia, ankyrin-B- Catecholaminergic Polymorphic Ventricular ANK2 106410 related AD Tachycardia; Long / Short Qt Syndrome; 600919: AD Long QT syndrome 4 Comprehensive Arrythmias; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 616247: AD Long QT syndrome 14 CALM1 114180 Catecholaminergic Polymorphic Ventricular 614916: AD Ventricular tachycardia, AD Tachycardia; Long / Short Qt Syndrome; catecholaminergic polymorphic, 4 Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; CALM2 114182 Catecholaminergic Polymorphic Ventricular 616249: AD Long QT syndrome 15 AD Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; CALM3 114183 Catecholaminergic Polymorphic Ventricular None None Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 611938: AR Ventricular tachycardia, CASQ2 114251 AR Catecholaminergic Polymorphic Ventricular catecholaminergic polymorphic, 2 Tachycardia; Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 170390: AD Andersen syndrome KCNJ2 600681 Catecholaminergic Polymorphic Ventricular 613980: AD Atrial fibrillation, familial, 9 AD Tachycardia; Long / Short Qt Syndrome; 609622: Short QT syndrome 3 Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 600996: AD Arrhythmogenic right ventricular Catecholaminergic Polymorphic Ventricular dysplasia 2 RYR2 180902 Tachycardia; Arrythmogenic Right Ventricular AD 604772: AD Ventricular tachycardia, Cardiomyopathy; Comprehensive Arrythmias; catecholaminergic polymorphic, 1 Dilated Cardiomyopathy; Left Ventricular Ncompaction Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 615441: AR Ventricular tachycardia, TRDN 603283 Catecholaminergic Polymorphic Ventricular catecholaminergic polymorphic, 5, with or AR Tachycardia; Long / Short Qt Syndrome; without muscle weakness Comprehensive Arrythmias

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. TRDN: The following TRDN hg19 coordinates have been excluded from this assay: chr6:123851639-123851721, chr6:123576214- 123576281

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LONG / SHORT QT SYNDROME (LQTS / SQTS) SUBPANEL

Inherited arrhythmias such as long QT syndrome (LQTS) or short QT syndrome (SQTS) occur in a heterogeneous collection of Mendelian disorders, often leading to sudden cardiac death. These disorders are usually caused by rare, highly penetrant mutations in ion channel genes. LQTS is characterized by a prolongation of the QT interval and T-wave abnormalities on electrocardiograms along with a propensity to ventricular tachyarrhythmias, which lead to syncope and/or cardiac arrest. The fundamental arrhythmogenic triggering mechanisms are linked to the decreased outward potassium currents in LQTS. In contrast, SQTS is characterized by a short QT interval with the late portion of the T-wave being statistically prolonged in most SQTS reports. Individuals with SQTS may manifest symptoms such as syncope, cardiac arrest, atrial fibrillation, idiopathic ventricular fibrillation, bradycardia and irregular rhythm. However, for both syndromes, an abnormal QT interval is not always associated with an increased risk of cardiac events since a wide range of QT intervals are considered abnormal without a significant increase in risk. Additional risk factors can include administration of certain medications such as antidepressants or cholesterol- lowering drugs that can exacerbate the QT interval profile. Treatment options typically involve β‐ blockers and implantable cardioverter-defibrillators as therapeutic options to prevent cardiac arrest.

The Long / Short QT Syndrome Subpanel contains the following 19 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short AKAP9 604001 611820: AD ?Long QT syndrome-11 AD Qt Syndrome; Comprehensive Arrythmias; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 600919: AD Cardiac arrhythmia, ankyrin-B- Catecholaminergic Polymorphic Ventricular ANK2 106410 related AD Tachycardia; Long / Short Qt Syndrome; 600919: AD Long QT syndrome 4 Comprehensive Arrythmias; Dilated Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short 611875: Brugada syndrome 3 CACNA1C 114205 Qt Syndrome; Comprehensive Arrythmias; AD 601005: AD Timothy syndrome Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short CACNA2D1 114204 None None Qt Syndrome; Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short CACNB2 600003 611876: Brugada syndrome 4 None Qt Syndrome; Comprehensive Arrythmias; Brugada Syndrome Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 616247: AD Long QT syndrome 14 CALM1 114180 Catecholaminergic Polymorphic Ventricular 614916: AD Ventricular tachycardia, AD Tachycardia; Long / Short Qt Syndrome; catecholaminergic polymorphic, 4 Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; CALM2 114182 Catecholaminergic Polymorphic Ventricular 616249: AD Long QT syndrome 15 AD Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; CALM3 114183 Catecholaminergic Polymorphic Ventricular None None Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias 192600: AD Cardiomyopathy, familial Comprehensive Cardiovascular; hypertrophic Comprehensive Cardiomyopathy; Long / Short 123320: AD Creatine phosphokinase, elevated CAV3 601253 Qt Syndrome; Comprehensive Arrythmias; AD serum Dilated Cardiomyopathy; Hypertrophic 611818: AD Long QT syndrome 9 Cardiomyopathy 614321: AD Myopathy, distal, Tateyama type

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Gene MIM Disease Category OMIM Phenotype Inheritance 606072: AD Rippling muscle disease Comprehensive Cardiovascular; 612347: AR Jervell and Lange-Nielsen KCNE1 176261 Comprehensive Cardiomyopathy; Long / Short syndrome 2 AD, AR Qt Syndrome; Comprehensive Arrythmias 613695: AD Long QT syndrome 5 Comprehensive Cardiovascular; 611493: Atrial fibrillation, familial, 4 KCNE2 603796 Comprehensive Cardiomyopathy; Long / Short AD 613693: AD Long QT syndrome 6 Qt Syndrome; Comprehensive Arrythmias Comprehensive Cardiovascular; 613688: AD Long QT syndrome 2 Comprehensive Cardiomyopathy; Long / Short 613688: AD {Long QT syndrome 2, acquired, KCNH2 152427 AD Qt Syndrome; Comprehensive Arrythmias; susceptibility to} Brugada Syndrome 609620: Short QT syndrome 1 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 170390: AD Andersen syndrome KCNJ2 600681 Catecholaminergic Polymorphic Ventricular 613980: AD Atrial fibrillation, familial, 9 AD Tachycardia; Long / Short Qt Syndrome; 609622: Short QT syndrome 3 Comprehensive Arrythmias Comprehensive Cardiovascular; 613677: AD Hyperaldosteronism, familial, type KCNJ5 600734 Comprehensive Cardiomyopathy; Long / Short III AD Qt Syndrome; Comprehensive Arrythmias 613485: AD Long QT syndrome 13 607554: AD Atrial fibrillation, familial, 3 220400: AR Jervell and Lange-Nielsen Comprehensive Cardiovascular; syndrome KCNQ1 607542 Comprehensive Cardiomyopathy; Long / Short 192500: AD Long QT syndrome 1 AD, AR Qt Syndrome; Comprehensive Arrythmias 192500: AD {Long QT syndrome 1, acquired, susceptibility to} 609621: AD Short QT syndrome 2 Comprehensive Cardiovascular; 611819: AD Atrial fibrillation, familial, 17 SCN4B 608256 Comprehensive Cardiomyopathy; Long / Short AD Qt Syndrome; Comprehensive Arrythmias 611819: AD Long QT syndrome-10 614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E Comprehensive Cardiovascular; 113900: AD Heart block, nonprogressive Comprehensive Cardiomyopathy; Long / Short 113900: AD Heart block, progressive, type IA SCN5A 600163 Qt Syndrome; Comprehensive Arrythmias; AD, AR 603830: AD Long QT syndrome-3 Dilated Cardiomyopathy; Left Ventricular 608567: AR Sick sinus syndrome 1 Ncompaction; Brugada Syndrome 272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1 Comprehensive Cardiovascular; SNTA1 601017 Comprehensive Cardiomyopathy; Long / Short 612955: AD Long QT syndrome 12 AD Qt Syndrome; Comprehensive Arrythmias Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 615441: AR Ventricular tachycardia, TRDN 603283 Catecholaminergic Polymorphic Ventricular catecholaminergic polymorphic, 5, with or AR Tachycardia; Long / Short Qt Syndrome; without muscle weakness Comprehensive Arrythmias

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. TRDN: The following TRDN hg19 coordinates have been excluded from this assay: chr6:123851639-123851721, chr6:123576214- 123576281

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AORTOPATHIES PANEL

Aortopathies account for a significant healthcare burden that is likely underestimated and underdiagnosed due to early mortality caused by aneurysms. Typically, aortopathies are subcategorized into thoracic abdominal aortic aneurysm and abdominal aortic aneurysm. Abdominal aortic aneurysms are common degenerative disorders associated with traditional atherosclerotic risk factors such as advanced age, cigarette smoking, hypertension, and hypercholesterolemia. These aneurysms tend to arise from complicated interactions of multiple predisposing genes and environmental risk factors. By contrast, thoracic abdominal aneurysms occur across all age groups and can present as part of a genetic syndrome or an isolated anomaly. Most genetic causes of heritable aortopathies are transmitted as monogenic defects with autosomal dominant patterns of inheritance associated with high penetrance. Notably, since clinical variability between and within genetic subtypes is a hallmark of aortic disease, next- generation sequencing is a robust method to delineate loci associated with the hereditary aortopathies.

The Aortopathies Panel contains the following 33 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance 611788: AD Aortic aneurysm, familial thoracic 6 Comprehensive Cardiovascular; 614042: Moyamoya disease 5 ACTA2 102620 AD Comprehensive Cardiomyopathy; Aortopathies 613834: AD Multisystemic smooth muscle dysfunction syndrome 225410: AR Ehlers-Danlos syndrome, ADAMTS2 604539 Comprehensive Cardiovascular; Aortopathies AR dermatosparaxis type 309400: XLR 304150: XLR ATP7A 300011 Comprehensive Cardiovascular; Aortopathies XLR, XL 300489: XLR Spinal muscular atrophy, distal, XL 3 236200: AR Homocystinuria, B6-responsive Comprehensive Cardiovascular; and nonresponsive types CBS 613381 AR Comprehensive Cardiomyopathy; Aortopathies 236200: AR Thrombosis, hyperhomocysteinemic 601776: AR Ehlers-Danlos syndrome, CHST14 608429 Comprehensive Cardiovascular; Aortopathies AR musculocontractural type 1 166710: AD {Bone mineral density variation QTL, osteoporosis} 114000: AD Caffey disease 130060: AD Ehlers-Danlos syndrome, COL1A1 120150 Comprehensive Cardiovascular; Aortopathies arthrochalasia type, 1 AD 166200: AD Osteogenesis imperfecta, type I 166210: AD Osteogenesis imperfecta, type II 259420: AD Osteogenesis imperfecta, type III 166220: AD Osteogenesis imperfecta, type IV 617821: AD Ehlers-Danlos syndrome, arthrochalasia type, 2 225320: AR Ehlers-Danlos syndrome, cardiac valvular type COL1A2 120160 Comprehensive Cardiovascular; Aortopathies AD, AR 259420: AD imperfecta, type III 166210: AD Osteogenesis imperfecta, type II 166220: AD Osteogenesis imperfecta, type IV 166710: AD {Osteoporosis, postmenopausal} Comprehensive Cardiovascular; 130050: AD Ehlers-Danlos syndrome, vascular COL3A1 120180 AD Comprehensive Cardiomyopathy; Aortopathies type Comprehensive Cardiovascular; 130000: AD Ehlers-Danlos syndrome, classic COL5A1 120215 Comprehensive Cardiomyopathy; Aortopathies type, 1 AD Comprehensive Cardiovascular; 130010: AD Ehlers-Danlos syndrome, classic COL5A2 120190 AD Comprehensive Cardiomyopathy; Aortopathies type, 2 EFEMP2 604633 Comprehensive Cardiovascular; Aortopathies 614437: AR Cutis laxa, AR, type IB AR 102370: AD Acromicric dysplasia Comprehensive Cardiovascular; 129600: AD Ectopia lentis, familial FBN1 134797 AD Comprehensive Cardiomyopathy; Aortopathies 614185: AD Geleophysic dysplasia 2 604308: MASS syndrome 616914: AD Marfan lipodystrophy syndrome 154700: AD Marfan syndrome 184900: AD Stiff skin syndrome 608328: AD Weill-Marchesani syndrome 2, dominant

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Gene MIM Disease Category OMIM Phenotype Inheritance 121050: AD Contractural arachnodactyly, Comprehensive Cardiovascular; FBN2 612570 congenital AD Comprehensive Cardiomyopathy; Aortopathies 616118: AD Macular degeneration, early-onset 614557: AR Ehlers-Danlos syndrome, FKBP14 614505 Comprehensive Cardiovascular; Aortopathies AR kyphoscoliotic type, 2 314400: XLR Cardiac valvular dysplasia, XL 300048: XLR Congenital short bowel syndrome 300321: XL ?FG syndrome 2 305620: XLR Frontometaphyseal dysplasia 1

300049: XLD Heterotopia, periventricular Comprehensive Cardiovascular; XLD, XLR, FLNA 300017 300048: XLR Intestinal pseudoobstruction, Comprehensive Cardiomyopathy; Aortopathies XL neuronal 309350: XLD Melnick-Needles syndrome 311300: XLD Otopalatodigital syndrome, type I 304120: XLD Otopalatodigital syndrome, type II 300244: XLD Terminal osseous dysplasia MAT2A 601468 Comprehensive Cardiovascular; Aortopathies None None 309520: XLR Lujan-Fryns syndrome Comprehensive Cardiovascular; MED12 300188 300895: XLR Ohdo syndrome, XL XLR, XL Comprehensive Cardiomyopathy; Aortopathies 305450: XLR Opitz-Kaveggia syndrome MFAP5 601103 Comprehensive Cardiovascular; Aortopathies 616166: AD Aortic aneurysm, familial thoracic 9 AD Comprehensive Cardiovascular; MYH11 160745 Comprehensive Cardiomyopathy; Aortopathies 132900: AD Aortic aneurysm, familial thoracic 4 AD Comprehensive Cardiovascular; MYLK 600922 613780: AD Aortic aneurysm, familial thoracic 7 AD Comprehensive Cardiomyopathy; Aortopathies Comprehensive Cardiovascular; 616028: AD Adams-Oliver syndrome 5 NOTCH1 190198 Comprehensive Cardiomyopathy; Aortopathies; AD Congenital Heart Disease 109730: AD Aortic valve disease 1 Comprehensive Cardiovascular; 225400: AR Ehlers-Danlos syndrome, PLOD1 153454 AR Comprehensive Cardiomyopathy; Aortopathies kyphoscoliotic type, 1 Comprehensive Cardiovascular; PRKG1 176894 Comprehensive Cardiomyopathy; Aortopathies 615436: AD Aortic aneurysm, familial thoracic 8 AD Comprehensive Cardiovascular; SKI 164780 182212: AD Shprintzen-Goldberg syndrome AD Comprehensive Cardiomyopathy; Aortopathies Comprehensive Cardiovascular; SLC2A10 606145 208050: AR Arterial tortuosity syndrome AR Comprehensive Cardiomyopathy; Aortopathies 612350: AR Ehlers-Danlos syndrome, SLC39A13 608735 Comprehensive Cardiovascular; Aortopathies AR spondylodysplastic type, 3 Comprehensive Cardiovascular; SMAD3 603109 Comprehensive Cardiomyopathy; Aortopathies 613795: AD Loeys-Dietz syndrome 3 AD 175050: AD Juvenile polyposis/hereditary Comprehensive Cardiovascular; hemorrhagic telangiectasia syndrome SMAD4 600993 Comprehensive Cardiomyopathy; Aortopathies; 139210: AD Myhre syndrome AD Hereditary Hemorrhagic Telangiectasia 260350: Pancreatic cancer, somatic 174900: AD Polyposis, juvenile intestinal 614823: AD Aortic valve disease 2 Comprehensive Cardiovascular; Aortopathies; SMAD6 602931 617439: AD {Craniosynostosis 7, susceptibility AD Congenital Heart Disease to} Comprehensive Cardiovascular; TGFB2 190220 614816: AD Loeys-Dietz syndrome 4 AD Comprehensive Cardiomyopathy; Aortopathies Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; 107970: AD Arrhythmogenic right ventricular TGFB3 190230 Arrythmogenic Right Ventricular dysplasia 1 AD Cardiomyopathy; Aortopathies; Comprehensive 615582: AD Loeys-Dietz syndrome 5 Arrythmias 609192: AD Loeys-Dietz syndrome 1 Comprehensive Cardiovascular; TGFBR1 190181 132800: AD {Multiple self-healing squamous AD Comprehensive Cardiomyopathy; Aortopathies epithelioma, susceptibility to} 614331: Colorectal cancer, hereditary Comprehensive Cardiovascular; nonpolyposis, type 6 TGFBR2 190182 AD Comprehensive Cardiomyopathy; Aortopathies 133239: Esophageal cancer, somatic 610168: AD Loeys-Dietz syndrome 2

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. ATP7A: The following ATP7A hg19 coordinates have been excluded from this assay: chrX:77269723-77269729, chrX:77278955- 77279156

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CONGENITAL HEART DISEASE (CHD) PANEL

Congenital heart disease (CHD) is a common cause of neonatal morbidity and mortality. CHD can present in multifactorial and syndromic forms. CHD-associated genetic syndromes may occur in association with teratogens, chromosomal abnormalities, or single gene defects. A genetics evaluation is warranted in neonates who have congenital cardiac malformations associated with unusual physical features or other organ system malformations. Early molecular diagnosis of CHD-associated genetic syndromes is important as the genetic etiology may guide further diagnosis, management, and treatment. In addition, the presence of a syndrome in the family may warrant genetic counseling for the patient’s family.

The Congenital Heart Disease (CHD) Panel contains the following 43 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; Comprehensive 612794: AD Atrial septal defect 5 Cardiomyopathy; Congenital Heart Disease; Dilated 613424: AD Cardiomyopathy, dilated, 1R ACTC1 102540 AD Cardiomyopathy; Hypertrophic Cardiomyopathy; 612098: AD Cardiomyopathy, hypertrophic, 11 Left Ventricular Ncompaction 613424: AD Left ventricular noncompaction 4 Comprehensive Cardiovascular; Congenital Heart ACVR2B 602730 613751: Heterotaxy, visceral, 4, autosomal None Disease Comprehensive Cardiovascular; Comprehensive ALMS1 606844 203800: AR Alstrom syndrome AR Cardiomyopathy; Congenital Heart Disease Comprehensive Cardiovascular; Congenital Heart BCOR 300485 300166: XLD Microphthalmia, syndromic 2 XLD Disease 211980: Adenocarcinoma of lung, somatic 115150: AD Cardiofaciocutaneous syndrome Comprehensive Cardiovascular; Comprehensive Colorectal cancer, somatic (3) BRAF 164757 Cardiomyopathy; Congenital Heart Disease; Noonan 613707: AD LEOPARD syndrome 3 AD Spectrum Disorders Melanoma, malignant, somatic (3) Nonsmall cell lung cancer, somatic (3) 613706: AD Noonan syndrome 7 607785: AD, SM ?Juvenile myelomonocytic Comprehensive Cardiovascular; Comprehensive leukemia CBL 165360 Cardiomyopathy; Congenital Heart Disease; Noonan AD, SM 613563: AD Noonan syndrome-like disorder with or Spectrum Disorders without juvenile myelomonocytic leukemia 214800: AD CHARGE syndrome Comprehensive Cardiovascular; Congenital Heart CHD7 608892 612370: AD Hypogonadotropic hypogonadism 5 AD Disease with or without anosmia 606217: AD Atrioventricular septal defect, partial, Comprehensive Cardiovascular; Congenital Heart with heterotaxy syndrome CRELD1 607170 AD Disease 606217: AD {Atrioventricular septal defect, susceptibility to, 2} Comprehensive Cardiovascular; Congenital Heart 608644: Ciliary dyskinesia, primary, 3, with or DNAH5 603335 None Disease without situs inversus Comprehensive Cardiovascular; Congenital Heart 123700: AD Cutis laxa, AD ELN 130160 AD Disease 185500: AD Supravalvar aortic stenosis Comprehensive Cardiovascular; Congenital Heart FOXH1 603621 None None Disease 607941: AD Atrial septal defect 2 614430: AD Atrioventricular septal defect 4 Comprehensive Cardiovascular; Comprehensive 615542: AD ?Testicular anomalies with or without GATA4 600576 AD Cardiomyopathy; Congenital Heart Disease congenital heart disease 187500: AD Tetralogy of Fallot 614429: AD Ventricular septal defect 1 614475: AD Atrial septal defect 9 Comprehensive Cardiovascular; Comprehensive GATA6 601656 614474: AD Atrioventricular septal defect 5 AD Cardiomyopathy; Congenital Heart Disease 600001: AD Pancreatic agenesis and congenital

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Gene MIM Disease Category OMIM Phenotype Inheritance heart defects 217095: Persistent truncus arteriosus 187500: AD Tetralogy of Fallot 613854: AD Congenital heart defects, multiple Comprehensive Cardiovascular; Congenital Heart GDF1 602880 types, 6 AD, AR Disease 208530: AR Right atrial isomerism (Ivemark) 600309: AD Atrioventricular septal defect 3 218400: AR Craniometaphyseal dysplasia, AR 617525: AD Erythrokeratodermia variabilis et

progressiva 3

Comprehensive Cardiovascular; Congenital Heart 241550: AR Hypoplastic left heart syndrome 1 GJA1 121014 AD, AR Disease 164200: AD Oculodentodigital dysplasia 257850: AR Oculodentodigital dysplasia, AR 104100: AD with congenital alopecia 186100: AD Syndactyly, type III 312870: XLR Simpson-Golabi-Behmel syndrome, Comprehensive Cardiovascular; Congenital Heart GPC3 300037 type 1 XLR Disease 194070: Wilms tumor, somatic Comprehensive Cardiovascular; Congenital Heart HAND1 602406 None None Disease 109800: {Bladder cancer, somatic} 218040: AD, IC Congenital myopathy with excess of muscle spindles

