HEARING AND VISION LOSS NEXT-

GENERATION SEQUENCING PANEL

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Table of Contents

GENETIC TESTING FOR HEARING AND VISION LOSS 5

GENETICS 5 INDICATIONS 5 TESTING METHODS, SENSITIVITY, AND LIMITATIONS 6 TURNAROUND TIME 8 SPECIMEN AND SHIPPING REQUIREMENTS 8 CUSTOMER SERVICES AND GENETIC COUNSELING 9

THE COMPREHENSIVE VISION LOSS PANEL 9

RETINAL DISEASE SUBPANEL 14

ALBINISM, HERMANSKY-PUDLAK SYNDROME, AND SUBPANEL 24

DEVELOPMENTAL SUBPANEL (ANOPHTHALMIA//) 26

STICKLER & SUBPANEL 28

THE COMPREHENSIVE PANEL 32

BRANCHIO-OTO-RENAL SYNDROME SUBPANEL 37

USHER SYNDROME SUBPANEL 38

ZELLWEGER SYNDROME SUBPANEL 39

REFERENCES 41

DISCLAIMER 41

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Genetic Testing For HEARING AND VISION LOSS

Hearing and/or vision loss can result from both genetic and non-genetic etiologies. In general, up to 50% of prelingual hearing loss has a genetic basis, as does up to 60% of congenital blindness among infants. Next generation sequencing (NGS) technology is ideal for diagnostic testing of these disorders due to the extreme locus heterogeneity and phenotypic overlap of the involved. Our customizable targeted NGS panel uses Agilent SureSelectTM XT target enrichment and Illumina HiSeq sequencing to detect pathogenic variants in genes involved in hearing and or vision loss. These genes were selected for inclusion based on literature review, clinical actionablity scores, and comparison with commercially available assays. The Hearing and Vision Loss Panel (308 genes) includes the Comprehensive Hearing Loss (92) and Comprehensive Vision Loss (250) panels. Hearing loss subpanels include Usher Syndrome (11 genes), Zellweger Spectrum Disorder (9), and Branchio-Oto-Renal Syndrome (3). Vision loss subpanels include Retinal Disease (154 genes), , Hermansky-Pudlak Syndrome, and Waardenburg Syndrome (18), Developmental Eye Disorders (21), and Stickler Disease and (41). Customizable testing is available for ordering a hearing-specific or vision-specific panel. Targeted familial testing is also available. Genetic testing may clarify the cause of an individual’s deafness and/or vision loss, provide information on the likelihood of related health issues, and also 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), or X-linked manner (XL). 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 . The parents of an affected child are most often obligate carriers (heterozygotes) and each carry one mutant allele (unless a de novo 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.

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).

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2. Treatment: to clarify the cause of an individual’s hearing and/or vision loss, provide information on the likelihood of related health issues, and guide treatment. 3. Family risk: to establish risk to other family members and future generations.

For patients with a suspected syndrome or disorder, please consider individual gene sequencing or syndromic subpanels prior to ordering the full panel.

Testing Methods, Sensitivity, and Limitations

Next Generation Sequencing (NGS)

Agilent SureSelectTM XT technology uses a custom capture library to target the exonic regions of the genes listed below. These targeted regions are sequenced using the Illumina HiSeq2500 system with 100 bp paired-end reads. The DNA sequences are mapped to and analyzed in comparison with the published genome build UCSC hg19 reference sequence. The targeted coding exons and splice junctions of the known protein-coding RefSeq genes are assessed for the average depth of coverage and data quality threshold values. In our validation, average coverage was greater than 500X per sample with 99% of regions covered at greater than 20X. Sanger sequencing, as indicated, is performed in both directions using BigDye Terminator chemistry on the ABI 3730 DNA Analyzer with target specific amplicons as a confirmatory method for NGS positive results. Sanger sequencing may also be used to supplement targets for which NGS returned a low depth of coverage (<20 reads) or poor mapping scores. False negative results may occur if rare variants interfere with amplification or annealing. In addition, SALSA® MLPA® P163-D1 probemix is used to test the copy number of GJB2 and GJB6 where all testing is approximately 99% accurate. This MLPA test will detect the two most common GJB6 deletions, del(GJB6-D13S18830) and del(GJB6-D13S1854). SALSA® MLPA® P461-A1 probemix is used to test the copy number of OTOA and STRC where all testing is approximately 99% accurate.

The sensitivity of this NGS panel is estimated at 99% for single base substitutions. This NGS technology may not detect all small insertions/deletions and is not diagnostic for large duplications/deletions, repeat expansions, and structural genomic variation. Therefore, oligonucleotide array CGH is available for this test for deletion duplication analysis (please see details below). Variant interpretation and classification was performed based on the American College of Standards and guidelines for the interpretation of sequence variants (Richards et al, 2015). Frequency in control populations were evaluated based on the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/) and Genome Aggregation Database (http://gnomad.broadinstitute.org/). All potentially pathogenic variants may have been confirmed by either a specific genotyping assay or Sanger sequencing as indicated. Variants classified as likely benign in the proband and any further familial testing of such variants will only be confirmed by Sanger sequencing if indicated. Any benign polymorphisms identified during this analysis were not reported. Variant interpretations, based on current knowledge, may change over time as more information arises.

Sanger Sequencing

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Sanger sequencing, as indicated, was performed in both directions 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.

Oligonucleotide array Comparative Genomic Hybridization (Optional Add-on)

The customized oligonucleotide microarray 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 human genome NCBI Build 37 (hg19) and the CGH probes are selected to target the exonic regions of 304 genes. This test does not include analysis of MT-RNR1, P2RX2, STRC, and RAB28. 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 304 medically-relevant genes. Variant interpretation and classification is performed based on the American College of Medical Genetics 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 MT-RNR1, P2RX2, STRC, or RAB28 • Copy number gains and losses associated with genetic susceptibility, quantitative trait loci, pharmacogenetic alleles, and cancer predisposition

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• 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

Test limitations

The NGS technology may not detect all small insertions/deletions and is not diagnostic for large duplications/deletions, repeat expansions, and structural genomic variation. This test will only detect variants within the exons and the intron-exon boundaries of the target genes as listed in the report table. Variants outside these regions will not be detected. 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. A large segmental duplication in the OTOA gene (hg19, chr16:21740425-21808829) of exons 19 to 27 (NM_144672) was excluded due to 99% homology to another proximal genomic region on chromosome 16. A complex repeat region in the TRIOBP gene was also excluded from this test as it was problematic for both targeted capture based NGS and Sanger sequencing (hg19, chr22: 38118937-38122716). NGS of the MT-RNR1 gene is limited to targeted variant analysis of variants chrM:1494C>T and chrM:1555A>G.

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 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.

Turnaround Time

Results are reported to the referring physician within 7-10 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 both parents is requested.

Prenatal Specimens: 2 confluent T-25 flasks of cultured cells (originating from amniotic fluid or chorionic villi) or more than

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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 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.

Tubes of blood, cultured cells, direct CVS, and direct AF should be kept and shipped refrigerated or at room temperature (PLEASE DO NOT FREEZE).

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 VISION LOSS PANEL

The Comprehensive Vision Loss Panel includes 250 genes with four subpanels: the Retinal Disease (154 genes), the Albinism, Hermansky-Pudlak Syndrome and Waardenburg Syndrome (18 genes), the Developmental Eye (21 genes), and the Stickler & Cataract (41 genes) Panels.

The below genes are found on the Comprehensive Vision Loss Panel and are not on any subpanels.

Mim Proportion of Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance No. Disease* 182230: Growth hormone deficiency with pituitary anomalies 182230: Pituitary hormone deficiency, Anophthalmia/Microphthalmia/ MAC: Less common HESX1 601802 combined AD, AR (MAC) Spectrum (<1%) 182230: Septooptic dysplasia Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum 310700: , congenital, infantile Congenital nystagmus FRMD7 300628 XL FIN: Only known gene periodic alternating (FIN) 610427: Cone-rod synaptic disorder, Retinal dystrophy: Congenital stationary night blindness CABP4 608965 AR congenital nonprogressive <1% (1/170 patients) 610444: AD Night blindness, congenital Nougaret CSNB: One stationary (CSNB) Congenital stationary night blindness GNAT1 139330 AD, AR family reported with 616389: AR Night blindness, congenital >135 cases stationary, type 1G ** XL CSNB: 45% 310500: Night blindness, congenital Congenital stationary night blindness NYX 300278 XLR cCSNB: 43% (69/161 stationary (complete) (XL CSNB) cases) 231300: AR , primary open PCG: 20-100%, angle, congenital, juvenile, or adult onset familial; 10-15%, Glaucoma CYP1B1 601771 AR (PCG) simplex 604229: Peters anomaly (PA) PA: Reported in

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Mim Proportion of Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance No. Disease* association with CYP1B1 137750: Glaucoma, primary open angle (PAOG) PAOG: 2-4%, JOAG: Glaucoma MYOC 601652 AD Juvenile onset open angle glaucoma ~33% (JOAG) 126600: Doyne honeycomb degeneration Doyne: 37 families EFEMP1 601548 of AD CD: 12.5% (1/8 cases) Cuticular drusen (CD) 614457: AR Ichthyosis, spastic Stargardt: 17% (1/6 quadriplegia, and mental retardation Macular degeneration ELOVL4 605512 AD, AR cases) not caused by 133190: AD ?Spinocerebellar ABCA4 600110: AD Stargardt disease Batten: Only known gene 204200: Ceroid lipofuscinosis, neuronal JNCL: Rare; Italian: (NCL, Batten disease) Neuronal ceroid lipofuscinosis CLN3 607042 AR 73% (16/22 patients) Juvenile Neuronal Ceroid Lipofucsinosis NCL: Rare; Italian (JNCL) 12.9% (16/124 patients) LINCL: Major in Finland; minor 256731: Ceroid lipofuscinosis, neuronal elsewhere; Finnish: (NCL) 21% (10/47 patients), Neuronal ceroid lipofuscinosis CLN5 608102 AR Late-infantile Neuronal Ceroid Italian: 7% (7/94 Lipofuscinosis (LINCL) patients) NCL: Rare; Italian 5.6% (7/124 patients) JNCL: Italian: ~14% 601780: Ceroid lipofuscinosis, neuronal (3/22 patients) 204300: Ceroid lipofuscinosis, neuronal, LINCL: Variant: Minor; Kufs type, adult onset Italian: 19% (18/94 Neuronal ceroid lipofuscinosis CLN6 606725 Juvenile Neuronal Ceroid Lipofucsinosis AR patients) (JNCL) NCL: Rare; Italian: Late-infantile Neuronal Ceroid 16.9% (21/124 Lipofuscinosis (LINCL) patients) 600143: Ceroid lipofuscinosis, neuronal LINCL: Variant: Rare; (NCL) Italian: 7% (7/94 610003: Ceroid lipofuscinosis, neuronal, Neuronal ceroid lipofuscinosis CLN8 607837 AR patients) Northern epilepsy variant NCL: Italian: 5.6% Late-infantile Neuronal Ceroid (7/124 patients) Lipofuscinosis (LINCL) LINCL: Italian: 1% (1/94 patients as 610127: AR Ceroid lipofuscinosis, CLN10) neuronal NCL: Italian: 0.8% Neuronal ceroid lipofuscinosis CTSD 116840 AR Late-infantile Neuronal Ceroid (1/124 patients) Lipofuscinosis (LINCL) ID: <0.1% (0/986 patients) Congenital NCL: Minor Parry: Only known 162350: Ceroid lipofuscinosis, neuronal, gene Parry type Neuronal ceroid lipofuscinosis DNAJC5 611203 AD NCL: Unknown Adult-onset neuronal ceroid lipofuscinosis AONCL: 10% (2/20 (AONCL) families/individuals) 610951: Ceroid lipofuscinosis, neuronal LINCL: Variant: Minor; (NCL) Italian: 15% (14/94 616170: Macular dystrophy with central Neuronal ceroid lipofuscinosis MFSD8 611124 AR patients as CLN7) cone involvement NCL: Italian: 11.3% Late-infantile Neuronal Ceroid (14/124 patients) Lipofuscinosis (LINCL) INCL: Major; Italian: 256730: Ceroid lipofuscinosis, neuronal 75% (6/8 patients as Infantile Neuronal Ceroid Lipofuscinosis CLN1) (INCL) JNCL: Minor; Italian: Neuronal ceroid lipofuscinosis PPT1 600722 Juvenile Neuronal Ceroid Lipofucsinosis AR 9% (2/22 patients) (JNCL) LINCL: Minor; Italian: Late-infantile Neuronal Ceroid 10% (9/94 patients) Lipofuscinosis (LINCL) Adult NCL: Rare;

