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Sema4 Cardiac Information Sheet

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CARDIAC NEXT-GENERATION SEQUENCING PANELS Mail: One Gustave L. Levy Place, Box 1497 1 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 New York, NY 10029 F: 212-241-0139 www.sema4.com 0 3 8 Mail: One Gustave L. Levy Place, Box 1497 2 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 New York, NY 10029 F: 212-241-0139 www.sema4.com Mail: One Gustave L. Levy Place, Box 1497 3 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 New York, NY 10029 F: 212-241-0139 www.sema4.com Mail: One Gustave L. Levy Place, Box 1497 4 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 New York, NY 10029 F: 212-241-0139 www.sema4.com 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 CARDIOMYOPATHY 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 44 AORTOPATHIES PANEL 46 CONGENITAL HEART DISEASE (CHD) PANEL 49 FAMILIAL HYPERCHOLESTEROLEMIA (FH) PANEL 52 PULMONARY HYPERTENSION (PAH) PANEL 54 METABOLIC CARDIOMYOPATHY PANEL 55 NOONAN SPECTRUM DISORDERS PANEL 57 HEREDITARY HEMORRHAGIC TELANGIECTASIA PANEL 59 REFERENCES 60 DISCLAIMER 69 Mail: One Gustave L. Levy Place, Box 1497 5 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 New York, NY 10029 F: 212-241-0139 www.sema4.com 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 diabetes, 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 genes 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 locus 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), Dilated Cardiomyopathy (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 gene 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. Mail: One Gustave L. Levy Place, Box 1497 6 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 New York, NY 10029 F: 212-241-0139 www.sema4.com 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 protein-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,
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  • Neoreviews Quiz

    Neoreviews Quiz

    Birthmarks of Potential Medical Significance Jacinto A. Hernández and Joseph G. Morelli NeoReviews 2003;4;263 DOI: 10.1542/neo.4-10-e263 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/cgi/content/full/neoreviews;4/10/e263 NeoReviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 2000. NeoReviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2003 by the American Academy of Pediatrics. All rights reserved. Online ISSN: 1526-9906. Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 19, 2010 Article dermatology Birthmarks of Potential Medical Significance Jacinto A. Herna´ndez, Objectives After completing this article, readers should be able to: MD*, Joseph G. Morelli, MD† 1. Describe the clinical manifestations of neurofibromatosis type 1. 2. List conditions associated with cafe´au lait macules. 3. Explain the clinical significance of congenital melanocytic nevi. 4. Characterize tuberous sclerosis complex. 5. List the two syndromes associated with port-wine stains and extracutaneous abnormalities. 6. Categorize and describe the three types of hemangiomas. Introduction Birthmarks are common (ϳ8% to 10%) in newborns. Most birthmarks represent vascular and pigmentary lesions. The natural history of these lesions varies from being transient phenomena and essentially normal variants of no clinical significance to permanent cutaneous abnormalities that may be associated with significant systemic complications or diseases. Table 1 lists some neonatal skin lesions that should be recognized by the clinician as clues to more serious disorders.