218040: AD, IC Costello syndrome Comprehensive Cardiovascular; Comprehensive 162900: {Nevus sebaceous or woolly hair nevus, HRAS 190020 Cardiomyopathy; Congenital Heart Disease; Noonan AD, IC somatic} Spectrum Disorders 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 137550: {Spitz nevus or nevus spilus, somatic} 188470: {Thyroid carcinoma, follicular, somatic} 118450: AD Alagille syndrome 1 Comprehensive Cardiovascular; Comprehensive 617992: ?Deafness, congenital heart defects, and JAG1 601920 AD Cardiomyopathy; Congenital Heart Disease posterior embryotoxon 187500: AD Tetralogy of Fallot 108010: Arteriovenous malformation of the brain, somatic 109800: Bladder cancer, somatic 114480: Breast cancer, somatic 615278: Cardiofaciocutaneous syndrome 2 137215: Gastric cancer, somatic Comprehensive Cardiovascular; Comprehensive 601626: AD Leukemia, acute myeloid KRAS 190070 Cardiomyopathy; Congenital Heart Disease; Noonan AD 211980: Lung cancer, somatic Spectrum Disorders 609942: AD Noonan syndrome 3 260350: Pancreatic carcinoma, somatic 614470: AD RAS-associated autoimmune leukoproliferative disorder 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic Comprehensive Cardiovascular; Congenital Heart LEFTY2 601877 None None Disease Comprehensive Cardiovascular; Comprehensive MAP2K1 176872 Cardiomyopathy; Congenital Heart Disease; Noonan 615279: Cardiofaciocutaneous syndrome 3 None Spectrum Disorders Comprehensive Cardiovascular; Comprehensive MAP2K2 601263 Cardiomyopathy; Congenital Heart Disease; Noonan 615280: Cardiofaciocutaneous syndrome 4 None Spectrum Disorders 616789: AD Mental retardation and distinctive Comprehensive Cardiovascular; Congenital Heart facial features with or without cardiac defects MED13L 608771 AD Disease 608808: AD Transposition of the great , dextro-looped 1 Comprehensive Cardiovascular; Congenital Heart 600987: AD Cleft palate, cardiac defects, and MEIS2 601740 AD Disease mental retardation MYH6 160710 Comprehensive Cardiovascular; Comprehensive 614089: Atrial septal defect 3 AD

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Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Congenital Heart Disease; Dilated 613252: Cardiomyopathy, dilated, 1EE Cardiomyopathy; Hypertrophic Cardiomyopathy 613251: AD Cardiomyopathy, hypertrophic, 14 614090: {Sick sinus syndrome 3} 108900: AD Atrial septal defect 7, with or without AV conduction defects 217095: Conotruncal heart malformations, variable Comprehensive Cardiovascular; Comprehensive 614435: AD Hypoplastic left heart syndrome 2 NKX2-5 600584 Cardiomyopathy; Comprehensive Arrythmias; AD 225250: AD Hypothyroidism, congenital Congenital Heart Disease nongoitrous, 5 187500: AD Tetralogy of Fallot 614432: AD Ventricular septal defect 3 Comprehensive Cardiovascular; Congenital Heart 217095: Conotruncal heart malformations NKX2-6 611770 None Disease 217095: Persistent truncus arteriosus Comprehensive Cardiovascular; Congenital Heart NODAL 601265 270100: AD Heterotaxy, visceral, 5 AD Disease Comprehensive Cardiovascular; Comprehensive 616028: AD Adams-Oliver syndrome 5 NOTCH1 190198 Cardiomyopathy; Aortopathies; Congenital Heart AD 109730: AD Aortic valve disease 1 Disease Comprehensive Cardiovascular; Congenital Heart 615779: AD Congenital heart defects, multiple NR2F2 107773 AD Disease types, 4 114500: Colorectal cancer, somatic 162900: Epidermal nevus, somatic 137550: Melanocytic nevus syndrome, congenital,

somatic Comprehensive Cardiovascular; Comprehensive 249400: Neurocutaneous melanosis, somatic NRAS 164790 Cardiomyopathy; Congenital Heart Disease; Noonan 613224: AD Noonan syndrome 6 AD Spectrum Disorders 614470: ?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 188470: Thyroid carcinoma, follicular, somatic Comprehensive Cardiovascular; Congenital Heart 601626: AD Leukemia, acute myeloid NSD1 606681 AD Disease 117550: AD Sotos syndrome 1 151100: AD LEOPARD syndrome 1 Comprehensive Cardiovascular; Comprehensive 607785: Leukemia, juvenile myelomonocytic, Cardiomyopathy; Congenital Heart Disease; PTPN11 176876 somatic AD Hypertrophic Cardiomyopathy; Noonan Spectrum 156250: AD Metachondromatosis Disorders 163950: AD Noonan syndrome 1 Comprehensive Cardiovascular; Comprehensive 615916: AD Cardiomyopathy, dilated, 1NN Cardiomyopathy; Congenital Heart Disease; Dilated RAF1 164760 611554: LEOPARD syndrome 2 AD Cardiomyopathy; Hypertrophic Cardiomyopathy; 611553: AD Noonan syndrome 5 Noonan Spectrum Disorders Comprehensive Cardiovascular; Comprehensive RIT1 609591 Cardiomyopathy; Congenital Heart Disease; Noonan 615355: AD Noonan syndrome 8 AD Spectrum Disorders Comprehensive Cardiovascular; Comprehensive 607721: AD Noonan-like syndrome with loose SHOC2 602775 Cardiomyopathy; Congenital Heart Disease; Noonan AD anagen hair Spectrum Disorders Comprehensive Cardiovascular; Aortopathies; 614823: AD Aortic valve disease 2 SMAD6 602931 AD Congenital Heart Disease 617439: AD {Craniosynostosis 7, susceptibility to} Comprehensive Cardiovascular; Comprehensive 135300: AD ?Fibromatosis, gingival, 1 SOS1 182530 Cardiomyopathy; Congenital Heart Disease; Noonan AD 610733: AD Noonan syndrome 4 Spectrum Disorders 217095: Conotruncal anomaly face syndrome Comprehensive Cardiovascular; Comprehensive 188400: AD DiGeorge syndrome TBX1 602054 AD Cardiomyopathy; Congenital Heart Disease 187500: AD Tetralogy of Fallot 192430: AD Velocardiofacial syndrome Comprehensive Cardiovascular; Comprehensive TBX5 601620 142900: AD Holt-Oram syndrome AD Cardiomyopathy; Congenital Heart Disease 610187: Diaphragmatic hernia 3 Comprehensive Cardiovascular; Congenital Heart ZFPM2 603693 187500: AD Tetralogy of Fallot AD Disease 616067: AD 46XY sex reversal 9 Comprehensive Cardiovascular; Congenital Heart 306955: XLR Congenital heart defects, ZIC3 300265 XLR, XL Disease nonsyndromic, 1, XL

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Gene MIM Disease Category OMIM Phenotype Inheritance 306955: XLR Heterotaxy, visceral, 1, XL 314390: XLR VACTERL association, XL

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. GATA6: The following GATA6 hg19 coordinates have been excluded from this assay: chr18:19749269-19749275 3. LEFTY2: The following LEFTY2 hg19 coordinates have been excluded from this assay: chr1:226127049-226127311 4. TBX1: The following TBX1 hg19 coordinates have been excluded from this assay: chr22:19748416-19748814

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FAMILIAL HYPERCHOLESTEROLEMIA (FH) PANEL

Familial hypercholesterolemia (FH) is characterized by elevated plasma levels of low-density lipoprotein (LDL) cholesterol from the time of birth. Commonly, mutations in genes encoding the LDL receptor, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 cause FH. These mutations are inherited in an autosomal dominant manner. In more rare cases, homozygous and compound heterozygosity FH as well as double heterozygosity have been reported. Typically, affected individuals may experience premature cardiovascular events, which may manifest as angina or myocardial infarction and can have an earlier onset in those with homozygous FH. External signs of hypercholesterolemia can also manifest in the form of xanthomata, which can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. Early diagnosis and treatment can reduce morbidity and mortality. The genetic status of at-risk family members can be clarified by molecular genetic testing, especially if the pathogenic variant has been identified in an affected family member, or by measurement of LDL cholesterol concentration.

The Familial Hypercholesterolemia (FH) Panel contains the following 4 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance 144010: AD Hypercholesterolemia, due to Comprehensive Cardiovascular; Familial APOB 107730 ligand-defective apo B AD, AR Hypercholesterolemia 615558: AR Hypobetalipoproteinemia Comprehensive Cardiovascular; Familial 143890: AD Hypercholesterolemia, familial LDLR 606945 AD Hypercholesterolemia 143890: AD LDL cholesterol level QTL2 Comprehensive Cardiovascular; Familial LDLRAP1 605747 603813: AR Hypercholesterolemia, familial, AR AR Hypercholesterolemia 603776: Hypercholesterolemia, familial, 3 Comprehensive Cardiovascular; Familial PCSK9 607786 603776: {Low density lipoprotein cholesterol None Hypercholesterolemia level QTL 1}

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive).

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PULMONARY HYPERTENSION (PAH) PANEL

Pulmonary arterial hypertension (PAH) is marked by obstruction of the small pulmonary arteries leading to an increase in resistance to blood flow through the . The abnormally elevated pressure in the pulmonary circulation system can lead to progressive heart failure with initial symptoms including dyspnea, fatigue, syncope, chest pain, palpitations, and leg edema. PAH can be heritable in an autosomal dominant form with identical signs and symptoms to PAH of unknown etiology. In some inherited instances, pathogenic variants that disrupt the assembly of bone morphogenetic protein receptors tend to exhibit a more severe phenotype. Continuous intravenous epoprostenol is standard care for individuals with life-threatening PAH. A small minority of individuals respond well to long term oral calcium channel blockers.

The Pulmonary Hypertension Panel contains the following 10 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; Hereditary 600376: AD Telangiectasia, hereditary ACVRL1 601284 Hemorrhagic Telangiectasia; Pulmonary AD hemorrhagic, type 2 Hypertension 609441: AR Acromesomelic dysplasia, Comprehensive Cardiovascular; Pulmonary Demirhan type BMPR1B 603248 AD, AR Hypertension 616849: AD Brachydactyly, type A1, D 112600: AD Brachydactyly, type A2 178600: AD Pulmonary hypertension, familial primary, 1, with or without HHT Comprehensive Cardiovascular; Pulmonary 178600: AD Pulmonary hypertension, primary, BMPR2 600799 AD Hypertension fenfluramine or dexfenfluramine-associated 265450: AD Pulmonary venoocclusive disease 1 612526: ?Lipodystrophy, congenital generalized, type 3 Comprehensive Cardiovascular; Pulmonary 606721: AD ?Partial lipodystrophy, congenital CAV1 601047 AD Hypertension cataracts, and neurodegeneration syndrome 615343: AD Pulmonary hypertension, primary, 3 Comprehensive Cardiovascular; Pulmonary 234810: AR Pulmonary venoocclusive disease EIF2AK4 609280 AR Hypertension 2 Comprehensive Cardiovascular; Hereditary 187300: AD Telangiectasia, hereditary ENG 131195 Hemorrhagic Telangiectasia; Pulmonary AD hemorrhagic, type 1 Hypertension Comprehensive Cardiovascular; Hereditary 615506: AD Telangiectasia, hereditary GDF2 605120 Hemorrhagic Telangiectasia; Pulmonary AD hemorrhagic, type 5 Hypertension Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; KCNA5 176267 612240: AD Atrial fibrillation, familial, 7 AD Comprehensive Arrythmias; Pulmonary Hypertension Comprehensive Cardiovascular; Pulmonary 615344: AD Pulmonary hypertension, primary, KCNK3 603220 AD Hypertension 4 Comprehensive Cardiovascular; Pulmonary 615342: AD Pulmonary hypertension, primary, SMAD9 603295 Hypertension 2 AD

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive).

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METABOLIC CARDIOMYOPATHY PANEL

Cardiometabolic syndrome is a constellation of metabolic dysfunction disorders characterized by insulin resistance, impaired glucose tolerance, atherogenic dyslipidemia, hypertension, intra-abdominal adiposity, and an overall clustering of these cardiovascular risk factors. Current approaches to the treatment of cardiometabolic syndrome include control of cardiovascular risk factors with an emphasis on regaining the balance between energy intake and expenditure. The highly heterogeneous nature of cardiometabolic conditions and overlapping phenotypes can challenge clinical assessment. Therefore, targeted gene panels utilizing next-generation sequencing can prove to be effective in prioritizing diagnosis of cardiometabolic conditions and may help distinguish patients who require further investigation.

The Metabolic Cardiomyopathy Panel contains the following 24 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; ACADVL 609575 Comprehensive Cardiomyopathy; Metabolic 201475: AR VLCAD deficiency AR Cardiomyopathy Comprehensive Cardiovascular; 232400: AR Glycogen storage disease IIIa AGL 610860 Comprehensive Cardiomyopathy; Hypertrophic AR Cardiomyopathy; Metabolic Cardiomyopathy 232400: AR Glycogen storage disease IIIb Comprehensive Cardiovascular; 608540: AR Congenital disorder of ALG1 605907 Comprehensive Cardiomyopathy; Metabolic AR glycosylation, type Ik Cardiomyopathy Comprehensive Cardiovascular; 607143: AR Congenital disorder of ALG12 607144 Comprehensive Cardiomyopathy; Metabolic AR glycosylation, type Ig Cardiomyopathy Comprehensive Cardiovascular; 253200: AR Mucopolysaccharidosis type VI ARSB 611542 Comprehensive Cardiomyopathy; Metabolic AR (Maroteaux-Lamy) Cardiomyopathy 600649: AR CPT II deficiency, infantile 608836: AR CPT II deficiency, lethal neonatal Comprehensive Cardiovascular; 255110: AR, AD CPT II deficiency, myopathic, CPT2 600650 Comprehensive Cardiomyopathy; Hypertrophic AD, AR stress-induced Cardiomyopathy; Metabolic Cardiomyopathy 614212: AR, AD {Encephalopathy, acute, infection-induced, 4, susceptibility to} Comprehensive Cardiovascular; 610768: AR Congenital disorder of DOLK 610746 Comprehensive Cardiomyopathy; Dilated AR glycosylation, type Im Cardiomyopathy; Metabolic Cardiomyopathy 613153: AR Muscular dystrophy- dystroglycanopathy (congenital with brain and eye anomalies), type A, 5 Comprehensive Cardiovascular; 606612: AR Muscular dystrophy- FKRP 606596 Comprehensive Cardiomyopathy; Metabolic AR dystroglycanopathy (congenital with or without Cardiomyopathy mental retardation), type B, 5 607155: AR Muscular dystrophy- dystroglycanopathy (limb-girdle), type C, 5 Comprehensive Cardiovascular; GAA 606800 Comprehensive Cardiomyopathy; Hypertrophic 232300: AR Glycogen storage disease II AR Cardiomyopathy; Metabolic Cardiomyopathy 608013: AR Gaucher disease, perinatal lethal 230800: AR Gaucher disease, type I 230900: AR Gaucher disease, type II Comprehensive Cardiovascular; 231000: AR Gaucher disease, type III AD, AR, IC, GBA 606463 Comprehensive Cardiomyopathy; Metabolic 231005: AR Gaucher disease, type IIIC MF Cardiomyopathy 127750: AD {Lewy body dementia, susceptibility to} 168600: IC, MF {Parkinson disease, late-onset, susceptibility to} Comprehensive Cardiovascular; 232500: AR Glycogen storage disease IV GBE1 607839 Comprehensive Cardiomyopathy; Metabolic 263570: AR Polyglucosan body disease, adult AR Cardiomyopathy form Comprehensive Cardiovascular; 301500: XL Fabry disease GLA 300644 Comprehensive Cardiomyopathy; Hypertrophic XL Cardiomyopathy; Metabolic Cardiomyopathy 301500: XL Fabry disease, cardiac variant GLB1 611458 Comprehensive Cardiovascular; 230500: AR GM1-gangliosidosis, type I AR

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Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiomyopathy; Metabolic 230600: AR GM1-gangliosidosis, type II Cardiomyopathy 230650: AR GM1-gangliosidosis, type III 253010: AR Mucopolysaccharidosis type IVB (Morquio) Comprehensive Cardiovascular; GUSB 611499 Comprehensive Cardiomyopathy; Metabolic 253220: AR Mucopolysaccharidosis VII AR Cardiomyopathy 609016: AR Fatty liver, acute, of pregnancy Comprehensive Cardiovascular; 609016: AR HELLP syndrome, maternal, of HADHA 600890 Comprehensive Cardiomyopathy; Metabolic pregnancy AR Cardiomyopathy 609016: AR LCHAD deficiency 609015: AR Trifunctional protein deficiency Comprehensive Cardiovascular; 268800: AR Sandhoff disease, infantile, HEXB 606873 Comprehensive Cardiomyopathy; Metabolic AR juvenile, and adult forms Cardiomyopathy Comprehensive Cardiovascular; 607014: AR Mucopolysaccharidosis Ih IDUA 252800 Comprehensive Cardiomyopathy; Metabolic 607015: AR Mucopolysaccharidosis Ih/s AR Cardiomyopathy 607016: AR Mucopolysaccharidosis Is Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated LAMP2 309060 Cardiomyopathy; Hypertrophic 300257: XLD Danon disease XLD Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathy Comprehensive Cardiovascular; 614702: AR Combined oxidative MTO1 614667 Comprehensive Cardiomyopathy; Metabolic AR phosphorylation deficiency 10 Cardiomyopathy Comprehensive Cardiovascular; PCCA 232000 Comprehensive Cardiomyopathy; Metabolic 606054: AR Propionicacidemia AR Cardiomyopathy Comprehensive Cardiovascular; PCCB 232050 Comprehensive Cardiomyopathy; Metabolic 606054: AR Propionicacidemia AR Cardiomyopathy Comprehensive Cardiovascular; 212140: AR Carnitine deficiency, systemic SLC22A5 603377 Comprehensive Cardiomyopathy; Dilated AR primary Cardiomyopathy; Metabolic Cardiomyopathy Comprehensive Cardiovascular; 212138: AR Carnitine-acylcarnitine translocase SLC25A20 613698 Comprehensive Cardiomyopathy; Metabolic AR deficiency Cardiomyopathy Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated TAZ 300394 302060: XLR Barth syndrome XLR Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathy

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. GBA: The following GBA hg19 coordinates have been excluded from this assay: chr1:155207120-155207380, chr1:155204774- 155204902, chr1:155208296-155208452 3. LAMP2: The following LAMP2 hg19 coordinates have been excluded from this assay: chrX:119604075-119604081

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NOONAN SPECTRUM DISORDERS PANEL

Noonan Spectrum Disorders (NSD), or RASopathies, are genetically heterogeneous developmental syndromes caused by heterozygous germline mutations in genes involved in the Ras/MAPK signaling pathway. This pathway is essential for regulation of the cell cycle, cell differentiation, and cellular growth. Noonan Spectrum Disorders occur in 1 in 1,000 to 1 in 2,500 live births. Performing postnatal genetic testing can be clinically useful for individuals that display characteristic features (cardiac abnormalities, specific facial dysmorphisms, developmental delay/, etc.), or prenatally for fetuses that present with certain ultrasound findings (, increased nuchal translucency, etc.) after a normal analysis.