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Mim Proportion of Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance No. Disease* Italian: 13.7% (17/124 patients) ID: <0.1% (0/986 patients) Epilepsy: <1% (1/293 patients) LINCL: Italian: 31% (29/94 patients as CLN2) 204500: Ceroid lipofuscinosis, neuronal NCL: Italian: 23.5% (NCL) (31/124 patients) Neuronal ceroid lipofuscinosis TPP1 607998 Late-infantile Neuronal Ceroid AR Classic late-infantile Lipofuscinosis (LINCL) NCL: Major 609270: Spinocerebellar ataxia Variant Juvenile NCL: Rare Epilepsy: <1% (2/293 patients) 607541: AD Corneal dystrophy, Avellino type 121900: AD , Groenouw type I 608470: Corneal dystrophy, Reis-Bucklers type CD: 100% in Chinese 602082: AD Corneal dystrophy, Thiel- -related gene TGFBI 601692 AD (21 families), Korean Behnke type 86.5% (77/89 patients) 121820: AD Corneal dystrophy, epithelial basement membrane 122200: AD Corneal dystrophy, lattice type I (LCD) 608471: AD Corneal dystrophy, lattice type IIIA SFD: Only known Retinopathy-related gene TIMP3 188826 136900: Sorsby fundus dystrophy (SFD) AD gene 121800: Corneal dystrophy, Schnyder Retinopathy-related gene UBIAD1 611632 AD SCD: 10 families type (SCD) 225280: Ectodermal dysplasia, ectrodactyly, and macular dystrophy EEM: Only known Retinopathy-related gene CDH3 114021 (EEM) AR gene 601553: Hypotrichosis, congenital, with juvenile macular dystrophy 133780: Exudative vitreoretinopathy, Retinopathy-related gene FZD4 604579 AD ADFEVR: 4-40% Retinopathy of prematurity (ADFEVR) PGK1D: Only known gene 300653: Phosphoglycerate 1 ID: <0.1% (0/986 Retinopathy-related gene PGK1 311800 XLR deficiency (PGK1D) patients) XLID: >5 total mutations Bradyopsia: One of Retinopathy-related gene RGS9 604067 608415: Bradyopsia None two genes with RGS9BP Bradyopsia: One of Retinopathy-related gene RGS9BP 607814 608415: Bradyopsia None two genes with RGS9 XL Juvenile Retinopathy-related gene RS1 300839 312700: XLD retinoschisis: Only known gene 613310: Exudative vitreoretinopathy Retinopathy-related gene TSPAN12 613138 AD ADFEVR: 3-10% (ADFEVR) 225750: AR, AD Aicardi-Goutieres syndrome (AGS) 610448: AD Chilblain lupus Retinopathy-related gene (syndromic) TREX1 606609 152700: AD {Systemic lupus AD, AR AGS: 23% erythematosus, susceptibility to} 192315: AD Vasculopathy, retinal, with cerebral leukodystrophy Only known gene Syndromic hearing and vision loss: Mohr- ID: <0.1% (0/986 TIMM8A 300356 304700: Mohr-Tranebjaerg syndrome XLR Tranebjaerg syndrome patients) XL: >5 total mutations

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Mim Proportion of Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance No. Disease* Syndromic vision loss related gene (with 200100: AR Abetalipoproteinemia (ABL) ABL: Only known MTTP 157147 AD, AR retinopathy) 605552: AD Metabolic syndrome ** gene ARS: 55% (21/38 180500: AD Axenfeld-Rieger syndrome, probands) of all ARS type 1 (ARS) Syndromic vision loss: Axenfeld-Rieger and 78% (21/27 PITX2 601542 137600: AD Iridogoniodysgenesis, type 2 AD syndrome probands) of ARS with 604229: Peters anomaly dental and/or umbilical 180550: AD Ring dermoid of defects Syndromic vision loss: Chediak-Higashi 214500: Chediak-Higashi syndrome CHS: Only known LYST 606897 AR syndrome (CHS) gene

*Proportion of disease attributed to mutation of this gene. **The relationship between the phenotype and gene is provisional.

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RETINAL DISEASE SUBPANEL

Retinitis pigmentosa (RP) is a group of inherited disorders in which abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium of the retina lead to progressive visual loss. Affected individuals first experience defective dark adaptation or "night blindness", followed by constriction of peripheral visual fields. Many patients with pigmentosa (RP) retain a small degree of central vision throughout their life, but eventually, loss of central vision may occur late in the course of the disease. RP can be isolated (non-syndromic) or syndromic (part of a disease affecting multiple tissues and organs).

Main syndromic causes of RP are the , diseases caused by dysfunctional cilia. These diseases include Leber congenital amaurosis (LCA), Bardet-Biedl syndrome (BBS), (JS), and Senior-Loken syndrome (SLS). Leber congenital amaurosis manifests with vision loss at birth or in early infancy. Patients have profound loss of vision at an early age, and some have been reported to have intellectual disability. Bardet-Biedl syndrome is characterized by obesity, intellectual disability, disease, and loss of vision beginning with loss of night vision and progression to tunnel vision and blindness. Clinical features of Joubert syndrome include intellectual disability, malformations, ocular problems including uncontrollable eye movements and loss of vision, and kidney cysts leading to end-stage renal disease. Senior- Loken syndrome is characterized by LCA and renal cysts and dysfunction, leading to end-stage renal disease.

The Retinal Disease Panel includes the following 154 genes.

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. Achomatopsia: 5-23% in European; 28% in CNGA3 600053 216900: Achromatopsia AR Israeli and Palestinian; 80% in Chinese 262300: Achromatopsia Achromatopsia: 47-87% in European; 72% Achromatopsia CNGB3 605080 248200: Macular degeneration, AR in Israeli and Palestinian juvenile Achromatopsia GNAT2 139340 613856: Achromatopsia AR Achromatopsia: Rare 613093: Cone dystrophy Achromatopsia PDE6C 600827 AR Achromatopsia: Rare Achromatopsia 610024: Achromatopsia Achromatopsia PDE6H 601190 AD, AR Achromatopsia: Rare 610024: Retinal cone dystrophy 209900: AR, DR {Bardet-Biedl syndrome, modifier of} 600151: AR Bardet-Biedl syndrome BBS: <1% Bardet-Biedl syndrome ARL6 608845 AR (BBS) ARRP: 1% 613575: AR (ARRP)** 209900: Bardet-Biedl syndrome Bardet-Biedl syndrome BBS1 209901 AR, DR BBS: ~23% (BBS) 615987: Bardet-Biedl syndrome Bardet-Biedl syndrome BBS10 610148 AR BBS: ~20% (BBS) 615989: Bardet-Biedl syndrome Bardet-Biedl syndrome BBS12 610683 AR BBS: ~5% (BBS) 615981: Bardet-Biedl syndrome Bardet-Biedl syndrome BBS2 606151 (BBS) AR BBS: ~8% 616562: Retinitis pigmentosa 615982: Bardet-Biedl syndrome Bardet-Biedl syndrome BBS4 600374 AR BBS: ~2% (BBS) Bardet-Biedl syndrome BBS5 603650 615983: Bardet-Biedl syndrome AR BBS: ~0.5%

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. (BBS) 615984: Bardet-Biedl syndrome Bardet-Biedl syndrome BBS7 607590 AR BBS: ~1.5% (BBS) 615986: Bardet-Biedl syndrome Bardet-Biedl syndrome BBS9 607968 AR BBS: ~6% (BBS) 615994: Bardet-Biedl syndrome Bardet-Biedl syndrome LZTFL1 606568 AR BBS: Two families (BBS) 605231: Bardet-Biedl syndrome (BBS) Bardet-Biedl syndrome MKKS 604896 AR BBS: ~6% 236700: McKusick-Kaufman syndrome 615990: Bardet-Biedl syndrome (BBS) BBS: ~4.5% Bardet-Biedl syndrome MKS1 609883 AR 617121: Joubert syndrome Joubert: 2.1% (8/375 families) 249000: Meckel syndrome 615993: AR Bardet-Biedl syndrome Bardet-Biedl syndrome SDCCAG8 613524 613615: Senior-Loken syndrome AR NPH: <1% Nephronophthisis (NPH) 615985: Bardet-Biedl syndrome (BBS) BBS: ~1% Bardet-Biedl syndrome TTC8 608132 AR 613464: Retinitis pigmentosa ARRP: 1% (ARRP)** Bardet-Biedl 615988: Bardet-Biedl syndrome syndrome, Limb TRIM32 602290 254110: Muscular dystrophy, limb- AR AR LGMD: Italy: <1% (1 / 198 patients) Girdle Muscular girdle (LGMD), type 2H Dystrophy Colorblindness-related OPN1SW 613522 190900: Colorblindness, tritan AD Tritan: Only known gene gene 604116: Cone-rod dystrophy 248200: AR Fundus flavimaculatus 153800: AD {Macular degeneration, age-related} (AMD) Cone or cone-rod Stargardt: Primary cause ABCA4 601691 248200: AR Retinal dystrophy, AD, AR dystrophy ARRP: 2-5% early-onset severe 601718: AR Retinitis pigmentosa (ARRP) 248200: AR Stargardt disease Cone or cone-rod ADAM9 602713 612775: Cone-rod dystrophy (CRD) None CRD: Four consanguineous families dystrophy 614500: Cone-rod dystrophy Cone or cone-rod C8ORF37 614477 614500: Retinitis pigmentosa AR ARRP: 1% dystrophy (ARRP) 300600: Aland Island Cone or cone-rod 300476: Cone-rod dystrophy CACNA1F 300110 XLR XL CSNB: 55% dystrophy 300071: Night blindness, congenital stationary (incomplete) (CSNB) Cone or cone-rod Inherited retinal dystrophy: <1% (1/179 CACNA2D4 608171 610478: Retinal cone dystrophy None dystrophy Chinese patients, 2/222 unrelated patients) Cone or cone-rod 613660: Cone-rod dystrophy CDHR1 609502 AR Retinal dystrophy: ~1% (3/292 families) dystrophy 613660: Retinitis pigmentosa Cone or cone-rod 608380: Retinitis pigmentosa CERKL 608381 AR ARRP: 3-4% in Spain dystrophy (ARRP) Jalili: Only known gene Cone or cone-rod 217080: Jalili syndrome CNNM4 607805 AR NF1: Identified in one child with concomitant dystrophy Neurofibromatosis 1 (NF1) NF1 and Jalili syndrome Cone or cone-rod 610356: Retinal cone dystrophy KCNV2 607604 AR CRD: 4% (4/90 probands) dystrophy Cone-rod dystrophy (CRD) Cone or cone-rod RAB28 612994 615374: Cone-rod dystrophy (CRD) AR CRD: Four families dystrophy 610381: AD Cone-rod dystrophy Cone or cone-rod (CRD) AD CRD: One family RAX2 610362 AD dystrophy 613757: Macular degeneration, age- Retinal degeneration: Three individuals related ** FA: Primary cause with RLBP1 and RPE65 Cone or cone-rod 136880: Fundus albipunctatus (FA) secondary (~89%, 40/45 cases, ~7%, 3/45 RDH5 601617 AD, AR dystrophy Leber congenital amaurosis (LCA) cases, and 4%, 2/45 cases, respectively) LCA: 1.8% (1/56 patients) Cone or cone-rod 608194: Cone-rod dystrophy RPGRIP1 605446 None LCA: ~5% dystrophy 613826: Leber congenital amaurosis

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. (LCA) Cone-rod retinal 602093: Cone dystrophy (CD) GUCA1A 600364 AD CD/CRD: ~3% (6/216 patients) dystrophy 602093: Cone-rod dystrophy (CRD) Cone-rod retinal Inherited retinal dystrophy: <1% (1/179 PITPNM3 608921 600977: Cone-rod dystrophy AD dystrophy Chinese patients) 612657: Cone-rod dystrophy 608051: AD Macular dystrophy, Cone-rod retinal retinal PROM1 604365 AD, AR ARRP: 1% dystrophy 612095: AR Retinitis pigmentosa (ARRP) 603786: Stargardt disease Cone-rod retinal RIMS1 606629 603649: Cone-rod dystrophy None Retinal dystrophy: <1% (1/170 patients) dystrophy 304020: Cone-rod dystrophy 300834: Macular degeneration, atrophic Cone-rod retinal 300029: Retinitis pigmentosa RPGR 312610 XLR XLRP: 70-90% dystrophy (XLRP) 300455: Retinitis pigmentosa, and sinorespiratory infections, with or without deafness 610283: AR Cone-rod dystrophy Cone-rod retinal SEMA4A 607292 610282: AR, AD Retinitis AD, AR ADRP: 3%-4% in Pakistan dystrophy pigmentosa (ADRP) Congenital stationary 614565: Night blindness, congenital cCSNB: ~3-9%% (5/160 patients, 14/161 GPR179 614515 AR night blindness stationary (complete) (cCSNB) cases) Congenital stationary GRK1 180381 613411: AR Oguchi: One of two genes with SAG night blindness 257270: AR Night blindness, Congenital stationary GRM6 604096 congenital stationary (complete) AR cCSNB: ~14% (22/161 cases) night blindness (cCSNB) Congenital stationary 615058: Night blindness, congenital LRIT3 615004 AR cCSNB: ~3% (5/161 cases) night blindness stationary (complete) (cCSNB) 163500: AD Night blindness, Congenital stationary congenital stationary PDE6B 180072 AD, AR ARRP: 2-5% night blindness 613801: AR Retinitis pigmentosa (ARRP) 610445: Night blindness, congenital stationary Congenital stationary 613731: AR, AD Retinitis ADRP: 20-30% RHO 180380 AD, AR night blindness pigmentosa (ADRP, ARRP) ARRP: 1% 136880: AR, AD Retinitis punctata albescens 258100: Oguchi disease Congenital stationary Oguchi: One of two genes with GRK1 SAG 181031 613758: Retinitis pigmentosa AR night blindness ARRP: 2-3% in Japan (ARRP) Congenital stationary 613830: Night blindness, congenital CSNB with a Riggs- SLC24A1 603617 AR night blindness stationary (complete) typeERG: 10% (1/10 cases) Congenital stationary 613216: Night blindness, congenital TRPM1 603576 AR cCSNB: ~31% (51/161 cases) night blindness stationary (complete) Joubert: 7-10%; 6.9% (26/375 families) Joubert syndrome AHI1 608894 608629: Joubert syndrome AR ID: 1% (2/136 consanguineous Iranian families) Joubert syndrome ARL13B 608922 612291: Joubert syndrome AR Joubert: <1%; 0.5% (2/375 families) Joubert syndrome CEP41 610523 614464: Joubert syndrome AR Joubert: <1% 213300: Joubert syndrome 610156: Mental retardation, truncal Joubert syndrome INPP5E 613037 AR Joubert: 2.4% (9/375 families) obesity, retinal dystrophy, and 200990: 607131: Al-Gazali-Bakalinova Joubert syndrome KIF7 611254 syndrome ** AR Joubert: 0.8% (3/375 families) 614120: ** 200990: Joubert syndrome Joubert syndrome TCTN1 609863 614173: Joubert syndrome AR Joubert: 0.2% (1/375 families) 616654: Joubert syndrome Joubert syndrome TCTN2 613846 AR Joubert: 1.3% (5/375 families) 613885: Meckel syndrome ** 614815: Joubert syndrome Joubert syndrome TCTN3 613847 AR Joubert: 0.2% (1/375 families) 258860: Orofaciodigital syndrome IV

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. 608091: Joubert syndrome Joubert syndrome TMEM216 613277 AR Joubert: ~3%; 2.9% (11/375 families) 603194: Meckel syndrome 614970: Joubert syndrome Joubert: N. European 2% (1/51 cases) Joubert syndrome TMEM231 614949 AR 615397: Meckel syndrome Meckel: 10 cases Joubert syndrome TMEM237 614423 614424: Joubert syndrome AR Joubert: <1%; 0.2% (1/375 families) 615991: {Bardet-Biedl syndrome, modifier of} 216360: COACH syndrome Joubert: ~10%; 6.1% (23/375 families) Joubert syndrome TMEM67 609884 AR 610688: Joubert syndrome NPH: 2-3% 607361: Meckel syndrome 613550: (NPH) Joubert: Unknown NPH: Detected in 7 families w/NPH w/ or w/out extrarenal features, 3 families w/Jeune 613820: AR, AD Nephronophthisis asphyxiating thoracic dystrophy, & additional Joubert syndrome TTC21B 612014 613819: AR Short-rib thoracic AD, AR families w/a NPH-related . Also dysplasia with or without identified in persons w/familial primary focal segmental glomerulosclerosis. Two families had infantile NPH w/extrarenal features. Estimated <1% Joubert syndrome and 614615: Joubert syndrome orofaciodigital C5ORF42 614571 AR Joubert: 8.8% (33/375 families) 277170: Orofaciodigital syndrome VI syndrome 300804: XLR Joubert syndrome 311200: XLD Orofaciodigital Joubert: 1% (4/375 families) Joubert syndrome and syndrome I XLID: <1% (0/150 male patients); >5 total orofaciodigital OFD1 300170 XLD, XLR 300424: XLR Retinitis pigmentosa ** mutations syndrome 300209: XLR Simpson-Golabi- ID: 0.1% (1/986 patients) Behmel syndrome, type 2 216360: COACH syndrome COACH: One of three genes Joubert syndrome and CC2D2A 612013 612285: Joubert syndrome AR Joubert: ~10%; 8.2% (31/375 families) other ciliopathies 612284: Meckel syndrome Meckel: One of 11 genes 615991: AR Bardet-Biedl syndrome ** 610188: AR Joubert syndrome Joubert: ~10%; 7.2% (27/375 families) Joubert syndrome and 611755: Leber congenital amaurosis CEP290 610142 AR LCA: 20% other ciliopathies (LCA) NPH: 2-3% 611134: AR Meckel syndrome 610189: AR Senior-Loken syndrome Nephronophthisis (NPH) 609583: Joubert syndrome Joubert syndrome and 256100: Nephronophthisis, juvenile NPH: 20-25% NPHP1 607100 AR other ciliopathies (NPH) Joubert: 1-2%; 1.3% (5/375 families) 266900: Senior-Loken syndrome 604393: AR Cone-rod dystrophy 604393: AR Leber congenital Leber congenital LCA: 4-8% AIPL1 604392 amaurosis (LCA) AD, AR amaurosis ADRP: Rare 604393: AD Retinitis pigmentosa, juvenile (ADRP) 613835: Leber congenital amaurosis (LCA) Leber congenital 172870: AD Pigmented paravenous LCA: Unknown CRB1 604210 AD, AR amaurosis chorioretinal atrophy ARRP: 6-7% in Spain 600105: AR Retinitis pigmentosa (ARRP) 120970: AD Cone-rod retinal dystrophy Leber congenital LCA: 3% CRX 602225 613829: Leber congenital amaurosis AD amaurosis ADRP: 1% (LCA) Retinitis Pigmentosa (ADRP) 601777: AD Cone-rod dystrophy Leber congenital GUCY2D 600179 204000: AR Leber congenital AD, AR LCA: 6-21% amaurosis amaurosis (LCA) 266920: Short-rib thoracic dysplasia Leber congenital with or without polydactyly IFT140 614620 AR NSRD: ~1% amaurosis Non-syndromic retinal dystrophy (NSRD) Leber congenital 613837: Leber congenital amaurosis LCA: Rare IMPDH1 146690 AD amaurosis 180105: AD Retinitis pigmentosa ADRP: 2-3%

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. (ADRP) 609254: Senior-Loken syndrome Leber congenital LCA: Unknown IQCB1 609237 Leber Congenital Amaurosis (LCA) AR amaurosis NPH: 2-3% Nephronophthisis (NPH) 614186: AR Leber congenital Leber congenital amaurosis (LCA) KCNJ13 603208 AD, AR LCA: Unknown amaurosis 193230: AD Snowflake vitreoretinal degeneration Leber congenital 604537: Leber congenital amaurosis LCA5 611408 None LCA: ~1-2% amaurosis (LCA) 613341: Leber congenital amaurosis (LCA) Leber congenital 613341: Retinal dystrophy, early- LCA: Unknown LRAT 604863 AR amaurosis onset severe ARRP: 1% 613341: Retinitis pigmentosa, juvenile (ARRP) Leber congenital 608553: Leber congenital amaurosis NMNAT1 608700 AR LCA: Unknown amaurosis (LCA) Leber congenital 610612: Leber congenital amaurosis RD3 180040 AR LCA: Unknown amaurosis (LCA) 612712: AR Leber congenital Leber congenital LCA: ~4% RDH12 608830 amaurosis AD, AR amaurosis ADRP: Unknown AD Retinitis Pigmentosa (ADRP) 204100: Leber congenital amaurosis (LCA) LCA: 3-16% Leber congenital RPE65 180069 613794: Retinitis pigmentosa AR ARRP: 2-5% amaurosis (ARRP) FA: 4% (2/45 cases) Fundus albipunctatus (FA) 216360: COACH syndrome Leber congenital 611560: Joubert syndrome Joubert: 2-4%; 2.1% (8/375 families) RPGRIP1L 610937 AR amaurosis 611561: Meckel syndrome NPH: <1% Nephronophthisis (NPH) 604232: Leber congenital amaurosis Leber congenital (LCA) LCA: Unknown SPATA7 609868 AR amaurosis 604232: AR Retinitis pigmentosa, ARRP: 1% juvenile (ARRP) 613105: AD Choriodal dystrophy, central areolar 608133: AR, AD Leber congenital amaurosis 169150: AD Macular dystrophy, Leber congenital patterned amaurosis, cone-rod PRPH2 179605 AD, AR ADRP: 5-10% 608161: AD Macular dystrophy, retinal dystrophy vitelliform 608133: AR, AD Retinitis pigmentosa and digenic (ADRP) 136880: AR, AD Retinitis punctata albescens 613843: Leber congenital amaurosis Leber congenital (LCA) LCA: Unknown amaurosis, retinitis TULP1 602280 AR 600132: Retinitis pigmentosa ARRP: 1% pigmentosa (ARRP) 611809: AR Bestrophinopathy (ARB) 153700: AD Macular dystrophy, Best vitelliform (VMD2) 193220: AD Microcornea, rod-cone dystrophy, cataract, and posterior ARB, VMD2: Only known gene Macular degeneration BEST1 607854 AD, AR staphyloma, AMD, ADRP: Rare Vitreoretinochoroidopathy Age-related macular degeneration (AMD) 613194: AD Retinitis pigmentosa, concentric (ADRP) 607921: Retinitis pigmentosa Macular degeneration FSCN2 607643 AD ADRP: 3% of Japanese; otherwise rare (ADRP) 613827: Retinitis pigmentosa Macular degeneration GUCA1B 602275 AD ADRP: 4%-5% in Japan; rare in UK (ADRP) Macular degeneration RP1L1 608581 613587: Occult macular dystrophy AD OCMD: ~36% (10/28 cases), Japanese:

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. (OCMD) 57% (12/21 families) 607084: Deafness Non-syndromic WHRN 607928 611383: Usher syndrome, type 2D AR Usher syndrome, type 2D : ~0-10% hearing loss (USH2) 301835: Arts syndrome 311070: Charcot-Marie-Tooth Non-syndromic disease (CMTX) CMTX: Unknown hearing loss or 304500: Deafness (X-linked) Arts: Only known gene (4 families reported) syndromic PRPS1 311850 XLR 300661: ID: <0.1% (0/986 patients) neuropathies, Charcot Phosphoribosylpyrophosphate XLID: >5 missense/regulatory mutations Marie Tooth Disease synthetase superactivity; Gout, PRPS-related 613428: Retinitis pigmentosa Retinitis pigmentosa C2ORF71 613425 AR ARRP: 1% (ARRP) 600852: Retinitis pigmentosa Retinitis pigmentosa CA4 114760 AD ADRP: Rare (ADRP) 613756: Retinitis pigmentosa Retinitis pigmentosa CNGA1 123825 AR ARRP: 1-2% (ARRP) 613767: Retinitis pigmentosa Retinitis pigmentosa CNGB1 600724 AR ARRP: 1% (ARRP) 210370: Bietti crystalline Retinitis pigmentosa CYP4V2 608614 AR BCD: Only known gene corneoretinal dystrophy (BCD) 613861: Retinitis pigmentosa ARRP: 1% Retinitis pigmentosa DHDDS 608172 AR (ARRP) CDG: <2 cases 602772: Retinitis pigmentosa Retinitis pigmentosa EYS 612424 AR ARRP: 10-30% in Spain; common in China (ARRP) 606068: Retinitis pigmentosa Retinitis pigmentosa FAM161A 613596 AR ARRP: 1% (ARRP) 616152: AD Macular dystrophy, vitelliform Retinitis pigmentosa IMPG2 607056 AD, AR ARRP: 1% 613581: AR Retinitis pigmentosa (ARRP) 617055: Cold-induced sweating syndrome Retinitis pigmentosa KLHL7 611119 AD ADRP: 1-2% 612943: AD Retinitis pigmentosa (ADRP) 614181: Retinitis pigmentosa Retinitis pigmentosa MAK 154235 AR ARRP: 1% (ARRP) 613862: Retinitis pigmentosa Retinitis pigmentosa MERTK 604705 AR ARRP: 1% (ARRP) 268100: AR Enhanced S-cone ADRP: 1-2% syndrome Retinitis pigmentosa NR2E3 604485 AD, AR ARRP: Rare; found in Sephardic Jews in 611131: AR, AD Retinitis Portugal pigmentosa (ADRP, ARRP) AR Retinal degeneration, clumped pigment type ARRP: 1% Retinitis pigmentosa NRL 162080 AD, AR 613750: AD Retinitis pigmentosa ADRP: Rare (ADRP, ARRP) 613810: Retinitis pigmentosa Retinitis pigmentosa PDE6A 180071 AR ARRP: 2-5% (ARRP) 613582: Retinitis pigmentosa Retinitis pigmentosa PDE6G 180073 AR ARRP: 1% (ARRP) 610599: Retinitis pigmentosa Retinitis pigmentosa PRCD 610598 AR ARRP: 1% (ARRP) 601414: Retinitis pigmentosa Retinitis pigmentosa PRPF3 607301 AD ADRP: 1% (ADRP) 600138: Retinitis pigmentosa Retinitis pigmentosa PRPF31 606419 AD ADRP: 5-10% (ADRP) 613983: Retinitis pigmentosa Retinitis pigmentosa PRPF6 613979 AD ADRP: Rare (ADRP) 600059: Retinitis pigmentosa Retinitis pigmentosa PRPF8 607300 AD ADRP: 2-3% (ADRP) 615233: Retinitis pigmentosa Retinitis pigmentosa RBP3 180290 AR ARRP: 1% (ARRP) ** 613769: Retinitis pigmentosa Retinitis pigmentosa RGR 600342 AR ARRP: 1% (ARRP) 607475: AR Bothnia retinal FA: ~7% (3/45 casees) Retinitis pigmentosa RLBP1 180090 AD, AR dystrophy ARRP: 1%

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. 136880: AR, AD Fundus albipunctatus (FA) 607476: Newfoundland rod-cone dystrophy 136880: AR, AD Retinitis punctata albescens AR Retinitis Pigmentosa (ARRP) 608133: AR, AD Retinitis Retinitis pigmentosa ROM1 180721 AD, AR ADRP: Rare pigmentosa, digenic (ADRP) Retinitis pigmentosa RP1 603937 180100: Retinitis pigmentosa AD, AR AD: 3-4%; AR: 1% 312600: Retinitis pigmentosa Retinitis pigmentosa RP2 300757 XLR XLRP: 10-20% (XLRP) 610359: Retinitis pigmentosa Retinitis pigmentosa SNRNP200 601664 AD ADRP: Unknown (ADRP) Retinopathy-related 193235: Vitreoretinopathy, CAPN5 602537 AD ADNIV: Three families gene neovascular inflammatory (ADNIV) Retinopathy-related CHM 300390 303100: (CHM) XLD CHM: Only known gene gene 611040: AR Microphthalmia, High hyperopia: Chinese: ~7% (3/46 Retinopathy-related isolated MFRP 606227 AR probands) gene 609549: Nanophthalmos ARRP: ~2% (1/65 patients) Retinitis pigmentosa (ARRP) 616428: AD Microphthalmia, isolated, with coloboma Retinopathy-related RBP4 180250 615147: AR Retinal dystrophy, AD, AR Retinal dystrophy: Three families gene coloboma, and comedogenic acne syndrome Retinopathy-related 609923: Retinitis pigmentosa TOPORS 609507 AD ADRP: 1% gene (ADRP) 607236: HARP syndrome Retinopathy-related NBIA: 35-50% PANK2 606157 234200: Neurodegeneration with AR gene (syndromic) Epilepsy: <1% (1/293 patients) brain iron accumulation (NBIA) Syndromic hearing and vision loss: Alstrom ALMS1 606844 203800: Alstrom syndrome AR Alstrom: Only known gene syndrome Syndromic hearing and vision loss: optic TMEM126A 612988 612989: Optic atrophy (OPA7) AR OPA7: Rare atrophy with or without auditory neuropathy 616896: Mitochondrial DNA Syndromic hearing and depletion syndrome vision loss: optic One of three genes in which mutations are (encephalocardiomyopathic type) atrophy, auditory known to cause mtDNA deletion or mtDNA OPA1 605290 210000: AR Behr syndrome AD, AR neuropathy, axonal depletion-related ataxia neuropathy 165500: AD Optic atrophy sensorineural syndromes 125250: AD Optic atrophy plus polyneuropathy syndrome Syndromic hearing and vision loss: 612674: Polyneuropathy, hearing polyneuropathy ABHD12 613599 loss, ataxia, retinitis pigmentosa, AR Cerebral ataxia: Reported in 1-5 families hearing loss ataxia and cataract (PHARC) retinitis pigmentosa 605472: AR, DD Usher syndrome, Syndromic hearing and type 2C vision loss: Usher ADGRV1 602851 AR, DD Usher Type II: ~7-19% 605472: AR, DD Usher syndrome, syndrome type 2C Syndromic hearing and 601386: AR Deafness vision loss: Usher CDH23 605516 601067: AR, DR Usher syndrome, AR, DR USH1: 7-20% syndrome type 1D/F (USH1) Syndromic hearing and 609439: Deafness vision loss: Usher CIB2 605564 614869: Usher syndrome, type IJ AR USH1: Unknown syndrome (USH1) 614180: Retinitis pigmentosa Syndromic hearing and (ARRP) ARRP: 1% vision loss: Usher CLRN1 606397 AR 276902: Usher syndrome, type 3A USH3: One of two genes with HARS syndrome (USH3) 616625: AD Charcot-Marie-Tooth Syndromic hearing and disease, axonal, type 2W (CMT2W) CMT2W: 5 families vision loss: Usher HARS 142810 AD, AR 614504: AR Usher syndrome type USH3: One of two genes with CLRN1 syndrome 3B (USH3)