The Noonan Spectrum Disorders Panel contains the following 18 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance 211980: Adenocarcinoma of lung, somatic 115150: AD Cardiofaciocutaneous syndrome Comprehensive Cardiovascular; Comprehensive Colorectal cancer, somatic (3) BRAF 164757 Cardiomyopathy; Congenital Heart Disease; Noonan 613707: AD LEOPARD syndrome 3 AD Spectrum Disorders Melanoma, malignant, somatic (3) Nonsmall cell lung cancer, somatic (3) 613706: AD Noonan syndrome 7 607785: AD, SM ?Juvenile myelomonocytic Comprehensive Cardiovascular; Comprehensive leukemia CBL 165360 Cardiomyopathy; Congenital Heart Disease; Noonan AD, SM 613563: AD Noonan syndrome-like disorder with or Spectrum Disorders without juvenile myelomonocytic leukemia 109800: {Bladder cancer, somatic} 218040: AD, IC Congenital myopathy with excess of muscle spindles 218040: AD, IC Costello syndrome Comprehensive Cardiovascular; Comprehensive 162900: {Nevus sebaceous or woolly hair nevus, HRAS 190020 Cardiomyopathy; Congenital Heart Disease; Noonan AD, IC somatic} Spectrum Disorders 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 137550: {Spitz nevus or nevus spilus, somatic} 188470: {Thyroid carcinoma, follicular, somatic} 108010: Arteriovenous malformation of the brain, somatic 109800: Bladder cancer, somatic 114480: Breast cancer, somatic 615278: Cardiofaciocutaneous syndrome 2 137215: Gastric cancer, somatic Comprehensive Cardiovascular; Comprehensive 601626: AD Leukemia, acute myeloid KRAS 190070 Cardiomyopathy; Congenital Heart Disease; Noonan AD 211980: Lung cancer, somatic Spectrum Disorders 609942: AD Noonan syndrome 3 260350: Pancreatic carcinoma, somatic 614470: AD RAS-associated autoimmune leukoproliferative disorder 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 616564: AD Noonan syndrome 10 LZTR1 600574 Noonan Spectrum Disorders AD 615670: AD {Schwannomatosis-2, susceptibility to} Comprehensive Cardiovascular; Comprehensive MAP2K1 176872 Cardiomyopathy; Congenital Heart Disease; Noonan 615279: Cardiofaciocutaneous syndrome 3 None Spectrum Disorders Comprehensive Cardiovascular; Comprehensive MAP2K2 601263 Cardiomyopathy; Congenital Heart Disease; Noonan 615280: Cardiofaciocutaneous syndrome 4 None Spectrum Disorders 607785: AD, SM Leukemia, juvenile myelomonocytic NF1 613113 Noonan Spectrum Disorders AD, SM 162210: AD , familial spinal 162200: AD Neurofibromatosis, type 1

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Gene MIM Disease Category OMIM Phenotype Inheritance 601321: AD Neurofibromatosis-Noonan syndrome 193520: AD 114500: Colorectal cancer, somatic 162900: Epidermal nevus, somatic 137550: Melanocytic nevus syndrome, congenital,

somatic Comprehensive Cardiovascular; Comprehensive 249400: Neurocutaneous melanosis, somatic NRAS 164790 Cardiomyopathy; Congenital Heart Disease; Noonan 613224: AD Noonan syndrome 6 AD Spectrum Disorders 614470: ?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 188470: Thyroid carcinoma, follicular, somatic 617506: AD Noonan syndrome-like disorder with PPP1CB 600590 Noonan Spectrum Disorders AD loose anagen hair 2 151100: AD LEOPARD syndrome 1 Comprehensive Cardiovascular; Comprehensive 607785: Leukemia, juvenile myelomonocytic, Cardiomyopathy; Congenital Heart Disease; PTPN11 176876 somatic AD Hypertrophic Cardiomyopathy; Noonan Spectrum 156250: AD Metachondromatosis Disorders 163950: AD Noonan syndrome 1 Comprehensive Cardiovascular; Comprehensive 615916: AD Cardiomyopathy, dilated, 1NN Cardiomyopathy; Congenital Heart Disease; Dilated RAF1 164760 611554: LEOPARD syndrome 2 AD Cardiomyopathy; Hypertrophic Cardiomyopathy; 611553: AD Noonan syndrome 5 Noonan Spectrum Disorders RASA2 601589 Noonan Spectrum Disorders None None Comprehensive Cardiovascular; Comprehensive RIT1 609591 Cardiomyopathy; Congenital Heart Disease; Noonan 615355: AD Noonan syndrome 8 AD Spectrum Disorders Comprehensive Cardiovascular; Comprehensive 607721: AD Noonan-like syndrome with loose SHOC2 602775 Cardiomyopathy; Congenital Heart Disease; Noonan AD anagen hair Spectrum Disorders Comprehensive Cardiovascular; Comprehensive 135300: AD ?Fibromatosis, gingival, 1 SOS1 182530 Cardiomyopathy; Congenital Heart Disease; Noonan AD 610733: AD Noonan syndrome 4 Spectrum Disorders SOS2 601247 Noonan Spectrum Disorders 616559: AD Noonan syndrome 9 AD SPRED1 609291 Noonan Spectrum Disorders 611431: AD AD

6. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 7. RASA2: The following RASA2 hg19 coordinates have been excluded from this assay: chr3:141235158-141235284.

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HEREDITARY HEMORRHAGIC TELANGIECTASIA PANEL

This group comprises genes with cardiac-related disease involvement that cannot be readily classified in the preceding groups that is often part of a constellation of findings associated with syndromic features.

The Hereditary Hemorrhagic Telangiectasia Panel contains the following 5 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance Comprehensive Cardiovascular; Hereditary 600376: AD Telangiectasia, hereditary ACVRL1 601284 Hemorrhagic Telangiectasia; Pulmonary AD hemorrhagic, type 2 Hypertension Comprehensive Cardiovascular; Hereditary 187300: AD Telangiectasia, hereditary ENG 131195 Hemorrhagic Telangiectasia; Pulmonary AD Hypertension hemorrhagic, type 1 Comprehensive Cardiovascular; Hereditary 615506: AD Telangiectasia, hereditary GDF2 605120 Hemorrhagic Telangiectasia; Pulmonary AD hemorrhagic, type 5 Hypertension 605462: Basal cell carcinoma, somatic Comprehensive Cardiovascular; 608354: AD Capillary malformation- RASA1 139150 Comprehensive Cardiomyopathy; Hereditary AD Hemorrhagic Telangiectasia arteriovenous malformation 608355: AD Parkes Weber syndrome 175050: AD Juvenile polyposis/hereditary Comprehensive Cardiovascular; hemorrhagic telangiectasia syndrome SMAD4 600993 Comprehensive Cardiomyopathy; Aortopathies; 139210: AD Myhre syndrome AD Hereditary Hemorrhagic Telangiectasia 260350: Pancreatic cancer, somatic 174900: AD Polyposis, juvenile intestinal

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive).

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References

General References:

1. Pua JC, et al. Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes. J Cardiovasc Transl Res. 2016 Feb;9(1):3-11. 2. Cirino AL, et al. Role of Genetic Testing in Inherited Cardiovascular Disease: A Review. JAMA Cardiol. 2017 Oct 1;2(10):1153-1160. 3. Mital S, et al. Enhancing Literacy in Cardiovascular Genetics: A Scientific Statement From the American Heart Association. Circ Cardiovasc Genet. 2016 Oct;9(5):448-467. 4. Nadar SK and Sandhu K. Genes and Cardiovascular Disease: Where do we go from here? Sultan Qaboos Univ Med J. 2015 Nov;15(4):e448-51. 5. Kathiresan S and Srivastava D. Genetics of human cardiovascular disease. Cell. 2012 Mar 16;148(6):1242-57. 6. Celestino-Soper PB, et al. Validation and Utilization of a Clinical Next-Generation Sequencing Panel for Selected Cardiovascular Disorders. Front Cardiovasc Med. 2017 Mar 15;4:11. http://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) 7. Lee KA, Williams B, Roza K, Ferguson H, David K, Eddleman K, Stone J, Edelmann L, Richard G, Gelb BD, Kornreich R. PTPN11 analysis for the prenatal diagnosis of Noonan syndrome in fetuses with abnormal ultrasound findings. Clin Genet. 2009 Feb;75(2):190-4. doi: 10.1111/j.1399-0004.2008.01085.x. Epub 2008 Aug 26. PMID: 18759865 8. Croonen EA, Nillesen WM, Stuurman KE, Oudesluijs G, van de Laar IM, Martens L, Ockeloen C, Mathijssen IB, Schepens M, Ruiterkamp-Versteeg M, Scheffer H, Faas BH, van der Burgt I, Yntema HG. Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings. Eu r J Hum Genet. 2013 Sep;21(9):936-42. doi: 10.1038/ejhg.2012.285. Epub 2013 Jan 16. PMID: 23321623

Gene-Specific References:

1. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT,Goldstein SA. MiRP1 forms IKr potassium channels with HERG and is associated withcardiac arrhythmia. Cell. 1999 Apr 16;97(2):175-87. PubMed PMID: 10219239. 2. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucl er I,Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, PratA, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomaldominant hypercholesterolemia. Nat Genet. 2003 Jun;34(2):154-6. PubMed PMID:12730697. 3. Adegbola A, Musante L, Callewaert B, Maciel P, Hu H, Isidor B, Picker-Minh S, Le Caignec C, Delle Chiaie B, Vanakker O, Menten B, Dheedene A, Bockaert N,Roelens F, Decaestecker K, Silva J, Soares G, Lopes F, Najmabadi H, Kahrizi K,Cox GF, Angus SP, Staropoli JF, Fischer U, Suckow V, Bartsch O, Chess A, RopersHH, Wienker TF, Hübner C, Kaindl AM, Kalscheuer VM. Redefining the MED13Lsyndrome. Eur J Hum Genet. 2015 Oct;23(10):1308-17. doi: 10.1038/ejhg.2015.26.Epub 2015 Mar 11. PubMed PMID: 25758992; PubMed Central PMCID: PMC4592099. 4. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in theglucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2004 Nov 4;351(19):1972- 7. PubMed PMID: 15525722. 5. Al Turki S, Manickaraj AK, Mercer CL, Gerety SS, Hitz MP, Lindsay S,D'Alessandro LC, Swaminathan GJ, Bentham J, Arndt AK, Louw J, Breckpot J,Gewillig M, Thienpont B, Abdul- Khaliq H, Harnack C, Hoff K, Kramer HH, SchubertS, Siebert R, Toka O, Cosgrove C, Watkins H, Lucassen AM, O'Kelly IM, Salmon AP, Bu'lock FA, Granados-Riveron J, Setchfield K, Thornborough C, Brook JD, Mulder B,Klaassen S, Bhattacharya S, Devriendt K, Fitzpatrick DF; UK10K Consortium, WilsonDI, Mital S, Hurles ME. Rare variants in NR2F2 cause congenital heart defects in humans. Am J Hum Genet. 2014 Apr 3;94(4):574-85. doi: 10.1016/j.ajhg.2014.03.007.Erratum in: Am J Hum Genet. 2016 Mar 3;98(3):592. Low, Jacoba [corrected to Louw,Jacoba]. Am J Hum Genet. 2014 Jul 3;95(1):126. PubMed PMID: 24702954; PubMedCentral PMCID: PMC3980509. 6. Aldahmesh MA, Khan AO, Mohamed JY, Alghamdi MH, Alkuraya FS. Identification ofa truncation mutation of acylglycerol (AGK) gene in a novel autosomalrecessive cataract locus. Hum Mutat. 2012 Jun;33(6):960-2. doi:10.1002/humu.22071. Epub 2012 Apr 16. PubMed PMID: 22415731. 7. Almomani R, Verhagen JM, Herkert JC, Brosens E, van Spaendonck-Zwarts KY,Asimaki A, van der Zwaag PA, Frohn-Mulder IM, Bertoli-Avella AM, Boven LG, vanSlegtenhorst MA, van der Smagt JJ, van IJcken WF, Timmer B, van Stuijvenberg M,Verdijk RM, Saffitz JE, du Plessis FA, Michels M, Hofstra RM, Sinke RJ, vanTintelen JP, Wessels MW, Jongbloed JD, van de Laar IM. Biallelic TruncatingMutations in ALPK3 Cause Severe Pediatric Cardiomyopathy. J Am Coll Cardiol. 2016Feb 9;67(5):515-25. doi: 10.1016/j.jacc.2015.10.093. PubMed PMID: 26846950. 8. Anderson SL, Chung WK, Frezzo J, Papp JC, Ekstein J, DiMauro S, Rubin BY. Anovel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family. JInherit Metab Dis. 2008 Dec;31 Suppl 2:S461-7. doi: 10.1007/s10545-008-1049-9.Epub 2008 Dec 26. PubMed PMID: 19107570. 9. Andresen BS, Bross P, Vianey-Saban C, Divry P, Zabot MT, Roe CR, Nada MA,Byskov A, Kruse TA, Neve S, Kristiansen K, Knudsen I, Corydon MJ, Gregersen N.Cloning and characterization of human very-long-chain acyl-CoA dehydrogenasecDNA, chromosomal assignment of the gene and identification in four patients ofnine different mutations within the VLCAD gene. Hum Mol Genet. 1996Apr;5(4):461-72. Erratum in: Hum Mol Genet 1996 Sep;5(9):1390. PubMed PMID:8845838. 10. Antonicka H, Leary SC, Guercin GH, Agar JN, Horvath R, Kennaway NG, HardingCO, Jaksch M, Shoubridge EA. Mutations in COX10 result in a defect inmitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum Mol Genet. 2003 Oct15;12(20):2693-702. Epub 2003 Aug 19. PubMed PMID: 12928484. 11. Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, KennawayNG, Shoubridge EA. Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am JHum Genet. 2003 Jan;72(1):101-14. Epub 2002 Dec 9. PubMed PMID: 12474143; PubMed Central PMCID: PMC378614. 12. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EP Jr,Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu LF,Haïssaguerre M, Schimpf R, Borggrefe M, Wolpert C. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized byST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007 Jan 30;115(4):442-9. Epub 2007 Jan 15. PubMed PMID: 17224476; PubMed CentralPMCID: PMC1952683. 13. Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, TakadaF, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S,Watanabe Y, Ogura T, Matsubara Y. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013 Jul 11;93(1):173-80. doi: 10.1016/j.ajhg.2013.05.021. Epub 2013 Jun 20. PubMed PMID: 23791108; PubMed Central PMCID: PMC3710767. 14. Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, TakadaF, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S,Watanabe Y, Ogura T, Matsubara Y. Gain-of-function mutations in RIT1 cause Noonansyndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013 Jul 11;93(1):173-80. doi: 10.1016/j.ajhg.2013.05.021. Epub 2013 Jun 20. PubMed PMID: 23791108; PubMed Central PMCID: PMC3710767. 15. Arndt AK, Schafer S, Drenckhahn JD, Sabeh MK, Plovie ER, Caliebe A, KlopockiE, Musso G, Werdich AA, Kalwa H, Heinig M, Padera RF, Wassilew K, Bluhm J,Harnack C, Martitz J, Barton PJ, Greutmann M, Berger F, Hubner N, Siebert R,Kramer HH, Cook SA, MacRae CA, Klaassen S. Fine mapping of the 1p36 deletionsyndrome identifies mutation of PRDM16 as a cause of cardiomyopathy. Am J HumGenet. 2013 Jul 11;93(1):67-77. doi: 10.1016/j.ajhg.2013.05.015. Epub 2013 Jun13. PubMed PMID: 23768516; PubMed Central PMCID: PMC3710750. 16. Awad MM, Dalal D, Cho E, Amat-Alarcon N, James C, Tichnell C, Tucker A,Russell SD, Bluemke DA, Dietz HC, Calkins H, Judge DP. DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Hum Genet.2006 Jul;79(1):136-42. Epub 2006 Apr 28. PubMed PMID: 16773573; PubMed CentralPMCID: PMC1474134. 17. Bagnall RD, Yeates L, Semsarian C. Analysis of the Z-disc genes PDLIM3 andMYPN in patients with hypertrophic cardiomyopathy. Int J Cardiol. 2010 Dec3;145(3):601-2. doi: 10.1016/j.ijcard.2010.08.004. PubMed PMID: 20801532. 18. Bao Y, Kishnani P, Wu JY, Chen YT. Hepatic and neuromuscular forms of glycogenstorage disease type IV caused by mutations in the same glycogen-branching enzymegene. J Clin Invest. 1996 Feb 15;97(4):941-8. PubMed PMID: 8613547; PubMedCentral PMCID: PMC507139. 19. Barbier M, Gross MS, Aubart M, Hanna N, Kessler K, Guo DC, Tosolini L,Ho-Tin-Noe B, Regalado E, Varret M, Abifadel M, Milleron O, Odent S, Dupuis-GirodS, Faivre L, Edouard T, Dulac Y, Busa T, Gouya L, Milewicz DM, Jondeau G, BoileauC. MFAP5 loss-of-function mutations underscore the involvement of matrixalteration in the pathogenesis of familial thoracic aortic aneurysms anddissections. Am J Hum Genet. 2014 Dec 4;95(6):736-43. doi:10.1016/j.ajhg.2014.10.018. Epub 2014 Nov 26. PubMed PMID: 25434006; PubMedCentral PMCID: PMC4259978. 20. Barghuti F, Elian K, Gomori JM, Shaag A, Edvardson S, Saada A, Elpeleg O. The unique neuroradiology of complex I deficiency due to NDUFA12L defect. Mol GenetMetab. 2008 May;94(1):78-82. doi: 10.1016/j.ymgme.2007.11.013. Epub 2008 Jan 3.PubMed PMID: 18180188. 21. Baruffini E, Dallabona C, Invernizzi F, Yarham JW, Melchionda L, Blakely EL,Lamantea E, Donnini C, Santra S, Vijayaraghavan S, Roper HP, Burlina A, KopajtichR, Walther A, Strom TM, Haack TB, Prokisch H, Taylor RW, Ferrero I, Zeviani M,Ghezzi D. MTO1 mutations are associated with hypertrophic cardiomyopathy andlactic acidosis and cause respiratory chain deficiency in humans and yeast. HumMutat. 2013 Nov;34(11):1501-9. doi: 10.1002/humu.22393. Epub 2013 Sep 17. PubMed PMID: 23929671; PubMed Central PMCID: PMC4028987. 22. Baskin B, Skinner JR, Sanatani S, Terespolsky D, Krahn AD, Ray PN, Scherer SW,Hamilton RM. TMEM43 mutations associated with arrhythmogenic right ventricularcardiomyopathy in non-Newfoundland populations. Hum Genet. 2013Nov;132(11):1245-52. doi: 10.1007/s00439-013-1323-2. Epub 2013 Jun 29. PubMedPMID: 23812740.