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. 601317: AD Deafness Syndromic hearing and 600060: AR Deafness vision loss: Usher MYO7A 276903 AD, AR USH1: 53-63% 276900: AR Usher syndrome, type syndrome 1B (USH1) 609533: AR Deafness Syndromic hearing and 601067: AR, DR Usher syndrome, vision loss: Usher PCDH15 605514 type 1D/F (USH1) AR, DR USH1: 7-12% syndrome 602083: AR Usher syndrome, type 1F Syndromic hearing and 602092: Deafness vision loss: Usher USH1C 605242 276904: Usher syndrome, type 1C AR USH1: 1-15% syndrome (USH1) Syndromic hearing and 606943: Usher syndrome, type 1G vision loss: Usher USH1G 607696 AR USH1: Rare (0-4%) (USH1) syndrome Syndromic hearing and 613809: Retinitis pigmentosa vision loss: Usher USH2A 608400 276901: AR Usher syndrome, type AR USH2: 57-79% syndrome 2A (USH2) 234580: AR Heimler syndrome Syndromic hearing and 214100: AR Peroxisome biogenesis vision loss: Zellweger PEX1 602136 disorder 1A (Zellweger) AR Zellweger: 57-68% syndrome 601539: Peroxisome biogenesis disorder 1B (NALD/IRD) 614870: Peroxisome biogenesis Syndromic hearing and disorder 6A (Zellweger) vision loss: Zellweger PEX10 602859 AR Zellweger: ~3-5% 614871: Peroxisome biogenesis syndrome disorder 6B Syndromic hearing and 614887: Peroxisome biogenesis vision loss: Zellweger PEX14 601791 AR Zellweger: <1% disorder 13A (Zellweger) syndrome 614876: Peroxisome biogenesis Syndromic hearing and disorder 8A, (Zellweger) vision loss: Zellweger PEX16 603360 None Zellweger: 0.5-1% 614877: Peroxisome biogenesis syndrome disorder 8B Syndromic hearing and 614886: Peroxisome biogenesis vision loss: Zellweger PEX19 600279 None Zellweger: <1% disorder 12A (Zellweger) syndrome 614866: Peroxisome biogenesis Syndromic hearing and disorder 5A (Zellweger) vision loss: Zellweger PEX2 170993 AR Zellweger: 1-4% 614867: Peroxisome biogenesis syndrome disorder 5B 214110: Peroxisome biogenesis disorder 2A (Zellweger) Syndromic hearing and 202370: Peroxisome biogenesis vision loss: Zellweger PEX5 600414 AR Zellweger: 1.5-2% disorder 2B syndrome 616716: Rhizomelic chondrodysplasia punctata, type 5 616617: AR Heimler syndrome Syndromic hearing and 614862: Peroxisome biogenesis vision loss: Zellweger PEX6 601498 disorder 4A (Zellweger) AR Zellweger: ~11-16% syndrome 614863: Peroxisome biogenesis disorder 4B Syndromic hearing AR Ataxia: More common (>5 families) PHYH 602026 266500: Refsum disease AR loss: Refsum disease 266500: >90% Syndromic vision loss NPH: Identified in a Saudi child and in related gene (with CEP164 614848 614845: Nephronophthisis (NPH) AR in <1% (3/856) of families w/NPH-related retinopathy) ciliopathies; estimated <1% Syndromic vision loss 609033: Ataxia, posterior column, Cerebellar Ataxia: Less common (1-5 related gene (with FLVCR1 609144 AR with retinitis pigmentosa families) retinopathy) 267010: Meckel syndrome Syndromic vision loss 604387: Nephronophthisis (NPH) related gene (with NPHP3 608002 AR NPH: 1-2% 208540: Renal-hepatic-pancreatic retinopathy) dysplasia Syndromic vision loss 606966: Nephronophthisis (NPH), related gene (with NPHP4 607215 AR NPH: 3-4% Senior-Loken syndrome retinopathy) Syndromic vision loss 614378: Cranioectodermal NPH: Biallelic pathogenic variants identified WDR19 608151 AR related gene (with dysplasia** in families w/cranioectodermal dysplasia,

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. retinopathy) 614377: Nephronophthisis Jeune syndrome, Senior-Lken syndrome, & 616307: Senior-Loken syndrome isolated NPH. Eight individuals w/biallelic 614376: Short-rib thoracic dysplasia pathogenic variants had NPH & dilation of with or without polydactyly** the intrahepatic bile ducts. Estimated <1% NPH: <1% (Turkish siblings w/ infantile Syndromic vision loss 614844: Joubert syndrome, NPH, hypoplasia, & situs related gene (with ZNF423 604557 AD, AR Nephronophthisis inversus; 2 individuals w/ Joubert retinopathy) syndrome).

*Proportion of disease attributed to mutation of this gene. **The relationship between the phenotype and gene is provisional.

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ALBINISM, HERMANSKY-PUDLAK SYNDROME, AND WAARDENBURG SYNDROME SUBPANEL

Albinism refers to a set of disorders in which pigmentation of the skin, hair, and/or are lighter than expected due to deficiencies of the pigment . These diseases include oculocutanous albinism, Hermansky-Pudlak syndrome and Waardenburg syndrome.

Hermansky-Pudlak syndrome is an autosomal recessive disorder that is characterized by the presence of lighter-colored skin and hair than unaffected family members, as well as reduced vision. Patients also have a susceptibility to prolonged bleeding caused by abnormalities in the platelets, which normally function in the clotting process. A subset of patients may develop Crohn’s disease.

Oculocutanous albinism (OCA) is a group of disorders that affect pigmentation of the eyes, skin, and hair. Distinctive ocular changes include nystagmus, reduced iris pigment with iris translucency, reduced retinal pigmentation, and foveal hypoplasia with reduction in visual acuity. OCA is inherited in an autosomal recessive manner. Additionally, an X-linked form of leading to minor cutaneous manifestations in affected males also exists.

Waardenburg syndrome is an autosomal dominant auditory-pigmentary disorder characterized by sensorineural deafness, pigmentary disturbances of the hair, skin and eyes, and absence of dystopia canthorum which is the lateral displacement of the inner canthus of each eye. Individuals with WS2E may have neurologic abnormalities, including mental impairment, myelination defects, and ataxia.

The Albinism, Hermansky-Pudlak Syndrome and Waardenburg Syndrome Panel contains the following 18 genes.

Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. 300814: Nystagmus, congenital Albinism GPR143 300808 XL OA1: Only known gene 300500: Ocular albinism, type I, Nettleship-Falls type

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. 203200: Albinism, brown oculocutaneous, type II Albinism OCA2 611409 227220: [Skin/hair/eye pigmentation, blond/brown hair], AR OCA2: Only known gene [Skin/hair/eye pigmentation, blue/nonblue eyes] 606574: Albinism, oculocutaneous, type IV 227240: AR [Skin/hair/eye pigmentation, black/nonblack Albinism SLC45A2 606202 AR OCA4: Only known gene hair], [Skin/hair/eye pigmentation, dark/fair skin], [Skin/hair/eye pigmentation, dark/light eyes] 203100: AR Albinism, oculocutaneous, type IA 606952: Albinism, oculocutaneous, type IB 601800: {Melanoma, cutaneous malignant, Albinism TYR 606933 susceptibility to}, [Skin/hair/eye pigmentation, AD, AR OCA1: Only known gene blue/green eyes], [Skin/hair/eye pigmentation, light/dark/freckling skin] 103470: AD Waardenburg syndrome/albinism, digenic 203290: AR Albinism, oculocutaneous, type III Albinism TYRP1 115501 612271: [Skin/hair/eye pigmentation, variation in, AR OCA3: Only known gene (Melanesian blond hair)] 300600: Aland Island eye disease Cone or cone-rod 300476: Cone-rod dystrophy CACNA1F 300110 XLR XL CSNB: 55% dystrophy 300071: Night blindness, congenital stationary (incomplete) (CSNB) HPS: Puerto Rican: 0%; Hermansky-Pudlak AP3B1 603401 608233: Hermansky-Pudlak syndrome (HPS) AR Non-Puerto Rican: ~1- syndrome 10% Hermansky-Pudlak HPS: Puerto Rican: 0%; BLOC1S6 604310 614171: Hermansky-Pudlak syndrome (HPS) AR syndrome Non-Puerto Rican: 1% HPS: Puerto Rican: 0- Hermansky-Pudlak HPS1 604982 203300: Hermansky-Pudlak syndrome (HPS) AR 74%; Non-Puerto Rican: syndrome 0-43% HPS: Puerto Rican: 0- Hermansky-Pudlak HPS3 606118 614072: Hermansky-Pudlak syndrome (HPS) None 25%; Non-Puerto Rican: syndrome 0-~13% Hermansky-Pudlak HPS: Puerto Rican: 0%; HPS4 606682 614073: Hermansky-Pudlak syndrome (HPS) None syndrome Non-Puerto Rican: ~12% Hermansky-Pudlak HPS: Puerto Rican: 0%; HPS5 607521 614074: Hermansky-Pudlak syndrome (HPS) None syndrome Non-Puerto Rican: ~9% Hermansky-Pudlak HPS: Puerto Rican: 0%; HPS6 607522 614075: Hermansky-Pudlak syndrome (HPS) None syndrome Non-Puerto Rican: ~0-7% CCHS: AD, Identified in a 209880: congenital central hypoventilation syndrome Syndromic hearing subset of individuals (CCHS) loss: Waardenburg EDN3 131242 AD, AR Nonsyndromic HSCR: 5% 613265: Waardenburg syndrome, type 4B (WS4) syndrome WS4: AR, Common with 613712: Hirschsprung disease (HSCR)** EDNRB ABCD syndrome: (AR), only known gene 600501: albinism, black lock, cell migration disorder of Nonsyndromic Syndromic hearing neurocytes of the gut and deafness (ABCD) syndrome Hirschsprung disease: AR, loss: Waardenburg EDNRB 131244 600155: Hirschsprung disease (HSCR)** AD, AR 3-7% syndrome 277580: AR, AD Waardenburg syndrome, type 4A Waardenburg Type 4A: (WS4) (AR, AD) Common with EDN3 614456: cutaneous malignant melanoma ** Syndromic hearing 103500: AD Tietz albinism-deafness syndrome Waardenburg Type 2A loss: Waardenburg MITF 156845 193510: AD Waardenburg syndrome, type 2A (WS2) AD (AD): 10-20% syndrome 103470: AD Waardenburg syndrome/ocular albinism, digenic 122880: AD craniofacial-deafness-hand syndrome Syndromic hearing Waardenburg Type 1 / 3 268220: AR alveolar rhabdomyosarcoma, loss: Waardenburg PAX3 606597 AD, AR (AD, AR): Only known 193500: AD Waardenburg syndrome, type 1 (WS1) syndrome gene 148820: AR, AD Waardenburg syndrome, type 3 609136: peripheral demyleinating neuropathy, central dysmelination, Waardenburg syndrome, and Syndromic hearing Hirschsprung disease (PCWH syndrome) Waardenburg syndrome: loss: Waardenburg SOX10 602229 AD 611584: Waardenburg syndrome, type 2E, with or 15% syndrome without neurologic involvement 613266: Waardenburg syndrome, type 4C *Proportion of disease attributed to mutation of this gene. **The relationship between the phenotype and gene is provisional.

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DEVELOPMENTAL EYE SUBPANEL (ANOPHTHALMIA/MICROPHTHALMIA/ANIRIDIA)

Developmental ocular malformations are structural defects of the eye that are recognizable at birth and result from abnormalities in the normal development process, including anopthalmia (absence of the eye), microphtalmia (very small eye remnant), coloboma (failure of the optic fissure to close), aniridia (absent or partial iris), and hypoplasia (underdeveloped optic nerve).

The Developmental Eye Panel contains the following 21 genes.

Mim Proportion of Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance No. Disease* MAC: >1% 300166: Microphthalmia, syndromic ID: <0.1% Anophthalmia/Microphthalmia/Coloboma BCOR 300485 Anophthalmia/Microphthalmia/Coloboma (MAC) XLD (0/986 patients) (MAC) Spectrum Spectrum XLID: >5 total mutations 607932: AD Microphthalmia, syndromic Anophthalmia/Microphthalmia/Coloboma Anophthalmia/Microphthalmia/Coloboma (MAC) BMP4 112262 AD MAC: 2% (MAC) Spectrum Spectrum 600625: Orofacial cleft 107250: AD Anterior segment mesenchymal dysgenesis MAC: 2.5% Anophthalmia/Microphthalmia/Coloboma 610256: AR , congenital primary FOXE3 601094 AD, AR PA: One of six (MAC) Spectrum Anophthalmia/Microphthalmia/Coloboma (MAC) genes Spectrum Peters' Anomaly (PA) MLS: Only known gene Anophthalmia/Microphthalmia/Coloboma 309801: Linear skin defects with multiple ID: <0.1% HCCS 300056 XLD (MAC) Spectrum congenital anomalies (MLS) (0/986 patients) XLID: 2-5 total mutations 610125: Microphthalmia, syndromic Microphthalmia/Anophthalmia/Coloboma (MAC) Anophthalmia/Microphthalmia/Coloboma Spectrum OTX2 600037 AD MAC: 2-5% (MAC) Spectrum 613986: Pituitary hormone deficiency, combined 610125: Retinal dystrophy, early-onset, with or without pituitary dysfunction 106210: AD Aniridia, Cataract with late-onset corneal dystrophy 120430: AD Coloboma of optic nerve ** MAC: 2% Anophthalmia/Microphthalmia/Coloboma 120200: AD Coloboma, ocular ** PAX6 607108 AD ID: 0.1% (1/986 (MAC) Spectrum 136520: AD Foveal hypoplasia patients) 148190: AD 120430: AD Morning glory disc anomaly ** 165550: AD Optic nerve hypoplasia

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Mim Proportion of Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance No. Disease* 604229: Peters anomaly Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum 269400: Corneal opacification and other ocular Anophthalmia/Microphthalmia/Coloboma anomalies MAC: Less PXDN 605158 AR (MAC) Spectrum Anophthalmia/Microphthalmia/Coloboma (MAC) common (<1%) Spectrum 206920: Microphthalmia with limb anomalies Anophthalmia/Microphthalmia/Coloboma MAC: Less SMOC1 608488 Anophthalmia/Microphthalmia/Coloboma (MAC) AR (MAC) Spectrum common (<1%) Spectrum 206900: Microphthalmia, syndromic, Optic nerve hypoplasia and abnormalities of the central Anophthalmia/Microphthalmia/Coloboma SOX2 184429 nervous system AD MAC: 15-20% (MAC) Spectrum Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum 601186: Microphthalmia, isolated, with Anophthalmia/Microphthalmia/Coloboma coloboma, syndromic STRA6 610745 AR MAC: >1% (MAC) Spectrum Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum 610092: Microphthalmia with coloboma Anophthalmia/Microphthalmia/Coloboma 610093: Microphthalmia, isolated MAC: Less VSX2 142993 None (MAC) Spectrum Anophthalmia/Microphthalmia/Coloboma (MAC) common (<1%) Spectrum Eye anomolies: 107250: Anterior segment mesenchymal 2.5% (2/80 Cataract PITX3 602669 dysgenesis AD patients 610623: Cataract, multiple types, syndromic screened) High hyperopia: 611040: AR Microphthalmia, isolated Chinese: ~7% Retinopathy-related gene MFRP 606227 609549: Nanophthalmos AR (3/46 probands) Retinitis pigmentosa (ARRP) ARRP: ~2% (1/65 patients) FRFB: Only Retinopathy-related gene PLA2G5 601192 228980: [Fleck retina, familial benign] (FRFB) AR known gene 602482: Rieger or Axenfeld anomalies, Axenfeld-Rieger syndrome, type 3 PA: One of six Syndromic hearing and vision loss: 601631: Iris hypoplasia and glaucoma, FOXC1 601090 AD genes Axenfeld-Rieger syndrome Iridogoniodysgenesis, type 1 (Peters' Anomaly, PCG: Limited PA) Primary Congenital Glaucoma (PCG) Fraser: One of Syndromic hearing and vision loss: Fraser three genes FRAS1 607830 219000: Fraser syndrome AR syndrome with GRIP1 and FREM2 Fraser: One of Syndromic hearing and vision loss: Fraser three genes FREM2 608945 219000: Fraser syndrome AR syndrome with GRIP1 and FRAS1 Fraser: One of Syndromic hearing and vision loss: Fraser three genes GRIP1 604597 219000: Fraser syndrome AR syndrome with FRAS1 and FREM2 Norrie: Only known gene Syndromic hearing and vision loss: Norrie 305390: Exudative vitreoretinopathy ID: <0.1% NDP 300658 XLR disesae 310600: Norrie disease (0/986 patients) XLID: >5 total mutations 608980: Bifid nose with or without anorectal and renal anomalies MOTA: Only Syndromic vision loss related gene FREM1 608944 AD, AR 248450: AR Manitoba oculotrichoanal syndrome known gene 614485: AD Trigonocephaly 152950: with or without AD MCLMR: Syndromic vision loss related gene (with KIF11 148760 chorioretinopathy, lymphedema, or mental AD Only known retinopathy) retardation (AD MCLMR) gene *Proportion of disease attributed to mutation of this gene. **The relationship between the phenotype and gene is provisional.

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STICKLER & CATARACT SUBPANEL

Stickler syndrome is an inherited disorder that associates ocular signs with more or less complete forms of , bone disorders and sensorineural deafness. Ocular disorders may include juvenile cataract, , , vitreoretinal or chorioretinal degeneration, , and chronic . Robin sequence includes an opening in the roof of the mouth (a cleft palate), a large (macroglossia), and a small lower jaw (micrognathia). Bones are affected by slight platyspondylisis and large, often defective epiphyses. Juvenile laxity is followed by early signs of arthrosis. The degree of hearing loss varies among affected individuals and may become more severe over time.

Cataracts are partial or complete opacity in the or capsule of one or both eyes that impair vision or cause blindness. While most cataracts are age or injury-related, they may also be genetic and congenital or part of multi-systemic disorders.

The Stickler and Cataract Panel contains the following 41 genes.

Mim Proportion of Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance No. Disease* MAC: >1% 300166: Microphthalmia, syndromic ID: <0.1% (0/986 Anophthalmia/Microphthalmia/Coloboma BCOR 300485 Anophthalmia/Microphthalmia/Coloboma XLD patients) (MAC) Spectrum (MAC) Spectrum XLID: >5 total mutations 610125: Microphthalmia, syndromic Microphthalmia/Anophthalmia/Coloboma (MAC) Spectrum Anophthalmia/Microphthalmia/Coloboma OTX2 600037 613986: Pituitary hormone deficiency, AD MAC: 2-5% (MAC) Spectrum combined 610125: Retinal dystrophy, early-onset, with or without pituitary dysfunction 106210: AD Aniridia, Cataract with late- MAC: 2% Anophthalmia/Microphthalmia/Coloboma onset corneal dystrophy PAX6 607108 AD ID: 0.1% (1/986 (MAC) Spectrum 120430: AD Coloboma of optic nerve ** patients) 120200: AD Coloboma, ocular **

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Mim Proportion of Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance No. Disease* 136520: AD Foveal hypoplasia 148190: AD Keratitis 120430: AD Morning glory disc anomaly ** 165550: AD Optic nerve hypoplasia 604229: Peters anomaly Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum 269400: Corneal opacification and other Anophthalmia/Microphthalmia/Coloboma ocular anomalies MAC: Less common PXDN 605158 AR (MAC) Spectrum Anophthalmia/Microphthalmia/Coloboma (<1%) (MAC) Spectrum 610092: Microphthalmia with coloboma Anophthalmia/Microphthalmia/Coloboma 610093: Microphthalmia, isolated MAC: Less common VSX2 142993 None (MAC) Spectrum Anophthalmia/Microphthalmia/Coloboma (<1%) (MAC) Spectrum 614691: Cataract Sengers: Only Cataract AGK 610345 AR 212350: Sengers syndrome known gene NCC: 39.4% (46 probands) with 604219: Cataract, multiple types CRYAB, CRYBA4, Cataract CRYAA 123580 AD Nonsyndromic (NCC) CRYGC, CRYBB1, CRYBB2, CRYBB3, and CRYGD 615184: AD Cardiomyopathy, dilated 613763: AR,AD Cataract, multiple types 608810: AD Myopathy, myofibrillar (MFM) Cataract CRYAB 123590 AD, AR MFM: 3% 613869: AR Myopathy, myofibrillar, fatal infantile hypertrophy, alpha-B crystallin- related NCC: 39.4% (46 probands) with 611544: Cataract, multiple types CRYAA, CRYAB, Cataract CRYBB1 600929 None Nonsyndromic congenital cataract (NCC) CRYBA4, CRYGC, CRYBB2, CRYBB3, and CRYGD NCC: 39.4% (46 probands) with 609741: Cataract CRYAA, CRYAB, Cataract CRYBB3 123630 AD, AR Nonsyndromic congenital cataract (NCC) CRYBA4, CRYGC, CRYBB1, CRYBB2, and CRYGD NCC: 12 Pakistani 610019: Cataract families and one Cataract FYCO1 607182 AR Nonsyndromic congenital cataract (NCC) Arab Israeli family; 10% (2/20 patients) 110800: AD Adult i phenotype without NCC: 4 distantly cataract related Arab Israeli Cataract GCNT2 600429 110800: AD [Blood group, Ii] AD, AR families; one 116700: AR Cataract with adult i phenotype consanguineous Nonsyndromic congenital cataract (NCC) Pakistani family NCC: 21.2% (46 116200: Cataract, multiple types Cataract GJA8 600897 AD probands) with Nonsyndromic congenital cataract (NCC) GJA3 116800: Cataract, multiple types NCC: 5% (1/20 Cataract HSF4 602438 AD Nonsyndromic congenital cataract (NCC) patients) 107250: Anterior segment mesenchymal Eye anomolies: dysgenesis Cataract PITX3 602669 AD 2.5% (2/80 patients 610623: Cataract, multiple types, screened) syndromic 613887: Cataract SCC: ~4% (1/23 Cataract TDRD7 611258 None Sporadic Congenital Cataract (SCC) cases) 120970: AD Cone-rod retinal dystrophy LCA: 3% Leber congenital amaurosis CRX 602225 613829: Leber congenital amaurosis (LCA) AD ADRP: 1% Retinitis Pigmentosa (ADRP) 614186: AR Leber congenital amaurosis (LCA) Leber congenital amaurosis KCNJ13 603208 AD, AR LCA: Unknown 193230: AD Snowflake vitreoretinal degeneration Macular degeneration BEST1 607854 611809: AR Bestrophinopathy (ARB) AD, AR ARB, VMD2: Only