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23. Baumann M, Giunta C, Krabichler B, Rüschendorf F, Zoppi N, Colombi M, Bittner RE, Quijano-Roy S, Muntoni F, Cirak S, Schreiber G, Zou Y, Hu Y, Romero NB,Carlier RY, Amberger A, Deutschmann A, Straub V, Rohrbach M, Steinmann B, RostásyK, Karall D, Bönnemann CG, Zschocke J, Fauth C. Mutations in FKBP14 cause avariant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. Am J Hum Genet. 2012 Feb 10;90(2):201-16. doi:10.1016/j.ajhg.2011.12.004. Epub 2012 Jan 19. PubMed PMID: 22265013; PubMedCentral PMCID: PMC3276673. 24. Beffagna G, Occhi G, Nava A, Vitiello L, Ditadi A, Basso C, Bauce B, CarraroG, Thiene G, Towbin JA, Danieli GA, Rampazzo A. Regulatory mutations intransforming growth factor- beta3 gene cause arrhythmogenic right ventricularcardiomyopathy type 1. Cardiovasc Res. 2005 Feb 1;65(2):366-73. PubMed PMID:15639475. 25. Beltran-Valero de Bernabé D, Voit T, Longman C, Steinbrecher A, Straub V, YuvaY, Herrmann R, Sperner J, Korenke C, Diesen C, Dobyns W B, Brunner HG, vanBokhoven H, Brockington M, Muntoni F. Mutations in the FKRP gene can causemuscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet. 2004May;41(5):e61. PubMed PMID: 15121789; PubMed Central PMCID: PMC1735772. 26. Berry V, Francis P, Reddy MA, Collyer D, Vithana E, MacKay I, Dawson G, Carey AH, Moore A, Bhattacharya SS, Quinlan RA. Alpha-B crystallin gene (CRYAB)mutation causes dominant congenital posterior polar cataract in humans. Am J Hum Genet. 2001 Nov;69(5):1141-5. Epub 2001 Sep 27. PubMed PMID: 11577372; PubMedCentral PMCID: PMC1274358. 27. Best DH, Sumner KL, Austin ED, Chung WK, Brown LM, Borczuk AC, Rosenzweig EB, Bayrak-Toydemir P, Mao R, Cahill BC, Tazelaar HD, Leslie KO, Hemnes AR, RobbinsIM, Elliott CG. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest. 2014 Feb;145(2):231-236. doi: 10.1378/chest.13-2366. PubMed PMID: 24135949;PubMed Central PMCID: PMC3921094. 28. Betz RC, Schoser BG, Kasper D, Ricker K, Ramírez A, Stein V, Torbergsen T, LeeYA, Nöthen MM, Wienker TF, Malin JP, Propping P, Reis A, Mortier W, Jentsch TJ,Vorgerd M, Kubisch C. Mutations in CAV3 cause mechanical hyperirritability ofskeletal muscle in rippling muscle disease. Nat Genet. 2001 Jul;28(3):218-9.PubMed PMID: 11431690. 29. Bienengraeber M, Olson TM, Selivanov VA, Kathmann EC, O'Cochlain F, Gao F,Karger AB, Ballew JD, Hodgson DM, Zingman LV, Pang YP, Alekseev AE, Terzic A.ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATPchannel gating. Nat Genet. 2004 Apr;36(4):382-7. Epub 2004 Mar 21. PubMed PMID:15034580; PubMed Central PMCID: PMC1995438. 30. Bione S, D'Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D. A novelX-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet. 1996Apr;12(4):385-9. PubMed PMID: 8630491. 31. Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, Toniolo D.Identification of a novel X-linked gene responsible for Emery-Dreifuss musculardystrophy. Nat Genet. 1994 Dec;8(4):323-7. PubMed PMID: 7894480. 32. Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L, Varret M, Prakash SK, Li AH, d'Indy H, Braverman AC, Grandchamp B, Kwartler CS, Gouya L,Santos-Cortez RL, Abifadel M, Leal SM, Muti C, Shendure J, Gross MS, Rieder MJ,Vahanian A, Nickerson DA, Michel JB; National Heart, Lung, and Blood Institute(NHLBI) Go Exome Sequencing Project, Jondeau G, Milewicz DM. TGFB2 mutationscause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 2012 Jul 8;44(8):916- 21. doi:10.1038/ng.2348. PubMed PMID: 22772371; PubMed Central PMCID: PMC4033668. 33. Bonne G, Carrier L, Bercovici J, Cruaud C, Richard P, Hainque B, Gautel M,Labeit S, James M, Beckmann J, Weissenbach J, Vosberg HP, Fiszman M, Komajda M,Schwartz K. Cardiac myosin binding protein-C gene splice acceptor site mutationis associated with familial hypertrophic cardiomyopathy. Nat Genet. 1995Dec;11(4):438-40. PubMed PMID: 7493026. 34. Bonne G, Di Barletta MR, Varnous S, Bécane HM, Hammouda EH, Merlini L, MuntoniF, Greenberg CR, Gary F, Urtizberea JA, Duboc D, Fardeau M, Toniolo D, SchwartzK. Mutations in the gene encoding A/C cause autosomal dominantEmery-Dreifuss muscular dystrophy. Nat Genet. 1999 Mar;21(3):285-8. PubMed PMID: 10080180. 35. Borozdin W, Bravo-Ferrer Acosta AM, Seemanova E, Leipoldt M, Bamshad MJ, UngerS, Kohlhase J. Contiguous hemizygous deletion of TBX5, TBX3, and RBM19 resulting in a combined phenotype of Holt-Oram and ulnar-mammary syndromes. Am J Med Genet A. 2006 Sep 1;140A(17):1880-6. PubMed PMID: 16892408. 36. Brauch KM, Karst ML, Herron KJ, de Andrade M, Pellikka PA, Rodeheffer RJ,Michels VV, Olson TM. Mutations in ribonucleic acid binding protein gene causefamilial dilated cardiomyopathy. J Am Coll Cardiol. 2009 Sep 1;54(10):930-41.doi: 10.1016/j.jacc.2009.05.038. PubMed PMID: 19712804; PubMed Central PMCID:PMC2782634. 37. Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R,Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A,Legius E. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis1-like phenotype. Nat Genet. 2007 Sep;39(9):1120-6. Epub 2007 Aug 19. PubMedPMID: 17704776. 38. Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S, Benson MA, PontingCP, Estournet B, Romero NB, Mercuri E, Voit T, Sewry CA, Guicheney P, Muntoni F. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenitalmuscular dystrophy with secondary laminin alpha2 deficiency and abnormalglycosylation of alpha-. Am J Hum Genet. 2001 Dec;69(6):1198-209.Epub 2001 Oct 8. PubMed PMID: 11592034; PubMed Central PMCID: PMC1235559. 39. Burashnikov E, Pfeiffer R, Barajas-Martinez H, Delpón E, Hu D, Desai M,Borggrefe M, Häissaguerre M, Kanter R, Pollevick GD, Guerchicoff A, Laiño R,Marieb M, Nademanee K, Nam GB, Robles R, Schimpf R, Stapleton DD, Viskin S,Winters S, Wolpert C, Zimmern S, Veltmann C, Antzelevitch C. Mutations in thecardiac L-type calcium channel associated with inherited J-wave syndromes andsudden cardiac death. Heart Rhythm. 2010 Dec;7(12):1872-82. doi:10.1016/j.hrthm.2010.08.026. Epub 2010 Oct 14. PubMed PMID: 20817017; PubMedCentral PMCID: PMC2999985. 40. Bénit P, Slama A, Cartault F, Giurgea I, Chretien D, Lebon S, Marsac C,Munnich A, Rötig A, Rustin P. Mutant NDUFS3 subunit of mitochondrial complex Icauses Leigh syndrome. J Med Genet. 2004 Jan;41(1):14-7. PubMed PMID: 14729820;PubMed Central PMCID: PMC1757256. 41. Callewaert BL, Willaert A, Kerstjens-Frederikse WS, De Backer J, Devriendt K, Albrecht B, Ramos-Arroyo MA, Doco-Fenzy M, Hennekam RC, Pyeritz RE, Krogmann ON, Gillessen- kaesbach G, Wakeling EL, Nik-zainal S, Francannet C, Mauran P, Booth C,Barrow M, Dekens R, Loeys BL, Coucke PJ, De Paepe AM. Arterial tortuositysyndrome: clinical and molecular findings in 12 newly identified families. HumMutat. 2008 Jan;29(1):150-8. PubMed PMID: 17935213. 42. Cao H, Alston L, Ruschman J, Hegele RA. Heterozygous CAV1 frameshift mutations(MIM 601047) in patients with atypical partial lipodystrophy andhypertriglyceridemia. Lipids Health Dis. 2008 Jan 31;7:3. doi:10.1186/1476-511X-7-3. PubMed PMID: 18237401; PubMed Central PMCID: PMC2276215. 43. Carballo S, Robinson P, Otway R, Fatkin D, Jongbloed JD, de Jonge N, Blair E, van Tintelen JP, Redwood C, Watkins H. Identification and functionalcharacterization of cardiac I as a novel disease gene in autosomaldominant dilated cardiomyopathy. Circ Res. 2009 Aug 14;105(4):375-82. doi:10.1161/CIRCRESAHA.109.196055. Epub 2009 Jul 9. PubMed PMID: 19590045. 44. Carbone I, Bruno C, Sotgia F, Bado M, Broda P, Masetti E, Panella A, Zara F,Bricarelli FD, Cordone G, Lisanti MP, Minetti C. Mutation in the CAV3 gene causespartial caveolin-3 deficiency and hyperCKemia. Neurology. 2000 Mar28;54(6):1373-6. PubMed PMID: 10746614. 45. Carmignac V, Salih MA, Quijano-Roy S, Marchand S, Al Rayess MM, Mukhtar MM,Urtizberea JA, Labeit S, Guicheney P, Leturcq F, Gautel M, Fardeau M, CampbellKP, Richard I, Estournet B, Ferreiro A. C-terminal deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol. 2007Apr;61(4):340-51. Erratum in: Ann Neurol. 2012 May;71(5):728. PubMed PMID:17444505. 46. Carniel E, Taylor MR, Sinagra G, Di Lenarda A, Ku L, Fain PR, Boucek MM,Cavanaugh J, Miocic S, Slavov D, Graw SL, Feiger J, Zhu XZ, Dao D, Ferguson DA,Bristow MR, Mestroni L. Alpha-myosin heavy chain: a sarcomeric gene associatedwith dilated and hypertrophic phenotypes of cardiomyopathy. Circulation. 2005 Jul5;112(1):54-9. PubMed PMID: 15998695. 47. Cecconi M, Parodi MI, Formisano F, Spirito P, Autore C, Musumeci MB, Favale S,Forleo C, Rapezzi C, Biagini E, Davì S, Canepa E, Pennese L, Castagnetta M,Degiorgio D, Coviello DA. Targeted next-generation sequencing helps to decipherthe genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy. Int JMol Med. 2016 Oct;38(4):1111-24. doi: 10.3892/ijmm.2016.2732. Epub 2016 Sep 7.PubMed PMID: 27600940; PubMed Central PMCID: PMC5029966. 48. Cetin N, Balci-Hayta B, Gundesli H, Korkusuz P, Purali N, Talim B, Tan E,Selcen D, Erdem-Ozdamar S, Dincer P. A novel mutation leading to autosomalrecessive limb-girdle muscular dystrophy: distinct histopathological outcomescompared with desminopathies. J Med Genet. 2013 Jul;50(7):437-43. doi:10.1136/jmedgenet-2012-101487. Epub 2013 May 18. PubMed PMID: 23687351. 49. Chantret I, Dupré T, Delenda C, Bucher S, Dancourt J, Barnier A, Charollais A,Heron D, Bader-Meunier B, Danos O, Seta N, Durand G, Oriol R, Codogno P, MooreSE. Congenital disorders of glycosylation type Ig is defined by a deficiency indolichyl-P-mannose:Man7GlcNAc2-PP-dolichyl . J Biol Chem. 2002Jul 12;277(28):25815-22. Epub 2002 Apr 30. PubMed PMID: 11983712. 50. Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG,Garg A, Hanson NB, Martin GM, Mian IS, Kennedy BK, Oshima J. LMNA mutations inatypical Werner's syndrome. Lancet. 2003 Aug 9;362(9382):440-5. PubMed PMID:12927431. 51. Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS. Mutation ofan A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20990-5. Epub 2007 Dec 19. PubMed PMID: 18093912; PubMedCentral PMCID: PMC2409254. 52. Chen PC, Yin J, Yu HW, Yuan T, Fernandez M, Yung CK, Trinh QM, Peltekova VD,Reid JG, Tworog -Dube E, Morgan MB, Muzny DM, Stein L, McPherson JD, Roberts AE,Gibbs RA, Neel BG, Kucherlapati R. Next-generation sequencing identifies rarevariants associated with Noonan syndrome. Proc Natl Acad Sci U S A. 2014 Aug5;111(31):11473-8. doi: 10.1073/pnas.1324128111. Epub 2014 Jul 21. PubMed PMID:25049390; PubMed Central PMCID: PMC4128129. 53. Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y,Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G,Åkerström G, Wang W, Carling T, Lifton RP. K+ channel mutations in adrenalaldosterone-producing adenomas and hereditary hypertension. Science. 2011 Feb11;331(6018):768-72. doi: 10.1126/science.1198785. PubMed PMID: 21311022; PubMed Central PMCID: PMC3371087. 54. Colige A, Sieron AL, Li SW, Schwarze U, Petty E, Wertelecki W, Wilcox W,Krakow D, Cohn DH, Reardon W, Byers PH, Lapière CM, Prockop DJ, Nusgens BV. HumanEhlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused bymutations in the procollagen I N-proteinase gene. Am J Hum Genet. 1999Aug;65(2):308-17. PubMed PMID: 10417273; PubMed Central PMCID: PMC1377929. 55. Crane AM, Ledley FD. Clustering of mutations in methylmalonyl CoA mutaseassociated with mut- methylmalonic acidemia. Am J Hum Genet. 1994Jul;55(1):42-50. PubMed PMID: 7912889; PubMed Central PMCID: PMC1918235. 56. Crotti L, Johnson CN, Graf E, De Ferrari GM, Cuneo BF, Ovadia M, PapagiannisJ, Feldkamp MD, Rathi SG, Kunic JD, Pedrazzini M, Wieland T, Lichtner P, BeckmannBM, Clark T, Shaffer C, Benson DW, Kääb S, Meitinger T, Strom TM, Chazin WJ,Schwartz PJ, George AL Jr. mutations associated with recurrent cardiacarrest in infants. Circulation. 2013 Mar 5;127(9):1009-17. doi:10.1161/CIRCULATIONAHA.112.001216. Epub 2013 Feb 6. PubMed PMID: 23388215; PubMedCentral PMCID: PMC3834768. 57. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. Amolecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.Cell. 1995 Mar 10;80(5):795-803. PubMed PMID: 7889573.

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58. Cízková A, Stránecký V, Mayr JA, Tesarová M, Havlícková V, Paul J, Ivánek R,Kuss AW, Hansíková H, Kaplanová V, Vrbacký M, Hartmannová H, Nosková L, Honzík T,Drahota Z, Magner M, Hejzlarová K, Sperl W, Zeman J, Houstek J, Kmoch S. TMEM70mutations cause isolated ATP synthase deficiency and neonatal mitochondrialencephalocardiomyopathy. Nat Genet. 2008 Nov;40(11):1288-90. doi: 10.1038/ng.246.Epub 2008 Oct 26. PubMed PMID: 18953340. 59. Dasgupta C, Martinez AM, Zuppan CW, Shah MM, Bailey LL, Fletcher WH.Identification of connexin43 (alpha1) gap junction gene mutations in patientswith hypoplastic left heart syndrome by denaturing gradient gel electrophoresis(DGGE). Mutat Res. 2001 Aug 8;479(1-2):173-86. PubMed PMID: 11470490. 60. Davis JS, Hassanzadeh S, Winitsky S, Lin H, Satorius C, Vemuri R, Aletras AH, Wen H, Epstein ND. The overall pattern of cardiac contraction depends on aspatial gradient of myosin regulatory light chain phosphorylation. Cell. 2001 Nov30;107(5):631-41. PubMed PMID: 11733062. 61. De Bortoli M, Beffagna G, Bauce B, Lorenzon A, Smaniotto G, Rigato I, CaloreM, Li Mura IE, Basso C, Thiene G, Lanfranchi G, Danieli GA, Nava A, Rampazzo A.The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutationin arrhythmogenic right ventricular cardiomyopathy. Eur J Hum Genet. 2010Jul;18(7):776-82. doi: 10.1038/ejhg.2010.19. Epub 2010 Mar 3. PubMed PMID:20197793; PubMed Central PMCID: PMC2987370. 62. De Sandre-Giovannoli A, Chaouch M, Kozlov S, Vallat JM, Tazir M, Kassouri N,Szepetowski P, Hammadouche T, Vandenberghe A, Stewart CL, G rid D, Lévy N.Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, causeautosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type2) and mouse. Am J Hum Genet. 2002 Mar;70(3):726-36. Epub 2002 Jan 17. Erratumin: Am J Hum Genet 2002 Apr;70(4):1075. PubMed PMID: 11799477; PubMed CentralPMCID: PMC384949. 63. Del Bigio MR, Chudley AE, Sarnat HB, Campbell C, Goobie S, Chodirker BN,Selcen D. Infantile muscular dystrophy in Canadian aboriginals is anαB-crystallinopathy. Ann Neurol. 2011 May;69(5):866-71. doi: 10.1002/ana.22331.Epub 2011 Feb 18. PubMed PMID: 21337604; PubMed Central PMCID: PMC3085857. 64. Delpón E, Cordeiro JM, Núñez L, Thomsen PE, Guerchicoff A, Pollevick GD, Wu Y,Kanters JK, Larsen CT, Hofman -Bang J, Burashnikov E, Christiansen M, AntzelevitchC. Functional effects of KCNE3 mutation and its role in the development ofBrugada syndrome. Circ Arrhythm Electrophysiol. 2008 Aug;1(3):209-18. doi:10.1161/CIRCEP.107.748103. Erratum in: Circ Arrhythm Electrophysiol. 2008Aug;1(3):e2. Hofman-Bang, Jacob [added]. PubMed PMID: 19122847; PubMed CentralPMCID: PMC2585750. 65. Demirhan O, Türkmen S, Schwabe GC, Soyupak S, Akgül E, Tastemir D, Karahan D, Mundlos S, Lehmann K. A homozygous BMPR1B mutation causes a new subtype ofacromesomelic chondrodysplasia with genital anomalies. J Med Genet. 2005Apr;42(4):314-7. PubMed PMID: 15805157; PubMed Central PMCID: PMC1736042. 66. Den Dunnen JT, Grootscholten PM, Bakker E, Blonden LA, Ginjaar HB, WapenaarMC, van Paassen HM, van Broeckhoven C, Pearson PL, van Ommen GJ. Topography ofthe Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 casesreveals 115 deletions and 13 duplications. Am J Hum Genet. 1989 Dec;45(6):835-47.PubMed PMID: 2573997; PubMed Central PMCID: PMC1683480. 67. Desviat LR, Clavero S, Perez-Cerdá C, Navarrete R, Ugarte M, Perez B. Newsplicing mutations in propionic acidemia. J Hum Genet. 2006;51(11):992-7. Epub2006 Oct 19. PubMed PMID: 17051315. 68. Di Natale P, Villani GR, Di Domenico C, Daniele A, Dionisi Vici C, Bartuli A. Analysis of Sanfilippo A gene mutations in a large pedigree. Clin Genet. 2003Apr;63(4):314-8. PubMed PMID: 12702166. 69. Donaldson MR, Jensen JL, Tristani-Firouzi M, Tawil R, Bendahhou S, Suarez WA, Cobo AM, Poza JJ, Behr E, Wagstaff J, Szepetowski P, Pereira S, Mozaffar T,Escolar DM, Fu YH, Ptácek LJ. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology. 2003 Jun 10;60(11):1811-6.PubMed PMID: 12796536. 70. Douglas J, Hanks S, Temple IK, Davies S, Murray A, Upadhyaya M, Tomkins S,Hughes HE, Cole TR, Rahman N. NSD1 mutations are the major cause of Sotossyndrome and occur in some cases of Weaver syndrome but are rare in otherovergrowth phenotypes. Am J Hum Genet. 2003 Jan;72(1):132-43. Epub 2002 Dec 2.PubMed PMID: 12464997; PubMed Central PMCID: PMC378618. 71. Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, Gillis E,Mortier G, Homfray T, Sauls K, Norris RA, Huso ND, Leahy D, Mohr DW, CaulfieldMJ, Scott AF, Destrée A, Hennekam RC, Arn PH, Curry CJ, Van Laer L, McCallion AS,Loeys BL, Dietz HC. Mutations in the TGF-β SKI causeShprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet. 2012Nov;44(11):1249-54. doi: 10.1038/ng.2421. Epub 2012 Sep 30. PubMed PMID:23023332; PubMed Central PMCID: PMC3545695. 72. Drake KM, Zygmunt D, Mavrakis L, Harbor P, Wang L, Comhair SA, Erzurum SC,Aldred MA. Altered MicroRNA processing in herit able pulmonary arterialhypertension: an important role for Smad-8. Am J Respir Crit Care Med. 2011 Dec15;184(12):1400-8. doi: 10.1164/rccm.201106-1130OC. Epub 2011 Sep 15. PubMedPMID: 21920918; PubMed Central PMCID: PMC3262031. 73. Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, vanDijk F, Verschuuren-Bemelmans C, Hageman G, van de Vlies P, Küsters B, van deWarrenburg BP, Kremer B, Wijmenga C, Sinke RJ, Swertz MA, Kampinga HH, Boddeke E,Verbeek DS. Mutations in potassium channel kcnd3 cause spinocerebellar ataxiatype 19. Ann Neurol. 2012 Dec;72(6):870-80. doi: 10.1002/ana.23700. PubMed PMID: 23280838. 74. Duboscq-Bidot L, Xu P, Charron P, Neyroud N, Dilanian G, Millaire A, Bors V,Komajda M, Villard E. Mutations in the Z-band protein myopalladin gene andidiopathic dilated cardiomyopathy. Cardiovasc Res. 2008 Jan;77(1):118-25. Epub2007 Sep 19. PubMed PMID: 18006477. 75. Duff RM, Tay V, Hackman P, Ravenscroft G, McLean C, Kennedy P, Steinbach A,Schöffler W, van der Ven PFM, Fürst DO, Song J, Djinović-Carugo K, Penttilä S,Raheem O, Reardon K, Malandrini A, Gambelli S, Villanova M, Nowak KJ, WilliamsDR, Landers JE, Brown RH Jr, Udd B, Laing NG. Mutations in the N-terminalactin-binding domain of C cause a distal myopathy. Am J Hum Genet. 2011Jun 10;88(6):729-740. doi: 10.1016/j.ajhg.2011.04.021. Epub 2011 May 27. PubMedPMID: 21620354; PubMed Central PMCID: PMC3113346. 76. Dupré T, Vuillaumier-Barrot S, Chantret I, Sadou Yayé H, Le Bizec C, AfenjarA, Altuzarra C, Barnérias C, Burglen L, de Lonlay P, Feillet F, Napuri S, Seta N,Moore SE. Guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferasedeficiency (congenital disorders of glycosylation type Ik): five new patients andseven novel mutations. J Med Genet. 2010 Nov;47(11):729-35. doi:10.1136/jmg.2009.072504. Epub 2010 Aug 2. Erratum in: J Med Genet. 2015Mar;52(3):216. Yayé, H S [corrected to Sadou Yayé, H]. PubMed PMID: 20679665. 77. Dündar M, Müller T, Zhang Q, Pan J, Steinmann B, Vodopiutz J, Gruber R, SonodaT, Krabichler B, Utermann G, Baenziger JU, Zhang L, Janecke AR. Loss ofdermatan-4- sulfotransferase 1 function results in adducted thumb-clubfootsyndrome. Am J Hum Genet. 2009 Dec;85(6):873-82. doi: 10.1016/j.ajhg.2009.11.010.PubMed PMID: 20004762; PubMed Central PMCID: PMC2790573. 78. Echaniz-Laguna A, Ghezzi D, Chassagne M, Mayençon M, Padet S, Melchionda L,Rouvet I, Lannes B, Bozon D, Latour P, Zeviani M, Mousson de Camaret B. SURF1deficiency causes demyelinating Charcot-Marie-Tooth disease. Neurology. 2013 Oct 22;81(17):1523-30. doi: 10.1212/WNL.0b013e3182a4a518. Epub 2013 Sep 11. PubMedPMID: 24027061; PubMed Central PMCID: PMC3888171. 79. Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, VanwijckR, Vikkula M. Capillary malformation -arteriovenous malformation, a new clinicaland caused by RASA1 mutations. Am J Hum Genet. 2003Dec;73(6):1240-9. Epub 2003 Nov 24. PubMed PMID: 14639529; PubMed Central PMCID: PMC1180390. 80. Elstner M, Bettecken T, Wasner M, Anneser F, Dichgans M, Meitinger T, GasserT, Klopstock T. Familial carpal tunnel syndrome: further evidence for a geneticcontribution. Clin Genet. 2006 Feb;69(2):179-82. PubMed PMID: 16433699. 81. Eng CM, Resnick-Silverman LA, Niehaus DJ, Astrin KH, Desnick RJ. Nature andfrequency of mutations in the alpha-galactosidase A gene that cause Fabrydisease. Am J Hum Genet. 1993 Dec;53(6):1186-97. PubMed PMID: 7504405; PubMedCentral PMCID: PMC1682507. 82. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR,Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Recurrent de novo point mutations in lamin A causeHutchinson-Gilford progeria syndrome. Nature. 2003 May 15;423(6937):293-8. Epub2003 Apr 25. PubMed PMID: 12714972. 83. Faber CG, Lauria G, Merkies IS, Cheng X, Han C, Ahn HS, Persson AK,Hoeijmakers JG, Gerrits MM, Pierro T, Lombardi R, Kapetis D, Dib-Hajj SD, Waxman SG. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci US A. 2012 Nov 20;109(47):19444-9. doi: 10.1073/pnas.1216080109. Epub 2012 Oct 31.PubMed PMID: 23115331; PubMed Central PMCID: PMC3511073. 84. Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, Atherton J,Vidaillet HJ Jr, Spudich S, De Girolami U, Seidman JG, Seidman C, Muntoni F,Müehle G, Johnson W, McDonough B. Missense mutations in the rod domain of thelamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.N Engl J Med. 1999 Dec 2;341(23):1715- 24. PubMed PMID: 10580070. 85. Fisher JH, Miller YE, Sparkes RS, Bateman JB, Kimmel KA, Carey TE, Rodell T,Shoemaker SA, Scoggin CH. Wilms' tumor-aniridia association: segregation ofaffected chromosome in somatic cell hybrids, identification of cell surfaceantigen associated with deleted area, and regional mapping of c-Ha-ras-1oncogene, insulin gene, and beta-globin gene. Somat Cell Mol Genet. 1984Sep;10(5):455-64. PubMed PMID: 6089356. 86. Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S,Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH. Autosomalrecessive hypercholesterolemia caused by mutations in a putative LDL receptoradaptor protein. Science. 2001 May 18;292(5520):1394-8. Epub 2001 Apr 26. PubMed PMID: 11326085. 87. Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, RothrockCR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D. GATA4mutations cause human congenital heart defects and reveal an interaction withTBX5. Nature. 2003 Jul 24;424(6947):443-7. Epub 2003 Jul 6. PubMed PMID:12845333. 88. Garrido E, Chabás A, Coll MJ, Blanco M, Domínguez C, Grinberg D, Vilageliu L, Cormand B. Identification of the molecular defects in Spanish and Argentinianmucopolysaccharidosis VI (Maroteaux-Lamy syndrome) patients, including 9 novelmutations. Mol Genet Metab. 2007 Sep-Oct;92(1-2):122-30. Epub 2007 Jul 20. PubMedPMID: 17643332. 89. Gavish D, Brinton EA, Breslow JL. Heritable allele-specific differences inamounts of apoB and low-density lipoproteins in plasma. Science. 1989 Apr7;244(4900):72-6. PubMed PMID: 2565046. 90. Gebbia M, Ferrero GB, Pilia G, Bassi MT, Aylsworth A, Penman-Splitt M, BirdLM, Bamforth JS, Burn J, Schlessinger D, Nelson DL, Casey B. X-linked situsabnormalities result from mutations in ZIC3. Nat Genet. 1997 Nov;17(3):305-8.PubMed PMID: 9354794. 91. Geier C, Gehmlich K, Ehler E, Hassfeld S, Perrot A, Hayess K, Cardim N, WenzelK, Erdmann B, Krackhardt F, Posch MG, Osterziel KJ, Bublak A, Nägele H, ScheffoldT, Dietz R, Chien KR, Spuler S, Fürst DO, Nürnberg P, Ozcelik C. Beyond thesarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. Hum Mol Genet. 2008Sep 15;17(18):2753-65. doi: 10.1093/hmg/ddn160. Epub 2008 May 27. Erratum in: HumMol Genet. 2008 Nov 1;17(21):3436. Osterziel, Karl J [added]. PubMed PMID:18505755. 92. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE,Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a betacardiac myosin heavy chain gene missense mutation. Cell. 1990 Sep7;62(5):999-1006. PubMed PMID: 1975517. 93. Gerull B, Gramlich M, Atherton J, McNabb M, Trombitás K, Sasse-Klaassen S,Seidman JG, Seidman C, Granzier H, Labeit S, Frenneaux M, Thierfelder L.Mutations of TTN, encoding the giant muscle filament titin, cause familialdilated cardiomyopathy. Nat Genet. 2002 Feb;30(2):201-4. Epub 2002 Jan 14. PubMedPMID: 11788824.