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Mim Proportion of Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance No. Disease* 153700: AD Macular dystrophy, Best known gene vitelliform (VMD2) AMD, ADRP: Rare 193220: AD Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma, Vitreoretinochoroidopathy Age-related macular degeneration (AMD) 613194: AD Retinitis pigmentosa, concentric (ADRP) 603622: AD Deafness 153650: AD Epstein syndrome Epstein, Fechtner, 153640: AD Fechtner syndrome May-Hegglin, Non-syndromic hearing loss MYH9 160775 600208: AD Macrothrombocytopenia and AD Sebastian: Only progressive sensorineural deafness known gene 155100: AD May-Hegglin anomaly 605249: AD Sebastian syndrome 116400: AD Cataract ** 600965: AD Deafnes 125853: AD {noninsulin-dependent Wolfram: Only Non-syndromic hearing loss WFS1 606201 AD, AR diabetes mellitus, association} known gene 222300: AR Wolfram syndrome 614296: AD Wolfram-like syndrome 607475: AR Bothnia retinal dystrophy 136880: AR, AD Fundus albipunctatus (FA) FA: ~7% (3/45 607476: Newfoundland rod-cone dystrophy Retinitis pigmentosa RLBP1 180090 AD, AR casees) 136880: AR, AD Retinitis punctata ARRP: 1% albescens AR Retinitis Pigmentosa (ARRP) 193235: Vitreoretinopathy, neovascular ADNIV: Three Retinopathy-related gene CAPN5 602537 AD inflammatory (ADNIV) families 258870: Gyrate atrophy of and Gyrate atrophy: Retinopathy-related gene OAT 613349 AR retina with or without ornithinemia Only known gene 214150: AR Cerebrooculofacioskeletal syndrome 133540: AR Cockayne syndrome, type B 278800: AR De Sanctis-Cacchione Syndromic hearing and vision loss: syndrome ERCC6 609413 AD, AR Cockayne: 65% Cockayne syndrome 211980: AR {Lung cancer, susceptibility to} 613761: {Macular degeneration, age- related, susceptibility to} 616946: AD Premature ovarian failure 600630: AR UV-sensitive syndrome Norrie: Only known gene Syndromic hearing and vision loss: Norrie 305390: Exudative vitreoretinopathy ID: <0.1% (0/986 NDP 300658 XLR disesae 310600: patients) XLID: >5 total mutations 601884: AD [Bone mineral density variability] 601813: AR, AD Exudative vitreoretinopathy (ADFEVR) ARFEVR: 12-25% 144750: AD Hyperostosis, endosteal PCD: One of three Syndromic hearing and vision loss: 607634: AD LRP5 603506 AD, AR genes with osteoporosis-pseudoglioma syndrome 259770: AR Osteoporosis-pseudoglioma PRKCSH and syndrome SEC63 166710: AD {Osteoporosis} 144750: AD 607636: AD van Buchem disease, type 2 (PCD) Syndromic hearing and vision loss: 612674: Polyneuropathy, hearing loss, Cerebral ataxia: polyneuropathy hearing loss ataxia retinitis ABHD12 613599 ataxia, retinitis pigmentosa, and cataract AR Reported in 1-5 pigmentosa (PHARC) families AR Ataxia:>5 614879: Peroxisome biogenesis disorder Syndromic hearing and vision loss: families reported PEX7 601757 215100: AR Rhizomelic chondrodysplasia AR rhizomelic chondrodysplasia punctata Refsum: <10% punctata, type 1 (RCDP1) Only known gene 200610: AD , type II or CD, Kniest, LCPD, Syndromic hearing and vision loss: COL2A1 120140 AD, AR PLDST, SEDC, 608805: AD Avascular necrosis of the SMED1, SEDSTN:

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Mim Proportion of Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance No. Disease* femoral head Only known gene 609162: AD Czech dysplasia (CD) Stickler: 80-90% 132450: AD Epiphyseal dysplasia, multiple, with myopia and deafness 156550: AD 150600: AD Legg-Calve-Perthes disease (LCPD) 604864: AD with mild chondrodysplasia 215150: AR Otospondylomegaepiphyseal dysplasia 151210: AD Platyspondylic skeletal dysplasia, Torrance type (PLSDT) 183900: AD SED congenita (SEDC) 184250: AD SMED Strudwick type (SMED1) 616583: AD Spondyloepiphyseal dysplasia, Stanescu type (SEDSTN) 271700: AD Spondyloperipheral dysplasia 609508: AD Stickler sydrome, type I, nonsyndromic ocular 108300: AD Stickler syndrome, type I Vitreoretinopathy with phalangeal epiphyseal dysplasia 614135: AD Multiple epiphyseal dysplasia Syndromic hearing and vision loss: Stickler: Rare, COL9A1 120210 ** AD Stickler syndrome unknown 614134: Stickler syndrome, type IV Syndromic hearing and vision loss: 600204: AD Multiple epiphyseal dysplasia Stickler: Rare, COL9A2 120260 AD, AR Stickler syndrome 614284: AR ?Stickler syndrome, type V unknown 614876: Peroxisome biogenesis disorder Syndromic hearing and vision loss: 8A, (Zellweger) PEX16 603360 None Zellweger: 0.5-1% Zellweger syndrome 614877: Peroxisome biogenesis disorder 8B 113650: Branchiootorenal syndrome, Anterior segment anomalies with or without Syndromic hearing loss: Branchiootorenal EYA1 601653 cataract AD BOR: 40% syndrome 602588: Branchiootic syndrome (BOR) 166780: Otofaciocervical syndrome ** AR Ataxia: More common (>5 Syndromic hearing loss: Refsum disease PHYH 602026 266500: Refsum disease AR families) 266500: >90% 228520: AR 603932: Lumbar disc herniation ** Syndromic hearing loss: Stickler syndrome COL11A1 120280 AD, AR Stickler: 10-20% 154780: AD 604841: AD Stickler syndrome, type II 601868: AD Deafness 609706: AR Deafness 614524: AR, AD Fibrochondrogenesis 215150: AR Otospondylomegaepiphyseal Stickler: Rare, Syndromic hearing loss: Stickler syndrome COL11A2 120290 AD, AR dysplasia unknown 184840: AD Stickler syndrome, type III 277610: AD Weissenbacher-Zweymuller syndrome Syndromic vision loss related gene (with MLIII_: Only known GNPTG 607838 252605: Mucolipidosis III gamma AR retinopathy) gene 118450: AD (ALGS) ALGS: DelDup: ~5- Deafness, congenital heart defects, and 7%, Sequencing: Syndromic vision loss related gene (with posterior embryotoxon ** 89% JAG1 601920 AD retinopathy) 187500: AD Tetralogy of Fallot NIIC: Japanese Neonatal/infantile intrahepatic cholestasis 10% (11/109 (NIIC) patients) 258501: AR 3-methylglutaconic aciduria, Syndromic vision loss related gene (with 3-MGC: Only known OPA3 606580 type III AD, AR retinopathy) gene 165300: AD Optic atrophy with cataract Wagner, ERVR: Syndromic vision loss: Wagner syndrome VCAN 118661 143200: Wagner syndrome AD Only known gene *Proportion of disease attributed to mutation of this gene. **The relationship between the phenotype and gene is provisional.

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THE COMPREHENSIVE HEARING LOSS PANEL

Hearing loss can result from both genetic and non-genetic etiologies. In general, up to 50% of prelingual hearing loss has a genetic basis. Approximately 30% genetic-related cases are caused by syndromic deafness which are associated with other anomalies, such as Pendred (enlarged vesitibular aqueduct), Waardenburg (pigmentary anomalies), branchio-oto-renal (brancial-arch and renal anomalies) syndrome which are representative of the common forms of syndromic hearing loss (Alford et al. 2014). The remaining 70% of genetic-related deafness is due to non-syndromic, isolated forms of deafness. Non-syndromic hearing loss (NSHL) is a mild to profound hearing impairment that occurs in infancy or early childhood, most often prelingually. NSHL may result from genetic or non-genetic causes. While extremely heterogeneous, the majority (70- 80%) of genetic-related NSHL cases are inherited in an autosomal recessive manner, approximately 20% is inherited in an autosomal dominant manner, and the remainder is composed of X-linked and mitochondrial forms (Toriello et al, 2013).

The Comprehensive Hearing Loss Panel includes 92 genes that encompass well-established nonsyndromic hearing loss genes along with genes associated with syndromic hearing loss that includes Pendred and Waardenburg syndrome.Three additional subpanels for other syndromic forms of hereditary deafness include: Usher syndrome (11 genes), Branchio-Oto- Renal syndrome (3 genes) and Zellweger syndrome (9 genes), panels.

The below genes are found on the Comprehensive Hearing Loss Panel and are not on any subpanels.

Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. BWCFF: >20% 614583: Baraitser-Winter AD Deafness: 6.3% Non-syndromic hearing loss ACTG1 102560 Cerebrofrontofacial syndrome (BWCFF) AD Deafness: 0.9% 604717: Deafness MCPH: 1 family with intermediatephenotype AD Deafness: <1.6% Non-syndromic hearing loss CCDC50 611051 607453: Deafness ** AD Deafness: <0.2% Non-syndromic hearing loss CEACAM16 614591 614614: Deafness AD Deafness: 3 families AR Deafness: 0.5% Non-syndromic hearing loss CLDN14 605608 614035: Deafness AR Deafness: 0.5%

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. AD Deafness: 3.2% Non-syndromic hearing loss COCH 603196 601369: Deafness AD Deafness: 0.5% AD Deafness: <1.6% Non-syndromic hearing loss DFNA5 608798 600994: Deafness AD Deafness: <0.2% AR Deafness: 0.3% Non-syndromic hearing loss DFNB59 610219 610220: Deafness AR Deafness: 0.2% AD Deafness: 1.6% Non-syndromic hearing loss DIABLO 605219 614152: Deafness AD Deafness: 0.2% 124900: AD Deafness Non-syndromic hearing loss DIAPH1 602121 616632: AR , cortical blindness, AD, AR AD Deafness: One family microcephaly syndrome 609006: AR Deafness AR Deafness: <0.3% Non-syndromic hearing loss ESPN 606351 AD Deafness, neurosensory, without AD, AR AD Deafness: 3.2% vestibular involvement Deafness: 0.5% AR Deafness: <0.3% Non-syndromic hearing loss ESRRB 602167 608565: Deafness AR Deafness: <0.2% 605362: familial dilated cardiomyopathy, Non-syndromic hearing loss EYA4 603550 (FDC) AD FDC: Unknown (two families) 601316: AD Deafness AR Deafness: ~1% (2/160 families 601869: Deafness Non-syndromic hearing loss GIPC3 608792 AR from Turkey, Iran, Mexico, Non-syndromic Deafness (NSD) Ecuador, and Puerto Rico) 149200: AD Bart-Pumphrey syndrome 601544: AD Deafness 220290: AR, DD Deafness 602540: AD Hystrix-like ichthyosis with deafness Non-syndromic hearing loss GJB2 121011 AD, AR, DD AR Deafness: 50% with GJB6 148210: AD Keratitis-ichthyosis-deafness syndrome 148350: AD Keratoderma, palmoplantar, with deafness 124500: AD Vohwinkel syndrome 612643: AD Deafness 612645: AR Deafness 220290: AR, DD Deafness, digenic Non-syndromic hearing loss GJB6 604418 AD, AR, DD AR Deafness: 50% with GJB2 GJB2/GJB6 129500: AD Ectodermal dysplasia, Clouston type Chudley-McCullough syndrome: 604213: Chudley-McCullough syndrome Non-syndromic hearing loss GPSM2 609245 AR Only known gene (CMCS) AR Deafness: <50% 608641: AD Deafness AD Deafness: <1.6% Non-syndromic hearing loss GRHL2 608576 616029: AR Ectodermal dysplasia/short AD, AR Deafness: <0.2% stature syndrome AR Deafness: 0.3% Non-syndromic hearing loss GRXCR1 613283 613285: Deafness AR Deafness: 0.2% AR Deafness: <0.3% Non-syndromic hearing loss HGF 142409 608265: AR Deafness AR Deafness: <0.2% AR Deafness: ~3% (5/160 families Non-syndromic hearing loss ILDR1 609739 609646: Deafness AR from Turkey, Iran, Mexico, Ecuador, and Puerto Rico) 613641: Charcot-Marie-Tooth disease, hearing loss: Three unrelated, Non-syndromic hearing loss KARS 601421 intermediate, B AR consanguineous Pakistani 613916: Deafness families Non-syndromic hearing loss KCNQ4 603537 600101: Deafness AD DFNA2: Only known gene AR Deafness: 0.3% Non-syndromic hearing loss LHFPL5 609427 610265: Deafness AR Deafness: 0.2% AR Deafness: 2.2% Non-syndromic hearing loss LOXHD1 613072 613079: Deafness AR Deafness: 1.8% AR Deafness: 0.5% Non-syndromic hearing loss LRTOMT 612414 611451: Deafness AR Deafness: 0.5% AR Deafness: <0.3% Non-syndromic hearing loss MARVELD2 610572 610153: Deafness AR Deafness: <0.2% hearing loss: Pakistani: 3% without GJB2 or MYO15A (1/30 Non-syndromic hearing loss MSRB3 613719 613718: Deafness AR families); six other unrelated families reported 580000: Aminoglycoside-Induced Prevalence is population Non-syndromic hearing loss MT-RNR1 561000 Deafness, Mitochondrial 500008: dependent (e.g. NSHL detected