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94. Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB,Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckh ahn J,Michely B, Sasse- Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E,Thierfelder L. Mutations in the desmosomal protein -2 are common inarrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004Nov;36(11):1162-4. Epub 2004 Oct 17. Erratum in: Nat Genet. 2005 Jan;37(1):106.PubMed PMID: 15489853. 95. Ghezzi D, Goffrini P, Uziel G, Horvath R, Klopstock T, Lochmüller H, D'AdamoP, Gasparini P, Strom TM, Prokisch H, Invernizzi F, Ferrero I, Zeviani M. SDHAF1,encoding a LYR complex- II specific assembly factor, is mutated in SDH-defectiveinfantile leukoencephalopathy. Nat Genet. 2009 Jun;41(6):654-6. doi:10.1038/ng.378. Epub 2009 May 24. PubMed PMID: 19465911. 96. Giunta C, Elçioglu NH, Albrecht B, Eich G, Chambaz C, Janecke AR, Yeowell H,Weis M, Eyre DR, Kraenzlin M, Steinmann B. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome--an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet. 2008 Jun;82(6):1290-305. doi:10.1016/j.ajhg.2008.05.001. PubMed PMID: 18513683; PubMed Central PMCID:PMC2427271. 97. Goker-Alpan O, Giasson BI, Eblan MJ, Nguyen J, Hurtig HI, Lee VM, Trojanowski JQ, Sidransky E. Glucocerebrosidase mutations are an important risk factor forLewy body disorders. Neurology. 2006 Sep 12;67(5):908-10. Epub 2006 Jun 21.PubMed PMID: 16790605. 98. Goldfarb LG, Park KY, Cervenáková L, Gorokhova S, Lee HS, Vasconcelos O, NagleJW, Semino-Mora C, Sivakumar K, Dalakas MC. Missense mutations in desminassociated with familial cardiac and skeletal myopathy. Nat Genet. 1998Aug;19(4):402-3. PubMed PMID: 9697706. 99. Gomez-Hurtado N, Boczek NJ, Kryshtal DO, Johnson CN, Sun J, Nitu FR, CorneaRL, Chazin WJ, Calvert ML, Tester DJ, Ackerman MJ, Knollmann BC. NovelCPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) ActivatesArrhythmogenic Ca Waves and Sparks. Circ Arrhythm Electrophysiol. 2016 Aug;9(8). pii: e004161. doi: 10.1161/CIRCEP.116.004161. PubMed PMID: 27516456; PubMedCentral PMCID: PMC4988333. 100. Gripp KW, Aldinger KA, Bennett JT, Baker L, Tusi J, Powell-Hamilton N, StableyD, Sol-Church K, Timms AE, Dobyns WB. A novel rasopathy caused by recurrent denovo missense mutations in PPP1CB closely resembles Noonan syndrome with looseanagen hair. Am J Med Genet A. 2016 Sep;170(9):2237-47. doi:10.1002/ajmg.a.37781. Epub 2016 Jun 5. PubMed PMID: 27264673; PubMed CentralPMCID: PMC5134331. 101. Gueneau L, Bertrand AT, Jais JP, Salih MA, Stojkovic T, Wehnert M,Hoeltzenbein M, Spuler S, Saitoh S, Verschueren A, Tranchant C, Beuvin M, Lacene E, Romero NB, Heath S, Zelenika D, Voit T, Eymard B, Ben Yaou R, Bonne G.Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy. Am J HumGenet. 2009 Sep;85(3):338-53. doi: 10.1016/j.ajhg.2009.07.015. Epub 2009 Aug 27. PubMed PMID: 19716112; PubMed Central PMCID: PMC2771595. 102. Guo DC, Gong L, Regalado ES, Santos-Cortez RL, Zhao R, Cai B, Veeraraghavan S,Prakash SK, Johnson RJ, Muilenburg A, Willing M, Jondeau G, Boileau C, Pannu H,Moran R, Debacker J; GenTAC Investigators, National Heart, Lung, and BloodInstitute Go Exome Sequencing Project; Montalcino Aortic Con sortium, Bamshad MJ, Shendure J, Nickerson DA, Leal SM, Raman CS, Swindell EC, Milewicz DM. MAT2Amutations predispose individuals to thoracic aortic aneurysms. Am J Hum Genet.2015 Jan 8;96(1):170-7. doi: 10.1016/j.ajhg.2014.11.015. Epub 2014 Dec 31. PubMedPMID: 25557781; PubMed Central PMCID: PMC4289682. 103. Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N, Johnson RJ, Kim DH,Pannu H, Willing MC, Sparks E, Pyeritz RE, Singh MN, Dalman RL, Grotta JC, MarianAJ, Boerwinkle EA, Frazier LQ, LeMaire SA, Coselli JS, Estrera AL, Safi HJ,Veeraraghavan S, Muzny DM, Wheeler DA, Willerson JT, Yu RK, Shete SS, Scherer SE,Raman CS, Buja LM, Milewicz DM. Mutations in smooth muscle alpha- (ACTA2)cause coronary artery disease, , and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009 May;84(5):617-27. doi:10.1016/j.ajhg.2009.04.007. Epub 2009 Apr 30. PubMed PMID: 19409525; PubMedCentral PMCID: PMC2680995. 104. Guo DC, Regalado E, Casteel DE, Santos-Cortez RL, Gong L, Kim JJ, Dyack S,Horne SG, Chang G, Jondeau G, Boileau C, Coselli JS, Li Z, Leal SM, Shendure J,Rieder MJ, Bamshad MJ, Nickerson DA; GenTAC Registry Consortium; National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project, Kim C,Milewicz DM. Recurrent gain-of- function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet. 2013 Aug 8;93(2):398-404.doi: 10.1016/j.ajhg.2013.06.019. Epub 2013 Aug 1. PubMed PMID: 23910461; PubMedCentral PMCID: PMC3738837. 105. Haack TB, Kopajtich R, Freisinger P, Wieland T, Rorbach J, Nicholls TJ,Baruffini E, Walther A, Danhauser K, Zimmermann FA, Hu sain RA, Schum J, Mundy H, Ferrero I, Strom TM, Meitinger T, Taylor RW, Minczuk M, Mayr JA, Prokisch H.ELAC2 mutations cause a mitochondrial RNA processing defect associated withhypertrophic cardiomyopathy. Am J Hum Genet. 2013 Aug 8;93(2):211-23. doi:10.1016/j.ajhg.2013.06.006. Epub 2013 Jul 11. PubMed PMID: 23849775; PubMedCentral PMCID: PMC3738821. 106. Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B. Tibial muscular dystrophy is atitinopathy caused by mutations in TTN, the gene encoding the giantskeletal-muscle protein titin. Am J Hum Genet. 2002 Sep;71(3):492-500. Epub 2002 Jul 26. PubMed PMID: 12145747; PubMed Central PMCID: PMC379188. 107. Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, Takahashi M,Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Choi BY, Bae SW,You CW, Han KH, Park JE, Knöll R, Hoshijima M, Chien KR, Kimura A. Tcap genemutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am CollCardiol. 2004 Dec 7;44(11):2192- 201. PubMed PMID: 15582318. 108. Hayashi T, Arimura T, Ueda K, Shibata H, Hohda S, Takahashi M, Hori H, Koga Y,Oka N, Imaizumi T, Yasunami M, Kimura A. Identification and functional analysisof a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy.Biochem Biophys Res Commun. 2004 Jan 2;313(1):178-84. PubMed PMID: 14672715. 109. Haïssaguerre M, Chatel S, Sacher F, Weerasooriya R, Probst V, Loussouarn G,Horlitz M, Liersch R, Schulze-Bahr E, Wilde A, Kääb S, Koster J, Rudy Y, Le MarecH, Schott JJ. Ventricular fibrillation with prominent early repolarizationassociated with a rare variant of KCNJ8/KATP channel. J CardiovascElectrophysiol. 2009 Jan;20(1):93-8. doi: 10.1111/j.1540- 8167.2008.01326.x.PubMed PMID: 19120683. 110. Hermans MM, Kroos MA, de Graaff E, Oostra BA, Reuser AJ. Two mutationsaffecting the transport and maturation of lysosomal alpha-glucosidase in an adultcase of glycogen storage disease type II. Hum Mutat. 1993;2(4):268-73. PubMedPMID: 8401535. 111. Hoban R, Roberts AE, Demmer L, Jethva R, Shephard B. Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophiccardiomyopathy in a premature infant. Am J Med Genet A. 2012 Jun;158A(6):1411-3. doi: 10.1002/ajmg.a.35318. Epub 2012 Apr 23. PubMed PMID: 22528146. 112. Hodgson-Zingman DM, Karst ML, Zingman LV, Heublein DM, Darbar D, Herron KJ,Ballew JD, de Andrade M, Burnett JC Jr, Olson TM. Atrial natriuretic peptideframeshift mutation in familial atrial fibrillation. N Engl J Med. 2008 Jul10;359(2):158-65. doi: 10.1056/NEJMoa0706300. PubMed PMID: 18614783; PubMedCentral PMCID: PMC2518320. 113. Hoefs SJ, Dieteren CE, Distelmaier F, Janssen RJ, Epplen A, Swarts HG, ForkinkM, Rodenburg RJ, Nijtmans LG, Willems PH, Smeitink JA, van den Heuvel LP. NDUFA2 complex I mutation leads to Leigh disease. Am J Hum Genet. 2008Jun;82(6):1306-15. doi: 10.1016/j.ajhg.2008.05.007. PubMed PMID: 18513682; PubMedCentral PMCID: PMC2427319. 114. Hoefs SJ, van Spronsen FJ, Lenssen EW, Nijtmans LG, Rodenburg RJ, Smeitink JA,van den Heuvel LP. NDUFA10 mutations cause comp lex I deficiency in a patient withLeigh disease. Eur J Hum Genet. 2011 Mar;19(3):270-4. doi: 10.1038/ejhg.2010.204.Epub 2010 Dec 8. PubMed PMID: 21150889; PubMed Central PMCID: PMC3061993. 115. Horsthemke B, Beisiegel U, Dunning A, Havinga JR, Williamson R, Humphries S.Unequal crossing -over between two alu-repetitive DNA sequences in thelow-density-lipoprotein- receptor gene. A possible mechanism for the defect in apatient with familial hypercholesterolaemia. Eur J Biochem. 1987 Apr1;164(1):77-81. PubMed PMID: 3549308. 116. Howe JR, Ringold JC, Summers RW, Mitros FA, Nishimura DY, Stone EM. A gene forfamilial juvenile polyposis maps to chromosome 18q21.1. Am J Hum Genet. 1998May;62(5):1129- 36. PubMed PMID: 9545410; PubMed Central PMCID: PMC1377097. 117. Huizing M, Iacobazzi V, Ijlst L, Savelkoul P, Ruitenbeek W, van den Heuvel L, Indiveri C, Smeitink J, Trijbels F, Wanders R, Palmieri F. Cloning of the humancarnitine-acylcarnitine carrier cDNA and identification of the molecular defectin a patient. Am J Hum Genet. 1997 Dec;61(6):1239-45. PubMed PMID: 9399886;PubMed Central PMCID: PMC1716087. 118. IJlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ. Common missensemutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.Characterization and expression of the mutant protein, mutation analysis ongenomic DNA and chromosomal localization of the mitochondrial trifunctionalprotein alpha subunit gene. J Clin Invest. 1996 Aug 15;98(4):1028-33. PubMedPMID: 8770876; PubMed Central PMCID: PMC507519. 119. Ichida F, Tsubata S, Bowles KR, Haneda N, Uese K, Miyawaki T, Dreyer WJ,Messina J, Li H, Bowles NE, Towbin JA. Novel gene mutations in patients with leftventricular noncompaction or Barth syndrome. Circulation. 2001 Mar6;103(9):1256-63. PubMed PMID: 11238270. 120. Inagaki N, Hayashi T, Arimura T, Koga Y, Takahashi M, Shibata H, Teraoka K,Chikamori T, Yamashina A, Kimura A. Alpha B-crystallin mutation in dilatedcardiomyopathy. Biochem Biophys Res Commun. 2006 Apr 7;342(2):379-86. Epub 2006Feb 8. PubMed PMID: 16483541. 121. Ishikawa T, Sato A, Marcou CA, Tester DJ, Ackerman MJ, Crotti L, Schwartz PJ, On YK, Park JE, Nakamura K, Hiraoka M, Nakazawa K, Sakurada H, Arimura T, Makita N, Kimura A. A novel disease gene for Brugada syndrome: sarcolemmalmembrane-associated protein gene mutations impair intracellular trafficking ofhNav1.5. Circ Arrhythm Electrophysiol. 2012 Dec;5(6):1098-107. doi:10.1161/CIRCEP.111.969972. Epub 2012 Oct 12. PubMed PMID: 23064965. 122. Jansen GA, Ofman R, Ferdinandusse S, Ijlst L, Muijsers AO, Skjeldal OH, StokkeO, Jakobs C, Besley GT, Wraith JE, Wanders RJ. Refsum disease is caused bymutations in the phytanoyl-CoA hydroxylase gene. Nat Genet. 1997 Oct;17(2):190-3.PubMed PMID: 9326940. 123. Johansson S, Berland S, Gradek GA, Bongers E, de Leeuw N, Pfundt R, FannemelM, Rødningen O, Brendehaug A, Haukanes BI, Hovland R, Helland G, Houge G.Haploinsufficiency of MEIS2 is associated with orofacial clefting and learningdisability. Am J Med Genet A. 2014 Jul;164A(7):1622-6. doi: 10.1002/ajmg.a.36498.Epub 2014 Mar 26. PubMed PMID: 24678003. 124. Kaler SG, Gallo LK, Proud VK, Percy AK, Mark Y, Segal NA, Goldstein DS, HolmesCS, Gahl WA. Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nat Genet. 1994 Oct;8(2):195-202. PubMed PMID: 7842019. 125. Kamisago M, Sharma SD, DePalma SR, Solomon S, Sharma P, McDonough B, Smoot L, Mullen MP, Woolf PK, Wigle ED, Seidman JG, Seidman CE. Mutations in sarcomereprotein genes as a cause of dilated cardiomyopathy. N Engl J Med. 2000 Dec7;343(23):1688-96. PubMed PMID: 11106718. 126. Kappanayil M, Nampoothiri S, Kannan R, Renard M, Coucke P, Malfait F, Menon S,Ravindran HK, Kurup R, Faiyaz-Ul-Haque M, Kumar K, De Paepe A. Characterizationof a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a criticaldeterminant of human vascular elastogenesis. Orphanet J Rare Dis. 2012 Sep3;7:61. doi: 10.1186/1750-1172-7-61. PubMed PMID: 22943132; PubMed Central PMCID:PMC3598868. 127. Karkera JD, Lee JS, Roessler E, Banerjee-Basu S, Ouspenskaia MV, Mez J,Goldmuntz E, Bowers P, Towbin J, Belmont JW, Baxevanis AD, Schier AF, Muenke M.Loss-of-function mutations in growth differentiation factor-1 (GDF1) areassociated with congenital heart defects in humans. Am J Hum Genet. 2007Nov;81(5):987-94. Epub 2007 Sep 28. PubMed PMID: 17924340; PubMed Central PMCID: PMC2265655. 128. Kennerson ML, Nicholson GA, Kaler SG, Kowalski B, Mercer JF, Tang J, LlanosRM, Chu S, Takata RI, Speck-Martins CE, Baets J, Almeida-Souza L, Fischer D,Timmerman V, Taylor PE, Scherer SS, Ferguson TA, Bird TD, De Jonghe P, Feely SM, Shy ME, Garbern JY. Missense mutations in the copper transporter gene ATP7A causeX-linked distal hereditary motor neuropathy. Am J Hum Genet. 2010 Mar12;86(3):343-52. doi: 10.1016/j.ajhg.2010.01.027. Epub 2010 Feb 18. PubMed PMID: 20170900; PubMed Central PMCID: PMC2833394.

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129. Kluwe L, Friedrich RE, Mautner VF. Allelic loss of the NF1 gene inNF1-associated plexiform . Cancer Genet Cytogenet. 1999Aug;113(1):65-9. PubMed PMID: 10459349. 130. Knowles MR, Leigh MW, Ostrowski LE, Huang L, Carson JL, Hazucha MJ, Yin W,Berg JS, Davis SD, Dell SD, Ferkol TW, Rosenfeld M, Sagel SD, Milla CE, OlivierKN, Turner EH, Lewis AP, Bamshad MJ, Nickerson DA, Shendure J, Zariwala MA;Genetic Disorders of Mucociliary Clearance Consortium. Exome sequencingidentifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am JHum Genet. 2013 Jan 10;92(1):99-106. doi: 10.1016/j.ajhg.2012.11.003. Epub 2012Dec 20. PubMed PMID: 23261302; PubMed Central PMCID: PMC3542458. 131. Knöll R, Postel R, Wang J, Krätzner R, Hennecke G, Vacaru AM, Vakeel P,Schubert C, Murthy K, Rana BK, Kube D, Knöll G, Schäfer K, Hayashi T, Holm T,Kimura A, Schork N, Toliat MR, Nürnberg P, Schultheiss HP, Schaper W, Schaper J, Bos E, Den Hertog J, van Eeden FJ, Peters PJ, Hasenfuss G, Chien KR, Bakkers J.Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathyvia simultaneous defects in cardiomyocytes and endothelial cells. Circulation.2007 Jul 31;116(5):515-25. Epub 2007 Jul 23. PubMed PMID: 17646580. 132. Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, SegawaM, Yoshioka M, Saito K, Osawa M, Hamano K, Sakakihara Y, Nonaka I, Nakagome Y,Kanazawa I, Nakamura Y, Tokunaga K, Toda T. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature. 1998 Jul23;394(6691):388-92. PubMed PMID: 9690476. 133. Kodera T, Tan FK, Sasaki T, Arnett FC, Bona CA. Association of 5'-untranslatedregion of the -1 gene with Japanese scleroderma. Gene. 2002 Sep4;297(1-2):61-7. PubMed PMID: 12384286. 134. Kodo K, Nishizawa T, Furutani M, Arai S, Yamamura E, Joo K, Takahashi T,Matsuoka R, Yamagishi H. GATA6 mutations cause human cardiac outflow tractdefects by disrupting semaphorin-plexin signaling. Proc Natl Acad Sci U S A. 2009Aug 18;106(33):13933-8. doi: 10.1073/pnas.0904744106. Epub 2009 Aug 4. PubMedPMID: 19666519; PubMed Central PMCID: PMC2728998. 135. Kohda M, Tokuzawa Y, Kishita Y, Nyuzuki H, Moriyama Y, Mizuno Y, Hirata T,Yatsuka Y, Yamashita-Sugahara Y, Nakachi Y, Kato H, Okuda A, Tamaru S, Borna NN, Banshoya K, Aigaki T, Sato-Miyata Y, Ohnuma K, Suzuki T, Nagao A, Maehata H,Matsuda F, Higasa K, Nagasaki M, Yasuda J, Yamamoto M, Fushimi T, Shimura M, Kaiho-Ichimoto K, Harashima H, Yamazaki T, Mori M, Murayama K, Ohtake A, Okazaki Y. A Comprehensive Genomic Analysis Reveals the Genetic Landscape ofMitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet. 2016 Jan7;12(1):e1005679. doi: 10.1371/journal.pgen.1005679. eCollection 2016 Jan. PubMedPMID: 26741492; PubMed Central PMCID: PMC4704781. 136. Kosaki K, Bassi MT, Kosaki R, Lewin M, Belmont J, Schauer G, Casey B.Characterization and mutation analysis of human LEFTY A and LEFTY B, homologuesof murine genes implicated in left-right axis development. Am J Hum Genet. 1999Mar;64(3):712-21. PubMed PMID: 10053005; PubMed Central PMCID: PMC1377788. 137. Kosaki R, Gebbia M, Kosaki K, Lewin M, Bowers P, Towbin JA, Casey B.Left-right axis malformations associated with mutations in ACVR2B, the gene forhuman activin receptor type IIB. Am J Med Genet. 1999 Jan 1;82(1):70-6. PubMedPMID: 9916847. 138. Krantz ID, Colliton RP, Genin A, Rand EB, Li L, Piccoli DA, Spinner NB.Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet. 1998 Jun;62(6):1361-9. PubMed PMID: 9585603; PubMed Central PMCID: PMC1377154. 139. Kyndt F, Gueffet JP, Probst V, Jaafar P, Legendre A, Le Bouffant F, Toquet C, Roy E, McGregor L, Lynch SA, Newbury-Ecob R, Tran V, Young I, Trochu JN, Le MarecH, Schott JJ. Mutations in the gene encoding filamin A as a cause for familialcardiac valvular dystrophy. Circulation. 2007 Jan 2;115(1):40-9. Epub 2006 Dec26. PubMed PMID: 17190868. 140. Körkkö J, Ala-Kokko L, De Paepe A, Nuytinck L, Earley J, Prockop DJ. Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning byconformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15patients with osteogenesis imperfecta type I: identification of common sequences of null-allele mutations. Am J Hum Genet. 1998 Jan;62(1):98-110. PubMed PMID:9443882; PubMed Central PMCID: PMC1376813. 141. Landstrom AP, Weisleder N, Batalden KB, Bos JM, Tester DJ, Ommen SR, WehrensXH, Claycomb WC, Ko JK, Hwang M, Pan Z, Ma J, Ackerman MJ. Mutations inJPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy inhumans. J Mol Cell Cardiol. 2007 Jun;42(6):1026-35. Epub 2007 Apr 18. PubMedPMID: 17509612; PubMed Central PMCID: PMC4318564. 142. Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S,Sejersen T, Richard I, Edström L, Ehler E, Udd B, Gautel M. The kinase domain of titin controls muscle and protein turnover. Science. 2005 Jun10;308(5728):1599-603. Epub 2005 Mar 31. PubMed PMID: 15802564. 143. Lee SJ, Lee DH, Yoo HW, Koo SK, Park ES, Park JW, Lim HG, Jung SC.Identification and functional analysis of cystathionine beta-synthase genemutations in patients with homocystinuria. J Hum Genet. 2005;50(12):648-54. Epub 2005 Oct 5. PubMed PMID: 16205833. 144. Lefeber DJ, de Brouwer AP, Morava E, Riemersma M, Schuurs-Hoeijmakers JH,Absmanner B, Verrijp K, van den Akker WM, Huijben K, Steenbergen G, van Reeuwijk J, Jozwiak A, Zucker N, Lorber A, Lammens M, Knopf C, van Bokhoven H, GrünewaldS, Lehle L, Kapusta L, Mandel H, Wevers RA. Autosomal recessive dilatedcardiomyopathy due to DOLK mutations results from abnormal dystroglycanO-mannosylation. PLoS Genet. 2011 Dec;7(12):e1002427. doi:10.1371/journal.pgen.1002427. Epub 2011 Dec 29. PubMed PMID: 22242004; PubMedCentral PMCID: PMC3248466. 145. Levitas A, Muhammad E, Harel G, Saada A, Caspi VC, Manor E, Beck JC, SheffieldV, Parvari R. Familial neonatal isolated cardiomyopathy caused by a mutation inthe flavoprotein subunit of succinate dehydrogenase. Eur J Hum Genet. 2010Oct;18(10):1160-5. doi: 10.1038/ejhg.2010.83. Epub 2010 Jun 16. PubMed PMID:20551992; PubMed Central PMCID: PMC2987458. 146. Li D, Tapscoft T, Gonzalez O, Burch PE, Quiñones MA, Zoghbi WA, Hill R,Bachinski LL, Mann DL, Roberts R. Desmin mutation resp onsible for idiopathicdilated cardiomyopathy. Circulation. 1999 Aug 3;100(5):461-4. PubMed PMID:10430757. 147. Liang WC, Mitsuhashi H, Keduka E, Nonaka I, Noguchi S, Nishino I, Hayashi YK. TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy. AnnNeurol. 2011 Jun;69(6):1005-13. doi: 10.1002/ana.22338. Epub 2011 Mar 9. PubMedPMID: 21391237. 148. Lim SC, Smith KR, Stroud DA, Compton AG, Tucker EJ, Dasvarma A, Gandolfo LC,Marum JE, McKenzie M, Peters HL, Mowat D, Procopis PG, Wilcken B, ChristodoulouJ, Brown GK, Ryan MT, Bahlo M, Thorburn DR. A founder mutation in PET100 causesisolated complex IV deficiency in Lebanese individuals with Leigh syndrome. Am J Hum Genet. 2014 Feb 6;94(2):209-22. doi: 10.1016/j.ajhg.2013.12.015. Epub 2014Jan 23. PubMed PMID: 24462369; PubMed Central PMCID: PMC3928654. 149. Loeffen J, Smeitink J, Triepels R, Smeets R, Schuelke M, Sengers R, TrijbelsF, Hamel B, Mullaart R, van den Heuvel L. The first nuclear-encoded complex Imutation in a patient with Leigh syndrome. Am J Hum Genet. 1998Dec;63(6):1598-608. PubMed PMID: 9837812; PubMed Central PMCID: PMC1377631. 150. Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, LeitchCC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J,Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De PaepeAM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005Mar;37(3):275-81. Epub 2005 Jan 30. PubMed PMID: 15731757. 151. Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S, Mullighan CG, Chen L, Bergstraesser E, Bueso-Ramos CE, Emanuel PD, Hasle H, Issa JP, van denHeuvel-Eibrink MM, Locatelli F, Stary J, Trebo M, Wlodarski M, Zecca M, ShannonKM, Niemeyer CM. Mutations in CBL occur frequently in juvenile myelomonocyticleukemia. Blood. 2009 Aug 27;114(9):1859-63. doi: 10.1182/blood-2009-01-198416.Epub 2009 Jul 1. PubMed PMID: 19571318; PubMed Central PMCID: PMC2738571. 152. Lossos A, Meiner Z, Barash V, Soffer D, Schlesinger I, Abramsky O, Argov Z,Shpitzen S, Meiner V. Adult polyglucosan body disease in Ashkenazi Jewishpatients carrying the Tyr329Ser mutation in the glycogen-branching gene.Ann Neurol. 1998 Dec;44(6):867-72. PubMed PMID: 9851430. 153. Luxán G, Casanova JC, Martínez-Poveda B, Prados B, D'Amato G, MacGrogan D,Gonzalez-Rajal A, Dobarro D, Torroja C, Martinez F, Izquierdo-García JL,Fernández-Friera L, Sabater- Molina M, Kong YY, Pizarro G, Ibañez B, Medrano C,García-Pavía P, Gimeno JR, Monserrat L, Jiménez-Borreguero LJ, de la Pompa JL.Mutations in the NOTCH pathway regulator MIB1 cause left ventricularnoncompaction cardiomyopathy. Nat Med. 2013 Feb;19(2):193-201. doi:10.1038/nm.3046. Epub 2013 Jan 13. PubMed PMID: 23314057. 154. Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, Germain M, Trégouët DA, Borczuk A, Rosenzweig EB, Girerd B, Montani D, Humbert M, Loyd JE,Kass RS, Chung WK. A novel channelopathy in pulmonary arterial hypertension. NEngl J Med. 2013 Jul 25;369(4):351-361. doi: 10.1056/NEJMoa1211097. PubMed PMID: 23883380; PubMed Central PMCID: PMC3792227. 155. Makita N, Yagihara N, Crotti L, Johnson CN, Beckmann BM, Roh MS, Shigemizu D, Lichtner P, Ishikawa T, Aiba T, Homfray T, Behr ER, Klug D, Denjoy I, MastantuonoE, Theisen D, Tsunoda T, Satake W, Toda T, Nakagawa H, Tsuji Y, Tsuchiya T,Yamamoto H, Miyamoto Y, Endo N, Kimura A, Ozaki K, Motomura H, Suda K, Tanaka T, Schwartz PJ, Meitinger T, Kääb S, Guicheney P, Shimizu W, Bhuiyan ZA, Watanabe H,Chazin WJ, George AL Jr. Novel calmodulin mutations associated with congenitalarrhythmia susceptibility. Circ Cardiovasc Genet. 2014 Aug;7(4):466-74. doi:10.1161/CIRCGENETICS.113.000459. Epub 2014 Jun 10. PubMed PMID: 24917665; PubMed Central PMCID: PMC4140998. 156. Marston S, Montgiraud C, Munster AB, Copeland O, Choi O, Dos Remedios C,Messer AE, Ehler E, Knöll R. OBSCN Mutations Associated with DilatedCardiomyopathy and Haploinsufficiency. PLoS One. 2015 Sep 25;10(9):e0138568. doi:10.1371/journal.pone.0138568. eCollection 2015. PubMed PMID: 26406308; PubMedCentral PMCID: PMC4583186. 157. Maslen CL, Babcock D, Robinson SW, Bean LJ, Dooley KJ, Willour VL, Sherman SL.CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome. Am J Med Genet A. 2006 Nov 15;140(22):2501-5. PubMedPMID: 17036335. 158. Matsson H, Eason J, Bookwalter CS, Klar J, Gustavsson P, Sunnegårdh J, EnellH, Jonzon A, Vikkula M, Gutierrez I, Granados-Riveron J, Pope M, Bu'Lock F, CoxJ, Robinson TE, Song F, Brook DJ, Marston S, Trybus KM, Dahl N. Alpha-cardiacactin mutations produce atrial septal defects. Hum Mol Genet. 2008 Jan15;17(2):256-65. Epub 2007 Oct 18. PubMed PMID: 17947298. 159. Matthijs G, Schollen E, Pardon E, Veiga-Da-Cunha M, Jaeken J, Cassiman JJ, VanSchaftingen E. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). NatGenet. 1997 May;16(1):88-92. Erratum in: Nat Genet 1997 Jul;16(3):316. PubMedPMID: 9140401. 160. Mayr JA, Haack TB, Graf E, Zimmermann FA, Wieland T, Haberberger B,Superti-Furga A, Kirschner J, Steinmann B, Baumgartner MR, Moroni I, Lamantea E, Zeviani M, Rodenburg RJ, Smeitink J, Strom TM, Meitinger T, Sperl W, Prokisch H. Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. AmJ Hum Genet. 2012 Feb 10;90(2):314-20. doi: 10.1016/j.ajhg.2011.12.005. Epub 2012Jan 26. PubMed PMID: 22284826; PubMed Central PMCID: PMC3276657. 161. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE,Helmbold EA, Markel DS, McKinnon WC, Murrell J, et al. Endoglin, a TGF-betabinding protein of endothelial cells, is the gene for hereditary haemorrhagictelangiectasia type 1. Nat Genet. 1994 Dec;8(4):345-51. PubMed PMID: 7894484. 162. McBride KL, Riley MF, Zender GA, Fitzgerald-Butt SM, Towbin JA, Belmont JW,Cole SE. NOTCH1 mutations in individuals with left ventricular outflow tractmalformations redu ce ligand- induced signaling. Hum Mol Genet. 2008 Sep15;17(18):2886-93. doi: 10.1093/hmg/ddn187. Epub 2008 Jun 30. PubMed PMID:18593716; PubMed Central PMCID: PMC2722892.

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163. McKoy G, Protonotarios N, Crosby A, Tsatsopoulou A, Anastasakis A, Coonar A,Norman M, Baboonian C, Jeffery S, McKenna WJ. Identification of a deletion inplakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. 2000 Jun17;355(9221):2119-24. PubMed PMID: 10902626. 164. Medeiros-Domingo A, Kaku T, Tester DJ, Iturralde-Torres P, Itty A, Ye B,Valdivia C, Ueda K, Canizales-Quinteros S, Tusié-Luna MT, Makielski JC, Ackerman MJ. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome.Circulation. 2007 Jul 10;116(2):134-42. Epub 2007 Jun 25. PubMed PMID: 17592081; PubMed Central PMCID: PMC3332546. 165. Meder B, Haas J, Keller A, Heid C, Just S, Borries A, Boisguerin V,Scharfenberger-Schmeer M, Stähler P, Beier M, Weichenhan D, Strom TM, Pfeufer A, Korn B, Katus HA, Rottbauer W. Targeted next-generation sequencing for themolecular genetic diagnostics of cardiomyopathies. Circ Cardiovasc Genet. 2011Apr;4(2):110-22. doi: 10.1161/CIRCGENETICS.110.958322. Epub 2011 Jan 20. PubMedPMID: 21252143. 166. Mercuri E, Poppe M, Quinlivan R, Messina S, Kinali M, Demay L, Bourke J,Richard P, Sewry C, Pike M, Bonne G, Muntoni F, Bushby K. Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene: from congenital onset with severe phenotype to milder classic Emery-Dreifussvariant. Arch Neurol. 2004 May;61(5):690-4. PubMed PMID: 15148145. 167. Meredith C, Herrmann R, Parry C, Liyanage K, Dye DE, Durling HJ, Duff RM,Beckman K, de Visser M, van der Graaff MM, Hedera P, Fink JK, Petty EM, Lamon t P,Fabian V, Bridges L, Voit T, Mastaglia FL, Laing NG. Mutations in the slowskeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onsetdistal myopathy (MPD1). Am J Hum Genet. 2004 Oct;75(4):703-8. Epub 2004 Aug 20.PubMed PMID: 15322983; PubMed Central PMCID: PMC1182058. 168. Mihalik SJ, Morrell JC, Kim D, Sacksteder KA, Watkins PA, Gould SJ.Identification of PAHX, a Refsum disease gene. Nat Genet. 1997 Oct;17(2):185-9.PubMed PMID: 9326939. 169. Milewicz DM, Østergaard JR, Ala-Kokko LM, Khan N, Grange DK, Mendoza-LondonoR, Bradley TJ, Olney AH, Adès L, Maher JF, Guo D, Buja LM, Kim D, Hyland JC,Regalado ES. De novo ACTA2 mutation causes a novel syndrome of multisystemicsmooth muscle dysfunction. Am J Med Genet A. 2010 Oct;152A(10):2437-43. doi:10.1002/ajmg.a.33657. PubMed PMID: 20734336; PubMed Central PMCID: PMC3573757. 170. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Masetti E,Mazzocco M, Egeo A, Donati MA, Volonte D, Galbiati F, Cordone G, Bricarelli FD,Lisanti MP, Zara F. Mutations in the caveolin-3 gene cause autosomal dominantlimb-girdle muscular dystrophy. Nat Genet. 1998 Apr;18(4):365-8. PubMed PMID:9537420. 171. Mirza M, Marston S, Willott R, Ashley C, Mogensen J, McKenna W, Robinson P,Redwood C, Watkins H. Dilated cardiomyopathy mutations in three thin filamentregulatory proteins result in a common functional phenotype. J Biol Chem. 2005Aug 5;280(31):28498-506. Epub 2005 May 27. PubMed PMID: 15923195. 172. Mogensen J, Murphy RT, Shaw T, Bahl A, Redwood C, Watkins H, Burke M, Elliott PM, McKenna WJ. Severe disease expression of cardiac and T mutationsin patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2004 Nov16;44(10):2033-40. PubMed PMID: 15542288. 173. Mohapatra B, Casey B, Li H, Ho-Dawson T, Smith L, Fernbach SD, Molinari L,Niesh SR, Jefferies JL, Craigen WJ, Towbin JA, Belmont JW, Ware SM.Identification and functional characterization of NODAL rare variants inheterotaxy and isolated cardiovascular malformations. Hum Mol Genet. 2009 Mar1;18(5):861-71. doi: 10.1093/hmg/ddn411. Epub 2008 Dec 8. PubMed PMID: 19064609; PubMed Central PMCID: PMC2722226. 174. Mohler PJ, Le Scouarnec S, Denjoy I, Lowe JS, Guicheney P, Caron L, DriskellIM, Schott JJ, Norris K, Leenhardt A, Kim RB, Escande D, Roden DM. Defining thecellular phenotype of "ankyrin-B syndrome" variants: human ANK2 variantsassociated with clinical phenotypes display a spectrum of activities incardiomyocytes. Circulation. 2007 Jan 30;115(4):432-41. Epub 2007 Jan 22. PubMed PMID: 17242276. 175. Monserrat L, Hermida-Prieto M, Fernandez X, Rodríguez I, Dumont C, Cazón L,Cuesta MG, Gonzalez-Juanatey C, Peteiro J, Alvarez N, Penas-Lado M, Castro-BeirasA. Mutation in the alpha-cardiac actin gene associated with apical hypertrophiccardiomyopathy, left ventricular non-compaction, and septal defects. Eur Heart J.2007 Aug;28(16):1953-61. Epub 2007 Jul 4. PubMed PMID: 17611253. 176. Moreira ES, Wiltshire TJ, Faulkner G, Nilforoushan A, Vainzof M, Suzuki OT,Valle G, Reeves R, Zatz M, Passos-Bueno MR, Jenne DE. Limb-girdle musculardystrophy type 2G is caused by mutations in the gene encoding the sarcomericprotein telethonin. Nat Genet. 2000 Feb;24(2):163-6. PubMed PMID: 10655062. 177. Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, TowbinJA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy inchildren and adults. N Engl J Med. 2008 May 1;358(18):1899-908. doi:10.1056/NEJMoa075463. Epub 2008 Apr 9. PubMed PMID: 18403758; PubMed CentralPMCID: PMC2752150. 178. Moulik M, Vatta M, Witt SH, Arola AM, Murphy RT, McKenna WJ, Boriek AM, Oka K,Labeit S, Bowles NE, Arimura T, Kimura A, Towbin JA. ANKRD1, the gene encodingcardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene. J Am CollCardiol. 2009 Jul 21;54(4):325-33. doi: 10.1016/j.jacc.2009.02.076. PubMed PMID: 19608030; PubMed Central PMCID: PMC2915893. 179. Muhammad E, Levitas A, Singh SR, Braiman A, Ofir R, Etzion S, Sheffield VC,Etzion Y, Carrier L, Parvari R. PLEKHM2 mutation leads to abnormal localizationof lysosomes, impaired autophagy flux and associates with recessive dilatedcardiomyopathy and left ventricular noncompaction. Hum Mol Genet. 2015 Dec20;24(25):7227-40. doi: 10.1093/hmg/ddv423. Epub 2015 Oct 12. PubMed PMID:26464484; PubMed Central PMCID: PMC4664165. 180. Muntoni F, Cau M, Ganau A, Congiu R, Arvedi G, Mateddu A, Marrosu MG,Cianchetti C, Realdi G, Cao A, et al. Brief report: deletion of the dystrophinmuscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med. 1993 Sep 23;329(13):921-5. PubMed PMID: 8361506. 181. Murakami T, Hayashi YK, Noguchi S, Ogawa M, Nonaka I, Tanabe Y, Ogino M,Takada F, Eriguchi M, Kotooka N, Campbell KP, Osawa M, Nishino I. Fukutin genemutations cause dilated cardiomyopathy with minimal muscle weakness. Ann Neurol. 2006 Nov;60(5):597-602. PubMed PMID: 17036286. 182. Navarro CL, De Sandre-Giovannoli A, Bernard R, Boccaccio I, Boyer A, GenevièveD, Hadj-Rabia S, Gaudy-Marqueste C, Smitt HS, Vabres P, Faivre L, Verloes A, Van Essen T, Flori E, Hennekam R, Beemer FA, Laurent N, Le Merrer M, Cau P, Lévy N.Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal . Hum Mol Genet. 2004 Oct 15;13(20):2493-503. Epub 2004 Aug 18. PubMed PMID: 15317753. 183. Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N, Nikaido H, Sai Y,Koizumi A, Shoji Y, Takada G, Matsuishi T, Yoshin o M, Kato H, Ohura T, Tsujimoto G, Hayakawa J, Shimane M, Tsuji A. Primary systemic carnitine deficiency iscaused by mutations in a gene encoding sodium ion-dependent carnitinetransporter. Nat Genet. 1999 Jan;21(1):91-4. PubMed PMID: 9916797. 184. Nigro V, de Sá Moreira E, Piluso G, Vainzof M, Belsito A, Politano L, Puca AA,Passos-Bueno MR, Zatz M. Autosomal recessive limb-girdle muscular dystrophy,LGMD2F, is caused by a mutation in the delta-sarcoglycan gene. Nat Genet. 1996Oct;14(2):195-8. PubMed PMID: 8841194. 185. Nishino I, Fu J, Tanji K, Yamada T, Shimojo S, Koori T, Mora M, Riggs JE, OhSJ, Koga Y, Sue CM, Yamamoto A, Murakami N, Shanske S, Byrne E, Bonilla E, NonakaI, DiMauro S, Hirano M. Primary LAMP-2 deficiency causes X-linked vacuolarcardiomyopathy and myopathy (Danon disease). Nature. 2000 Aug24;406(6798):906-10. PubMed PMID: 10972294. 186. Norton N, Li D, Rieder MJ, Siegfried JD, Rampersaud E, Züchner S, Mangos S,Gonzalez-Quintana J, Wang L, McGee S, Reiser J, Martin E, Nickerson DA,Hershberger RE. Genome- wide studies of copy number variation and exome sequencingidentify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am J HumGenet. 2011 Mar 11;88(3):273-82. doi: 10.1016/j.ajhg.2011.01.016. Epub 2011 Feb25. PubMed PMID: 21353195; PubMed Central PMCID: PMC3059419. 187. Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D'Apice MR, Massart C,Capon F, Sbraccia P, Federici M, Lauro R, Tudisco C, Pallotta R, Scarano G,Dallapiccola B, Merlini L, Bonne G. Mandibuloacral dysplasia is caused by amutation in LMNA-encoding lamin A/C. Am J Hum Genet. 2002 Aug;71(2):426-31. Epub 2002 Jun 19. PubMed PMID: 12075506; PubMed Central PMCID: PMC379176. 188. Ohno S, Zankov DP, Ding WG, Itoh H, Makiyama T, Doi T, Shizuta S, Hattori T,Miyamoto A, Naiki N, Hancox JC, Matsuura H, Horie M. KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation.Circ Arrhythm Electrophysiol. 2011 Jun;4(3):352-61. doi:10.1161/CIRCEP.110.959619. Epub 2011 Apr 14. PubMed PMID: 21493962. 189. Oliveira C, Westra JL, Arango D, Ollikainen M, Domingo E, Ferreira A, Velho S,Niessen R, Lagerstedt K, Alhopuro P, Laiho P, Veiga I, Teixeira MR, Ligtenberg M,Kleibeuker JH, Sijmons RH, Plukker JT, Imai K, Lage P, Hamelin R, Albuquerque C, Schwartz S Jr, Lindblom A, Peltomaki P, Yamamoto H, Aaltonen LA, Seruca R,Hofstra RM. Distinct patterns of KRAS mutations in colorectal carcinomasaccording to germline mismatch repair defects and hMLH1 methylation status. HumMol Genet. 2004 Oct 1;13(19):2303-11. Epub 2004 Aug 4. PubMed PMID: 15294875. 190. Olson TM, Alekseev AE, Moreau C, Liu XK, Zingman LV, Miki T, Seino S,Asirvatham SJ, Jahangir A, Terzic A. KATP channel mutation confers risk for of Marsh all adrenergic atrial fibrillation. Nat Clin Pract Cardiovasc Med. 2007Feb;4(2):110-6. PubMed PMID: 17245405; PubMed Central PMCID: PMC2013306. 191. Olson TM, Illenberger S, Kishimoto NY, Huttelmaier S, Keating MT, Jockusch BM.Metavinculin mutations alter actin interaction in dilated cardiomyopathy.Circulation. 2002 Jan 29;105(4):431-7. PubMed PMID: 11815424. 192. Olson TM, Karst ML, Whitby FG, Driscoll DJ. mutation causesautosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation. 2002 May 21;105(20):2337-40. PubMed PMID: 12021217. 193. Olson TM, Kishimoto NY, Whitby FG, Michels VV. Mutations that alter thesurface charge of alpha- are associated with dilated cardiomyopathy. JMol Cell Cardiol. 2001 Apr;33(4):723-32. PubMed PMID: 11273725. 194. Olson TM, Michels VV, Thibodeau SN, Tai YS, Keating MT. Actin mutations indilated cardiomyopathy, a heritable form of heart failure. Science. 1998 May1;280(5364):750-2. PubMed PMID: 9563954. 195. Osio A, Tan L, Chen SN, Lombardi R, Nagueh SF, Shete S, Roberts R, WillersonJT, Marian AJ. Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. Circ Res. 2007 Mar 30;100(6):766-8. Epub 2007 Mar 8. PubMed PMID: 17347475;PubMed Central PMCID: PMC2775141. 196. Ostergaard E, Rodenburg RJ, van den Brand M, Thomsen LL, Duno M, Batbayli M,Wibrand F, Nijtmans L. Respiratory chain complex I deficiency due to NDUFA12mutations as a new cause of Leigh syndrome. J Med Genet. 2011 Nov;48(11):737-40. doi: 10.1136/jmg.2011.088856. Epub 2011 May 26. PubMed PMID: 21617257. 197. Pauli S, von Velsen N, Burfeind P, Steckel M, Mänz J, Buchholz A, Borozdin W, Kohlhase J. CHD7 mutations causing CHARGE syndrome are predominantly of paternal origin. Clin Genet. 2012 Mar;81(3):234-9. doi: 10.1111/j.1399-0004.2011.01701.x. Epub 2011 May 27. PubMed PMID: 21554267. 198. Pegoraro E, Gavassini BF, Borsato C, Melacini P, Vianello A, Stramare R,Cenacchi G, Angelini C. MYH7 gene mutation in myosin storage myopathy andscapulo-peroneal myopathy. Neuromuscul Disord. 2007 Apr;17(4):321-9. Epub 2007Mar 2. PubMed PMID: 17336526. 199. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000 Mar9;342(10):673-80. Erratum in: N Engl J Med 2001 Feb 1;344(5):392. PubMed PMID:10706896. 200. Pizzuti A, Sarkozy A, Newton AL, Conti E, Flex E, Digilio MC, Amati F, Gianni D, Tandoi C, Marino B, Crossley M, Dallapiccola B. Mutations of ZFPM2/FOG2 genein sporadic cases of tetralogy of Fallot. Hum Mutat. 2003 Nov;22(5):372-7. PubMedPMID: 14517948.

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201. Poetter K, Jiang H, Hassanzadeh S, Master SR, Chang A, Dalakas MC, Rayment I, Sellers JR, Fananapazir L, Epstein ND. Mutations in either the essential orregulatory light chains of myosin are associated with a rare myopathy in humanheart and . Nat Genet. 1996 May;13(1):63-9. PubMed PMID: 8673105. 202. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V,Danieli GA. Mutations in the cardiac ryanodine receptor gene (hRyR2) underliecatech olaminergic polymorphic ventricular tachycardia. Circulation. 2001 Jan16;103(2):196-200. PubMed PMID: 11208676. 203. Putnam EA, Zhang H, Ramirez F, Milewicz DM. Fibrillin-2 (FBN2) mutationsresult in the Marfan-like disorder, congenital contractural arachnodactyly. NatGenet. 1995 Dec;11(4):456-8. PubMed PMID: 7493032. 204. Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, Zimbello R,Simionati B, Basso C, Thiene G, Towbin JA, Danieli GA. Mutation in humandesmoplakin domain binding to causes a dominant form ofarrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2002Nov;71(5):1200-6. Epub 2002 Oct 8. PubMed PMID: 12373648; PubMed Central PMCID:PMC385098. 205. Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M,Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsu shima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R. Germline gain-of-functionmutations in RAF1 cause Noonan syndrome. Nat Genet. 2007 Aug;39(8):1013-7. Epub2007 Jul 1. PubMed PMID: 17603482. 206. Renou L, Stora S, Yaou RB, Volk M, Sinkovec M, Demay L, Richard P, Peterlin B,Bonne G. Heart-hand syndrome of Slovenian type: a new kind of laminopathy. J Med Genet. 2008 Oct;45(10):666-71. doi: 10.1136/jmg.2008.060020. Epub 2008 Jul 8.PubMed PMID: 18611980. 207. Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L,Yassin Y, Tamburino AM, Neel BG, Kucherlap ati RS. Germline gain-of-functionmutations in SOS1 cause Noonan syndrome. Nat Genet. 2007 Jan;39(1):70-4. Epub2006 Dec 3. PubMed PMID: 17143285. 208. Roder C, Peters V, Kasuya H, Nishizawa T, Wakita S, Berg D, Schulte C, Khan N,Tatagiba M, Krischek B. Analysis of ACTA2 in European Moyamoya disease patients. Eur J Paediatr Neurol. 2011 Mar;15(2):117-22. doi: 10.1016/j.ejpn.2010.09.002.Epub 2010 Oct 20. PubMed PMID: 20970362. 209. Rodriguez G, Ueyama T, Ogata T, Czernuszewicz G, Tan Y, Dorn GW 2nd, Bogaev R,Amano K, Oh H, Matsubara H, Willerson JT, Marian AJ. Molecular genetic andfunctional characterization implicate muscle-restricted coiled-coil gene (MURC)as a causal gene for familial dilated cardiomyopathy. Circ Cardiovasc Genet. 2011Aug 1;4(4):349-58. doi: 10.1161/CIRCGENETICS.111.959866. Epub 2011 Jun 3. PubMed PMID: 21642240; PubMed Central PMCID: PMC3157556. 210. Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS,McCormick F, Rauen KA. Germline mutations in genes within the MAPK pathway cause cardio-facio- cutaneous syndrome. Science. 2006 Mar 3;311(5765):1287-90. Epub 2006Jan 26. PubMed PMID: 16439621. 211. Roux-Buisson N, Cacheux M, Fourest-Lieuvin A, Fauconnier J, Brocard J, Denjoy I, Durand P, Guicheney P, Kyndt F, Leenhardt A, Le Marec H, Lucet V, Mabo P,Probst V, Monnier N, Ray PF, Santoni E, Trémeaux P, Lacampagne A, Fauré J,Lunardi J, Marty I. Absence of triadin, a protein of the calcium release complex,is responsible for cardiac arrhythmia with sudden death in human. Hum Mol Genet. 2012 Jun 15;21(12):2759-67. doi: 10.1093/hmg/dds104. Epub 2012 Mar 14. PubMedPMID: 22422768; PubMed Central PMCID: PMC3363337. 212. Sakazume S, Okamoto N, Yamamoto T, Kurosawa K, Numabe H, Ohashi Y, Kako Y,Nagai T, Ohashi H. GPC3 mutations in seven patients with Simpson-Golabi-Behmelsyndrome. Am J Med Genet A. 2007 Aug 1;143A(15):1703-7. PubMed PMID: 17603795. 213. Santamaria R, Blanco M, Chabás A, Grinberg D, Vilageliu L. Identification of14 novel GLB1 mutations, including five deletions, in 19 patients with GM1gangliosidosis from South America. Clin Genet. 2007 Mar;71(3):273-9. PubMed PMID:17309651. 214. Saraiva MJ. Transthyretin mutations in hyperthyroxinemia and amyloid diseases.Hum Mutat. 2001 Jun;17(6):493-503. Review. PubMed PMID: 11385707. 215. Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM,Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L,Stanzial F, Faravelli F, Stuppia L, Puxeddu E, Gelb BD, Dallapiccola B, TartagliaM. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneoussyndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat.2009 Apr;30(4):695-702. doi: 10.1002/humu.20955. PubMed PMID: 19206169; PubMedCentral PMCID: PMC4028130. 216. Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A. Structuralanalysis of the titin gene in hypertrophic cardiomyopathy: identification of anovel disease gene. Biochem Biophys Res Commun. 1999 Aug 27;262(2):411-7. PubMed PMID: 10462489. 217. Schessl J, Taratuto AL, Sewry C, Battini R, Chin SS, Maiti B, Dubrovsky AL,Erro MG, Espada G, Robertella M, Saccoliti M, Olmos P, Bridges LR, Standring P,Hu Y, Zou Y, Swoboda KJ, Scavina M, Goebel HH, Mitchell CA, Flanigan KM, Muntoni F, Bönnemann CG. Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1. Brain. 2009 Feb;132(Pt 2):452-64. doi:10.1093/brain/awn325. Epub 2009 Jan 29. PubMed PMID: 19181672; PubMed CentralPMCID: PMC2724920. 218. Schmitt JP, Kamisago M, Asahi M, Li GH, Ahmad F, Mende U, Kranias EG,MacLennan DH, Seidman JG, Seidman CE. Dilated cardiomyop athy and heart failurecaused by a mutation in . Science. 2003 Feb 28;299(5611):1410-3.PubMed PMID: 12610310. 219. Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ,Seidman CE, Seidman JG. Congenital heart disease caused by mutations in thetranscription factor NKX2-5. Science. 1998 Jul 3;281(5373):108-11. PubMed PMID:9651244. 220. Schulz AL, Albrecht B, Arici C, van der Burgt I, Buske A, Gillessen-KaesbachG, Heller R, Horn D, Hübner CA, Korenke GC, König R, Kress W, Krüger G, Meinecke P, Mücke J, Plecko B, Rossier E, Schinzel A, Schulze A, Seemanova E, Seidel H,Spranger S, Tuysuz B, Uhrig S, Wieczorek D, Kutsche K, Zenker M. Mutation andphenotypic spectrum in patients with cardio-facio-cutaneous and Costellosyndrome. Clin Genet. 2008 Jan;73(1):62-70. Epub 2007 Nov 27. PubMed PMID:18042262. 221. Schwartz CE, Tarpey PS, Lubs HA, Verloes A, May MM, Risheg H, Friez MJ,Futreal PA, Edkins S, Teague J, Briault S, Skinner C, Bauer-Carlin A, SimensenRJ, Joseph SM, Jones JR, Gecz J, Stratton MR, Raymond FL, Stevenson RE. Theoriginal Lujan syndrome family has a novel missense mutation (p.N1007S) in theMED12 gene. J Med Genet. 2007 Jul;44(7):472- 7. Epub 2007 Mar 16. PubMed PMID:17369503; PubMed Central PMCID: PMC2597996. 222. Schönberger J, Wang L, Shin JT, Kim SD, Depreux FF, Zhu H, Zon L, Pizard A,Kim JB, Macrae CA, Mungall AJ, Seidman JG, Seidman CE. Mutation in thetranscriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nat Genet. 2005 Apr;37(4):418-22. Epub 2005 Feb 27. PubMed PMID:15735644. 223. Scott HS, Bunge S, Gal A, Clarke LA, Morris CP, Hopwood JJ. Molecular geneticsof mucopolysaccharidosis type I: diagnostic, clinical, and biologicalimplications. Hum Mutat. 1995;6(4):288-302. Review. PubMed PMID: 8680403. 224. Scurr I, Wilson L, Lees M, Robertson S, Kirk E, Turner A, Morton J, Kidd A,Shashi V, Stanley C, Berry M, Irvine AD, Goudie D, Turner C, Brewer C, SmithsonS. Cantú syndrome: report of nine new cases and expansion of the clinicalphenotype. Am J Med Genet A. 2011 Mar;155A(3):508-18. doi: 10.1002/ajmg.a.33885. Epub 2011 Feb 22. PubMed PMID: 21344641. 225. Selcen D, Engel AG. Mutations in ZASP define a novel form of musculardystrophy in humans. Ann Neurol. 2005 Feb;57(2):269-76. PubMed PMID: 15668942. 226. Selcen D, Muntoni F, Burton BK, Pegoraro E, Sewry C, Bite AV, Engel AG.Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol.2009 Jan;65(1):83-9. doi: 10.1002/ana.21553. PubMed PMID: 19085932; PubMedCentral PMCID: PMC2639628. 227. Selga E, Campuzano O, Pinsach-Abuin ML, Pérez-Serra A, Mademont-Soler I, RiuróH, Picó F, Coll M, Iglesias A, Pagans S, Sarquella-Brugada G, Berne P, Benito B, Brugada J, Porres JM, López Zea M, Castro-Urda V, Fernández-Lozano I, Brugada R. Comprehensive Genetic Characterization of a Spanish Brugada Syndrome Cohort. PLoSOne. 2015 Jul 14;10(7):e0132888. doi: 10.1371/journal.pone.0132888. eCollection2015. PubMed PMID: 26173111; PubMed Central PMCID: PMC4501715. 228. Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM, Schmidt H, Brabant G, Kumar S, Durrington PN, Gregory S, O'Rahilly S, Trembath RC. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet. 2000Feb;24(2):153-6. PubMed PMID: 10655060. 229. Shen J, Bao Y, Liu HM, Lee P, Leonard JV, Chen YT. Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage diseasetype III that is differentially expressed in liver and muscle. J Clin Invest.1996 Jul 15;98(2):352-7. PubMed PMID: 8755644; PubMed Central PMCID: PMC507437. 230. Shinohara M, Saitoh M, Takanashi J, Yamanouchi H, Kubota M, Goto T, Kikuchi M,Shiihara T, Yamanaka G, Mizuguchi M. Carnitine palmitoyl IIpolymorphism is associated with multiple syndromes of acute encephalopathy withvarious infectious diseases. Brain Dev. 2011 Jun;33(6):512-7. doi:10.1016/j.braindev.2010.09.002. Epub 2010 Oct 12. PubMed PMID: 20934285. 231. Sibbing D, Pfeufer A, Perisic T, Mannes AM, Fritz-Wolf K, Unwin S, Sinner MF, Gieger C, Gloeckner CJ, Wichmann HE, Kremmer E, Schäfer Z, Walch A, Hinterseer M,Näbauer M, Kääb S, Kastrati A, Schömig A, Meitinger T, Bornkamm GW, Conrad M, vonBeckerath N. Mutations in the mitochondrial thioredoxin reductase gene TXNRD2cause dilated cardiomyopathy. Eur Heart J. 2011 May;32(9):1121-33. doi:10.1093/eurheartj/ehq507. Epub 2011 Jan 18. PubMed PMID: 21247928. 232. Simard C, Drolet B, Yang P, Kim RB, Roden DM. Polymorphism screening in thecardiac K+ channel gene KCNA5. Clin Pharmacol Ther. 2005 Mar;77(3):138-44. PubMedPMID: 15735608. 233. Smeitink J, van den Heuvel L. Human mitochondrial complex I in health anddisease. Am J Hum Genet. 1999 Jun;64(6):1505-10. Review. PubMed PMID: 10330338;PubMed Central PMCID: PMC1377894. 234. Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ,Schwartz PJ, Towbin JA, Vincent GM, Keating MT. Sp ectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep5;102(10):1178-85. PubMed PMID: 10973849. 235. Spotila LD, Sereda L, Prockop DJ. Partial isodisomy for maternal chromosome 7 and in an individual with a mutation at the COL1A2 locus. Am J Hum Genet. 1992 Dec;51(6):1396-405. PubMed PMID: 1463018; PubMed Central PMCID:PMC1682915. 236. Stallmeyer B, Zumhagen S, Denjoy I, Duthoit G, Hébert JL, Ferrer X, MaugenreS, Schmitz W, Kirchhefer U, Schulze-Bahr E, Guicheney P, Schulze-Bahr E.Mutational spectrum in the Ca(2+)--activated cation channel gene TRPM4 inpatients with cardiac conductance disturbances. Hum Mutat. 2012 Jan;33(1):109-17.doi: 10.1002/humu.21599. Epub 2011 Oct 20. PubMed PMID: 21887725. 237. Suzumori N, Kaname T, Muramatsu Y, Yanagi K, Kumagai K, Mizuno S, Naritomi K, Saitoh S, Sugiura-Ogasawara M. Prenatal diagnosis of X-linked recessive Lenzmicrophthalmia syndrome. J Obstet Gynaecol Res. 2013 Nov;39(11):1545-7. doi:10.1111/jog.12081. Epub 2013 Jul 2. PubMed PMID: 23815237. 238. Symoens S, Syx D, Malfait F, Callewaert B, De Backer J, Vanakker O, Coucke P, De Paepe A. Comprehensive molecular analysis demonstrates type V collagenmutations in over 90% of patients with classic EDS and allows to refinediagnostic criteria. Hum Mutat. 2012 Oct;33(10):1485-93. doi: 10.1002/humu.22137.Epub 2012 Jul 5. PubMed PMID: 22696272. 239. Szabo Z, Crepeau MW, Mitchell AL, Stephan MJ, Puntel RA, Yin Loke K, Kirk RC, Urban Z. Aortic aneurysmal disease and cutis laxa caused by defects in theelastin gene. J Med Genet. 2006 Mar;43(3):255-8. Epub 2005 Aug 5. PubMed PMID:16085695; PubMed Central PMCID: PMC2563239. 240. Ta-Shma A, El-lahham N, Edvardson S, Stepensky P, Nir A, Perles Z, Gavri S,Golender J, Yaakobi-Simhayoff N, Shaag A, Rein AJ, Elpeleg O. Conotruncalmalformations and absent thymus due to a deleterious NKX2-6 mutation. J MedGenet. 2014 Apr;51(4):268-70. doi: 10.1136/jmedgenet-2013-102100. Epub 2014 Jan13. PubMed PMID: 24421281.

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241. Tahara T, Kraus JP, Rosenberg LE. An unusual insertion/deletion in the geneencoding the beta-subunit of propionyl-CoA carboxylase is a frequent mutation in Caucasian propionic acidemia. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1372-6.PubMed PMID: 2154743; PubMed Central PMCID: PMC53477. 242. Tajsharghi H, Thornell LE, Lindberg C, Lindvall B, Henriksson KG, Oldfors A.Myosin storage myopathy associated with a heterozygous missense mutation in MYH7.Ann Neurol. 2003 Oct;54(4):494-500. PubMed PMID: 14520662. 243. Tan HL, Glen E, Töpf A, Hall D, O'Sullivan JJ, Sneddon L, Wren C, Avery P,Lewis RJ, ten Dijke P, Arthur HM, Goodship JA, Keavney BD. Nonsynonymous variantsin the SMAD6 gene predispose to congenital cardiovascular malformation. HumMutat. 2012 Apr;33(4):720-7. doi: 10.1002/humu.22030. Epub 2012 Feb 14. PubMedPMID: 22275001; PubMed Central PMCID: PMC3492913. 244. Taroni F, Verderio E, Fiorucci S, Cavadini P, Finocchiaro G, Uziel G, LamanteaE, Gellera C, DiDonato S. Molecular characterization of inherited carnitinepalmitoyltransferase II deficiency. Proc Natl Acad Sci U S A. 1992 Sep15;89(18):8429-33. PubMed PMID: 1528846; PubMed Central PMCID: PMC49933. 245. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van derBurgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, GelbBD. Mutations in PTPN11, encoding the protein tyrosine SHP-2, causeNoonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. Erratum in: Nat Genet 2002Jan;30(1):123. Nat Genet 2001 Dec;29(4):491. PubMed PMID: 11704759. 246. Tateyama M, Aoki M, Nishino I, Hayashi YK, Sekiguchi S, Shiga Y, Takahashi T, Onodera Y, Haginoya K, Kobayashi K, Iinuma K, Nonaka I, Arahata K, Itoyama Y.Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy.Neurology. 2002 Jan 22;58(2):323-5. Erratum in: Neurology 2002 Mar 12;58(5):839. Itoyoma Y [corrected to Itoyama Y]. PubMed PMID: 11805270. 247. Taylor MR, Slavov D, Gajewski A, Vlcek S, Ku L, Fain PR, Carniel E, Di LenardaA, Sinagra G, Boucek MM, Cavanaugh J, Graw SL, Ruegg P, Feiger J, Zhu X, FergusonDA, Bristow MR, Gotzmann J, Foisner R, Mestroni L; Familial CardiomyopathyRegistry Research Group. Thymopoietin (lamina-associated polypeptide 2) genemutation associated with dilated cardiomyopathy. Hum Mutat. 2005Dec;26(6):566-74. PubMed PMID: 16247757. 248. Taşkesen M, Collin GB, Evsikov AV, Güzel A, Özgül RK, Marshall JD, Naggert JK.Novel Alu retrotransposon insertion leading to Alström syndrome. Hum Genet. 2012 Mar;131(3):407- 13. doi: 10.1007/s00439-011-1083-9. Epub 2011 Aug 30. PubMed PMID:21877133; PubMed Central PMCID: PMC3264847. 249. Theis JL, Bos JM, Bartleson VB, Will ML, Binder J, Vatta M, Towbin JA, GershBJ, Ommen SR, Ackerman MJ. Echocardiographic-determined septal morphology inZ-disc hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 2006 Dec29;351(4):896-902. Epub 2006 Nov 9. PubMed PMID: 17097056. 250. Theis JL, Sharpe KM, Matsumoto ME, Chai HS, Nair AA, Theis JD, de Andrade M,Wieben ED, Michels VV, Olson TM. Homozygosity map ping and exome sequencing revealGATAD1 mutation in autosomal recessive dilated cardiomyopathy. Circ CardiovascGenet. 2011 Dec;4(6):585-94. doi: 10.1161/CIRCGENETICS.111.961052. Epub 2011 Sep 30. PubMed PMID: 21965549; PubMed Central PMCID: PMC3248690. 251. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K,Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T, Gibbs JS, EganJ, Crozier A, Peacock A, Allcock R, Corris P, Loyd JE, Trembath RC, Nichols WC.Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet.2000 Oct;37(10):741-5. PubMed PMID: 11015450; PubMed Central PMCID: PMC1757155. 252. Timal S, Hoischen A, Lehle L, Adamowicz M, Huijben K, Sykut-Cegielska J,Paprocka J, Jamroz E, van Spronsen FJ, Körner C, Gilissen C, Rodenburg RJ, EidhofI, Van den Heuvel L, Thiel C, Wevers RA, Morava E, Veltman J, Lefeber DJ. Geneidentification in the congenital disorders of glycosylation type I by whole-exomesequencing. Hum Mol Genet. 2012 Oct 1;21(19):4151-61. doi: 10.1093/hmg/dds123.Epub 2012 Apr 5. PubMed PMID: 22492991. 253. Tsubata S, Bowles KR, Vatta M, Zintz C, Titus J, Muhonen L, Bowles NE, Towbin JA. Mutations in the human delta-sarcoglycan gene in familial and sporadicdilated cardiomyopathy. J Clin Invest. 2000 Sep;106(5):655-62. PubMed PMID:10974018; PubMed Central PMCID: PMC381284. 254. Tsuji S, Choudary PV, Martin BM, Stubblefield BK, Mayor JA, Barranger JA,Ginns EI. A mutation in the human glucocerebrosidase gene in neuronopathicGaucher's disease. N Engl J Med. 1987 Mar 5;316(10):570-5. PubMed PMID: 2880291. 255. Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, Tana T,Ohya Y, Takishita S, Muratani H, Hiraoka M, Kimura A. Role of HCN4 channel inpreventing ventricular arrhythmia. J Hum Genet. 2009 Feb;54(2):115-21. doi:10.1038/jhg.2008.16. Epub 2009 Jan 23. PubMed PMID: 19165230. 256. Valdés-Mas R, Gutiérrez-Fernández A, Gómez J, Coto E, Astudillo A, Puente DA, Reguero JR, Álvarez V, Morís C, León D, Martín M, Puente XS, López-Otín C.Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy. Nat Commun. 2014 Oct 29;5:5326. doi: 10.1038/ncomms6326. PubMed PMID: 25351925. 257. Valnot I, Osmond S, Gigarel N, Mehaye B, Amiel J, Cormier-Daire V, Munnich A, Bonnefont JP, Rustin P, Rötig A. Mutations of the SCO1 gene in mitochondrialcytochrome c oxidase deficiency with neonatal-onset hepatic failure andencephalopathy. Am J Hum Genet. 2000 Nov;67(5):1104-9. Epub 2000 Sep 28. PubMedPMID: 11013136; PubMed Central PMCID: PMC1288552. 258. Van Norstrand DW, Valdivia CR, Tester DJ, Ueda K, London B, Makielski JC,Ackerman MJ. Molecular and functional characterization of novelglycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in suddeninfant death syndrome. Circulation. 2007 Nov 13;116(20):2253-9. Epub 2007 Oct 29.PubMed PMID: 17967976; PubMed Central PMCID: PMC3332545. 259. Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specificpattern of RAS oncogene mutations in follicular thyroid tumors. J Clin EndocrinolMetab. 2003 Jun;88(6):2745-52. PubMed PMID: 12788883. 260. Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, Tester DJ,Balijepalli RC, Foell JD, Li Z, Kamp TJ, Towbin JA. Mutant caveolin-3 inducespersistent late sodium current and is associated with long-QT syndrome.Circulation. 2006 Nov 14;114(20):2104-12. Epub 2006 Oct 23. PubMed PMID:17060380. 261. Vatta M, Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z, Sinagra G,Lin JH, Vu TM, Zhou Q, Bowles KR, Di Lenarda A, Schimmenti L, Fox M, Chrisco MA, Murphy RT, McKenna W, Elliott P, Bowles NE, Chen J, Valle G, Towbin JA. Mutationsin Cypher/ZASP in patients with dilated cardiomyopathy and left ventricularnon-compaction. J Am Coll Cardiol. 2003 Dec 3;42(11):2014-27. PubMed PMID:14662268. 262. Vervoort R, Islam MR, Sly WS, Zabot MT, Kleijer WJ, Chabas A, Fensom A, Young EP, Liebaers I, Lissens W. Molecular analysis of patients with beta-glucuronidasedeficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII.Am J Hum Genet. 1996 Mar;58(3):457-71. PubMed PMID: 8644704; PubMed CentralPMCID: PMC1914559. 263. Vicart P, Caron A, Guicheney P, Li Z, Prévost MC, Faure A, Chateau D, ChaponF, Tomé F, Dupret JM, Paulin D, Fardeau M. A missense mutation in thealphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet.1998 Sep;20(1):92-5. PubMed PMID: 9731540. 264. Villanueva MP, Aiyer AR, Muller S, Pletcher MT, Liu X, Emanuel B, SrivastavaD, Reeves RH. Genetic and comparative mapping of genes dysregulated in mousehearts lacking the Hand2 gene. Genomics. 2002Dec;80(6):593-600. PubMed PMID: 12504851. 265. Vorgerd M, van der Ven PF, Bruchertseifer V, Löwe T, Kley RA, Schröder R,Lochmüller H, Himmel M, Koehler K, Fürst DO, Huebner A. A mutation in thedimerization domain of filamin c causes a novel type of autosomal dominantmyofibrillar myopathy. Am J Hum Genet. 2005 Aug;77(2):297-304. Epub 2005 May 31. PubMed PMID: 15929027; PubMed Central PMCID: PMC1224531. 266. Wallace RH, Wang DW, Singh R, Scheffer IE, George AL Jr, Phillips HA, Saar K, Reis A, Johnson EW, Sutherland GR, Berkovic SF, Mulley JC. Febrile seizures andgeneralized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet. 1998 Aug;19(4):366-70. PubMed PMID: 9697698. 267. Walter MC, Reilich P, Huebner A, Fischer D, Schröder R, Vorgerd M, Kress W,Born C, Schoser BG, Krause KH, Klutzny U, Bulst S, Frey JR, Lochmüller H.Scapuloperoneal syndrome type Kaeser and a wide phenotypic spectrum ofadult-onset, dominant myopathies are associated with the desmin mutation R350P.Brain. 2007 Jun;130(Pt 6):1485-96. Epub 2007 Apr 17. PubMed PMID: 17439987. 268. Wang B, Yan J, Mi R, Zhou S, Xie X, Wang J, Ma X. Forkhead box H1 (FOXH1)sequence variants in ventricular septal defect. Int J Cardiol. 2010 Nov5;145(1):83-5. doi: 10.1016/j.ijcard.2009.05.030. Epub 2009 Jun 13. PubMed PMID: 19525021. 269. Wang H, Li Z, Wang J, Sun K, Cui Q, Song L, Zou Y, Wang X, Liu X, Hui R, FanY. Mutations in NEXN, a Z-disc gene, are associated with hypertrophiccardiomyopathy. Am J Hum Genet. 2010 Nov 12;87(5):687-93. doi:10.1016/j.ajhg.2010.10.002. Epub 2010 Oct 21. PubMed PMID: 20970104; PubMedCentral PMCID: PMC2978958. 270. Wang L, Guo DC, Cao J, Gong L, Kamm KE, Regalado E, Li L, Shete S, He WQ, Zhu MS, Offermanns S, Gilchrist D, Elefteriades J, Stull JT, Milewicz DM. Mutationsin myosin light chain kinase cause familial aortic dissections. Am J Hum Genet.2010 Nov 12;87(5):701-7. doi: 10.1016/j.ajhg.2010.10.006. Epub 2010 Nov 4.Erratum in: Am J Hum Genet. 2011 Apr 8;88(4):516. PubMed PMID: 21055718; PubMedCentral PMCID: PMC2978973. 271. Wang P, Yang Q, Wu X, Yang Y, Shi L, Wang C, Wu G, Xia Y, Yang B, Zhang R, Xu C, Cheng X, Li S, Zhao Y, Fu F, Liao Y, Fang F, Chen Q, Tu X, Wang QK. Functionaldominant- negative mutation of sodium channel subunit gene SCN3B associated withatrial fibrillation in a Chinese GeneID population. Biochem Biophys Res Commun.2010 Jul 16;398(1):98- 104. doi: 10.1016/j.bbrc.2010.06.042. Epub 2010 Jun 15.PubMed PMID: 20558140; PubMed Central PMCID: PMC3132081. 272. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J,Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL,Landes GM, Connors TD, Keating MT. Positional cloning of a novel potassiumchannel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996Jan;12(1):17-23. PubMed PMID: 8528244. 273. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA,Keating MT. SCN5A mutations associated with an inherited cardiac arrhythmia, longQT syndrome. Cell. 1995 Mar 10;80(5):805-11. PubMed PMID: 7889574. 274. Watanabe H, Darbar D, Kaiser DW, Jiramongkolchai K, Chopra S, Donahue BS,Kannankeril PJ, Roden DM. Mutations in sodium channel β1- and β2-subunitsassociated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2009Jun;2(3):268-75. doi: 10.1161/CIRCEP.108.779181. Epub 2009 Mar 6. PubMed PMID:19808477; PubMed Central PMCID: PMC2727725. 275. Wehner LE, Folz BJ, Argyriou L, Twelkemeyer S, Teske U, Geisthoff UW, WernerJA, Engel W, Nayernia K. Mutation analysis in hereditary haemorrhagictelangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1mutations. Clin Genet. 2006 Mar;69(3):239-45. PubMed PMID: 16542389. 276. Wightman PJ, Santer R, Ribes A, Dougherty F, McGill N, Thorburn DR,FitzPatrick DR. MLYCD mutation analysis: evidence for prot ein mistargeting as acause of MLYCD deficiency. Hum Mutat. 2003 Oct;22(4):288-300. PubMed PMID:12955715.

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277. Windpassinger C, Schoser B, Straub V, Hochmeister S, Noor A, Lohberger B,Farra N, Petek E, Schwarzbraun T, Ofner L, Löscher WN, Wagner K, Lochmüller H,Vincent JB, Quasthoff S. An X-linked myopathy with postural muscle atrophy andgeneralized hypertrophy, termed XMPMA, is caused by mutations in FHL1. Am J HumGenet. 2008 Jan;82(1):88-99. doi: 10.1016/j.ajhg.2007.09.004. PubMed PMID:18179888; PubMed Central PMCID: PMC2253986. 278. Wooderchak-Donahue WL, McDonald J, O'Fallon B, Upton PD, Li W, Roman BL, YoungS, Plant P, Fülöp GT, Langa C, Morrell NW, Botella LM, Bernabeu C, Stevenson DA, Runo JR, Bayrak-Toydemir P. BMP9 mutations cause a vascular-anomaly syndrome withphenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet.2013 Sep 5;93(3):530- 7. doi: 10.1016/j.ajhg.2013.07.004. Epub 2013 Aug 22. PubMedPMID: 23972370; PubMed Central PMCID: PMC3769931. 279. Wu G, Ai T, Kim JJ, Mohapatra B, Xi Y, Li Z, Abbasi S, Purevjav E, Samani K,Ackerman MJ, Qi M, Moss AJ, Shimizu W, Towbin JA, Cheng J, Vatta M.alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channeldisruption. Circ Arrhythm Electrophysiol. 2008 Aug;1(3):193-201. doi:10.1161/CIRCEP.108.769224. PubMed PMID: 19684871; PubMed Central PMCID:PMC2726717. 280. Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, Ichida F, Joo K, Kimura M, Imamura S, Kamatani N, Momma K, Takao A, Nakazawa M, Shimizu N,Matsuoka R. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003 Oct25;362(9393):1366-73. PubMed PMID: 14585638. 281. Yamamoto GL, Aguena M, Gos M, Hung C, Pilch J, Fahiminiya S, Abramowicz A,Cristian I, Buscarilli M, Naslavsky MS, Malaquias AC, Zatz M, Bodamer O, MajewskiJ, Jorge AA, Pereira AC, Kim CA, Passos-Bueno MR, Bertola DR. Rare variants inSOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015Jun;52(6):413-21. doi: 10.1136/jmedgenet- 2015-103018. Epub 2015 Mar 20. PubMedPMID: 25795793 282. Yamamoto GL, Aguena M, Gos M, Hung C, Pilch J, Fahiminiya S, Abramowicz A,Cristian I, Buscarilli M, Naslavsky MS, Malaquias AC, Zatz M, Bodamer O, MajewskiJ, Jorge AA, Pereira AC, Kim CA, Passos-Bueno MR, Bertola DR. Rare variants inSOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015Jun;52(6):413-21. doi: 10.1136/jmedgenet- 2015-103018. Epub 2015 Mar 20. PubMedPMID: 25795793. 283. Yang YQ, Zhang XL, Wang XH, Tan HW, Shi HF, Jiang WF, Fang WY, Liu X.Connexin40 nonsense mutation in familial atrial fibrillation. Int J Mol Med. 2010Oct;26(4):605-10. PubMed PMID: 20818502. 284. Yeowell HN, Walker LC. Mutations in the lysyl hydroxylase 1 gene that resultin enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome typeVI. Mol Genet Metab. 2000 Sep-Oct;71(1-2):212-24. Review. PubMed PMID: 11001813. 285. Zampieri S, Filocamo M, Buratti E, Stroppiano M, Vlahovicek K, Rosso N,Bignulin E, Regis S, Carnevale F, Bembi B, Dardis A. Molecular and functionalanalysis of the HEXB gene in Italian patients affected with Sandhoff disease:identification of six novel alleles. Neurogenetics. 2009 Feb;10(1):49-58. doi:10.1007/s10048-008-0145-1. Epub 2008 Aug 29. PubMed PMID: 18758829. 286. Zhang L, Hu A, Yuan H, Cui L, Miao G, Yang X, Wang L, Liu J, Liu X, Wang S,Zhang Z, Liu L, Zhao R, Shen Y. A missense mutatio n in the CHRM2 gene isassociated with familial dilated cardiomyopathy. Circ Res. 2008 Jun6;102(11):1426-32. doi: 10.1161/CIRCRESAHA.107.167783. Epub 2008 May 1. PubMedPMID: 18451336. 287. Zhou YM, Dai XY, Qiu XB, Yuan F, Li RG, Xu YJ, Qu XK, Huang RT, Xue S, YangYQ. HAND1 loss-of-function mutation associated with familial dilatedcardiomyopathy. Clin Chem Lab Med. 2016 Jul 1;54(7):1161-7. doi:10.1515/cclm-2015-0766. PubMed PMID: 26581070. 288. Zhu L, Vranckx R, Khau Van Kien P, Lalande A, Boisset N, Mathieu F, Wegman M, Glancy L, Gasc JM, Brunotte F, Bruneval P, Wolf JE, Michel JB, Jeunemaitre X.Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aorticaneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006Mar;38(3):343-9. Epub 2006 Jan 29. PubMed PMID: 16444274. 289. di Barletta MR, Viatchenko-Karpinski S, Nori A, Memmi M, Terentyev D, Turcato F, Valle G, Rizzi N, Napolitano C, Gyorke S, Volpe P, Priori SG. Clinicalphenotype and functional characterization of CASQ2 mutations associated withcatecholaminergic polymorphic ventricular tachycardia. Circulation. 2006 Sep5;114(10):1012-9. Epub 2006 Aug 14. PubMed PMID: 16908766. 290. van Engelen BG, Muchir A, Hutchison CJ, van der Kooi AJ, Bonne G, Lammens M.The lethal phenotype of a homozygous nonsense mut ation in the lamin A/C gene.Neurology. 2005 Jan 25;64(2):374-6. PubMed PMID: 15668447. 291. van Hengel J, Calore M, Bauce B, Dazzo E, Mazzotti E, De Bortoli M, LorenzonA, Li Mura IE, Beffagna G, Rigato I, Vleeschouwers M, Tyberghein K, Hulpiau P,van Hamme E, Zaglia T, Corrado D, Basso C, Thiene G, Daliento L, Nava A, van Roy F, Rampazzo A. Mutations in the area composita protein αT- are associated with arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2013Jan;34(3):201-10. doi: 10.1093/eurheartj/ehs373. Epub 2012 Nov 7. PubMed PMID:23136403. 292. van de Laar IM, van der Linde D, Oei EH, Bos PK, Bessems JH, Bierma-ZeinstraSM, van Meer BL, Pals G, Oldenburg RA, Bekkers JA, Moelker A, de Graaf BM, MatyasG, Frohn- Mulder IM, Timmermans J, Hilhorst-Hofstee Y, Cobben JM, Bruggenwirth HT,van Laer L, Loeys B, De Backer J, Coucke PJ, Dietz HC, Willems PJ, Oostra BA, De Paepe A, Roos- Hesselink JW, Bertoli-Avella AM, Wessels MW. Phenotypic spectrum ofthe SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet. 2012Jan;49(1):47-57. doi: 10.1136/jmedgenet-2011- 100382. PubMed PMID: 22167769. 293. van den Bosch BJ, Gerards M, Sluiter W, Stegmann AP, Jongen EL, HellebrekersDM, Oegema R, Lambrichs EH, Prokisch H, Danhauser K, Schoonderwoerd K, de Coo IF,Smeets HJ. Defective NDUFA9 as a novel cause of neonatally fatal complex Idisease. J Med Genet. 2012 Jan;49(1):10-5. doi: 10.1136/jmedgenet-2011-100466.Epub 2011 Nov 23. PubMed PMID: 22114105..

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Disclaimer

This test was developed and its performance characteristics were determined by Mount Sinai Genomics, Inc. DBA Sema4 and was considered acceptable for patient testing. It has not been cleared or approved by the FDA. The FDA has determined that such clearance or approval is not necessary. This type of mutation analysis generally provides highly accurate genotype information for microdeletions and microduplications. Despite this level of accuracy, it should be kept in mind that there are many potential sources of diagnostic error, including misidentification of samples, rare polymorphisms, or other rare genetic variants that interfere with analysis. In addition, families should understand the limitations of the testing and that rare diagnostic errors may occur for the reasons described.

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