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. Nonsyndromic hearing loss, 0.1% European, 15-20% Spanish, Mitochondrial 3-11% Asian) 600652: Deafness 614369: Peripheral neuropathy, AD Deafness: 7.9% Non-syndromic hearing loss MYH14 608568 AD myopathy, hoarseness, and hearing loss Deafness: 1.1% ** 603622: AD Deafness 153650: AD Epstein syndrome 153640: AD Fechtner syndrome Epstein, Fechtner, May-Hegglin, Non-syndromic hearing loss MYH9 160775 600208: AD Macrothrombocytopenia and AD Sebastian: Only known gene progressive sensorineural deafness 155100: AD May-Hegglin anomaly 605249: AD Sebastian syndrome AR Deafness: 5.6% Non-syndromic hearing loss MYO15A 602666 600316: Deafness AR Deafness: 4.8% AR Deafness: <0.3% Non-syndromic hearing loss MYO3A 606808 607101: Deafness AR Deafness: <0.2% 606346: AD Deafness AR Deafness:<0.3% 606346: AD Deafness, with hypertrophic Non-syndromic hearing loss MYO6 600970 AD, AR AD Deafness: 6.3% cardiomyopathy Deafness: 1.1% 607821: AR Deafness AR Deafness: 2.2% Non-syndromic hearing loss OTOA 607038 607039: Deafness AR Deafness: 1.8% 601071: Auditory neuropathy Non-syndromic hearing loss OTOF 603681 AR DFNB9: Only known gene 601071: Deafness Deafness: Two families (Dutch, Non-syndromic hearing loss OTOG 604487 614945: Deafness AR Spanish) ARNSD: ~1% (2/160 families from Non-syndromic hearing loss OTOGL 614925 614944: Deafness AR Turkey, Iran, Mexico, Ecuador, and Puerto Rico) AD Deafness: <1.6% Non-syndromic hearing loss P2RX2 600844 608224: Deafness AD Deafness: <0.2% XL or Mitochondrial Deafness: Non-syndromic hearing loss POU3F4 300039 304400: Deafness XLR 40% (2/5 cases) Non-syndromic hearing loss POU4F3 602460 602459: Deafness AD hearing loss: <1% (1/342 families) AR Deafness: 1.1% Non-syndromic hearing loss PTPRQ 603317 613391: Deafness AR Deafness: 0.9% AR Deafness: <0.3% Non-syndromic hearing loss RDX 179410 611022: Deafness AR Deafness: <0.2% hearing loss: One Korean Non-syndromic hearing loss SERPINB6 173321 613453: Deafness ** AR individual and one Turkish family XL Nonsyndromic hearing loss: Non-syndromic hearing loss SMPX 300226 300066: Deafness XLD One of three genes Deafness infertility syndrome: Non-syndromic hearing loss STRC 606440 603720: Deafness AR Only known gene AR Deafness: 2.2% 601543: AD Deafness Non-syndromic hearing loss TECTA 602574 AD, AR AD Deafness: 23.8% 603629: AR Deafness Deafness: 5.2% AR Deafness: 2.2% 606705: AD Deafness Non-syndromic hearing loss TMC1 606706 AD, AR AD Deafness: 3.2% 600974: AR Deafness Deafness: 2.3% AR Deafness: <0.3% Non-syndromic hearing loss TMIE 607237 600971: Deafness AR Deafness: <0.2% AR Deafness: 2.4% Non-syndromic hearing loss TMPRSS3 605511 601072: Deafness AR Deafness: 2.0% AR Deafness: 0.3% Non-syndromic hearing loss TPRN 613354 613307: Deafness AR AD Deafness: 1.6% Deafness: 0.5% AR Deafness: 0.8% Non-syndromic hearing loss TRIOBP 609761 609823: Deafness AR Deafness: 0.7% AR Deafness: 0.3% Non-syndromic hearing loss TSPEAR 612920 614861: Deafness AR Deafness: 0.2% 116400: AD Cataract ** 600965: AD Deafnes 125853: AD {noninsulin-dependent Non-syndromic hearing loss WFS1 606201 AD, AR Wolfram: Only known gene diabetes mellitus, association} 222300: AR Wolfram syndrome 614296: AD Wolfram-like syndrome

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. 301835: Arts syndrome CMTX: Unknown 311070: Charcot-Marie-Tooth disease Non-syndromic hearing loss Arts: Only known gene (4 families (CMTX) or syndromic neuropathies, reported) PRPS1 311850 304500: Deafness (X-linked) XLR Charcot Marie Tooth ID: <0.1% (0/986 patients) 300661: Phosphoribosylpyrophosphate Disease XLID: >5 missense/regulatory synthetase superactivity; Gout, PRPS- mutations related Syndromic hearing and Only known gene vision loss: Mohr- TIMM8A 300356 304700: Mohr-Tranebjaerg syndrome XLR ID: <0.1% (0/986 patients) Tranebjaerg syndrome XL: >5 total mutations Syndromic hearing and vision loss: optic atrophy TMEM126A 612988 612989: Optic atrophy (OPA7) AR OPA7: Rare with or without auditory neuropathy 616896: Mitochondrial DNA depletion Syndromic hearing and One of three genes in which syndrome (encephalocardiomyopathic vision loss: optic atrophy, mutations are known to cause type) auditory neuropathy, axonal OPA1 605290 AD, AR mtDNA deletion or mtDNA 210000: AR Behr syndrome sensorineural depletion-related ataxia 165500: AD Optic atrophy polyneuropathy neuropathy syndromes 125250: AD Optic atrophy plus syndrome 300816: Combined oxidative Syndromic hearing loss: phosphorylation deficiency (Leigh Cowchock syndrome, XL Leigh syndrome: One of three syndrome, subacute necrotizing combined oxidative AIFM1 300169 XLR genes encephalomyelopathy) phosphorylation deficiency, CMTX: Unknown 310490: Cowchock syndrome (CMTX) deafness 300614: Deafness (X-linked) 220500: AR DOORS syndrome Syndromic hearing loss: 614617: AR Deafness DOORS: Only known gene Deafness, 616044: AD Deafness EIEE: One of 35 known genes Onychodystrophy, 615338: AR Epileptic encephalopathy, NBIA: 1-2% TBC1D24 613577 AD, AR Osteodystrophy, Mental early infantile (EIEE) Epilepsy: <1% (2/293 patients) Retardation, and Seizures 605021: AR Myoclonic epilepsy, infantile, ID: 2% (1/41 patients) syndrome familial EE: <1% (1/358 patients) Epileptic encephalopathy (EE) 607554: AD Atrial fibrillation, familial 220400: AR Jervell and Lange-Nielsen Syndromic hearing loss: syndrome Jervell & Lange-Nielsen KCNQ1 607542 AD, AR LQTS: 30-35% 192500: AD Long QT syndrome, and syndrome acquired susceptibility to LQTS 609621: Short QT syndrome 600791: Deafness, with enlarged Syndromic hearing loss: SLC26A4 605646 vestibular aqueduct AR PDS: 50% Pendred syndrome 274600: Pendred syndrome (PDS) AR Ataxia: More common (>5 Syndromic hearing loss: PHYH 602026 266500: Refsum disease AR families) Refsum disease 266500: >90% Syndromic hearing loss: 615474: AD Primary aldosteronism, SANDD Sydrome, Sinoatrial seizures, and neurologic abnormalities Deafness: Two consanguineous CACNA1D 114206 AD, AR node dysfunction and 614896: AR Sinoatrial node dysfunction families deafness and deafness 601868: AD Deafness 609706: AR Deafness 614524: AR, AD Fibrochondrogenesis Syndromic hearing loss: 215150: AR Otospondylomegaepiphyseal COL11A2 120290 AD, AR Stickler: Rare, unknown Stickler syndrome dysplasia 184840: AD Stickler syndrome, type III 277610: AD Weissenbacher-Zweymuller syndrome 209880: congenital central CCHS: AD, Identified in a subset hypoventilation syndrome (CCHS) Syndromic hearing loss: of individuals EDN3 131242 613265: Waardenburg syndrome, type AD, AR Waardenburg syndrome Nonsyndromic HSCR: 5% 4B (WS4) WS4: AR, Common with EDNRB 613712: Hirschsprung disease (HSCR)** 600501: albinism, black lock, cell ABCD syndrome: (AR), only migration disorder of neurocytes of the known gene Syndromic hearing loss: gut and deafness (ABCD) syndrome Nonsyndromic Hirschsprung EDNRB 131244 AD, AR Waardenburg syndrome 600155: Hirschsprung disease (HSCR)** disease: AR, 3-7% 277580: AR, AD Waardenburg syndrome, Waardenburg Type 4A: (AR, AD) type 4A (WS4) Common with EDN3

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Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. 614456: cutaneous malignant melanoma ** 103500: AD Tietz albinism-deafness Syndromic hearing loss: syndrome Waardenburg Type 2A (AD): 10- MITF 156845 AD Waardenburg syndrome 193510: AD Waardenburg syndrome, 20% type 2A (WS2) 103470: AD Waardenburg syndrome/ocular albinism, digenic 122880: AD craniofacial-deafness-hand syndrome 268220: AR alveolar rhabdomyosarcoma, Syndromic hearing loss: Waardenburg Type 1 / 3 (AD, PAX3 606597 193500: AD Waardenburg syndrome, AD, AR Waardenburg syndrome AR): Only known gene type 1 (WS1) 148820: AR, AD Waardenburg syndrome, type 3 609136: peripheral demyleinating neuropathy, central dysmelination, Waardenburg syndrome, and Hirschsprung disease (PCWH syndrome) Syndromic hearing loss: SOX10 602229 611584: Waardenburg syndrome, type AD Waardenburg syndrome: 15% Waardenburg syndrome 2E, with or without neurologic involvement 613266: Waardenburg syndrome, type 4C

*Proportion of disease attributed to mutation of this gene. **The relationship between the phenotype and gene is provisional.

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BRANCHIO-OTO-RENAL SYNDROME SUBPANEL

Branchio-oto-renal (BOR) syndrome is characterized by branchial cleft fistulas or cysts, sensorineural and/or conductive hearing loss, pre-auricular pits, structural defects of the outer, middle or inner ear, and renal malformations. BOR sydrome is inherited in an autosomal dominant manner; approximately 10% of causative variants are de novo.

The Branchio-Oto-Renal Panel includes the following three genes.

Gene Mim Proportion of Disease Category OMIM: Prevalent Phenotype(s) Inheritance ID No. Disease* 113650: Branchiootorenal syndrome, Anterior segment Syndromic hearing loss: anomalies with or without cataract EYA1 601653 AD BOR: 40% Branchiootorenal syndrome 602588: Branchiootic syndrome (BOR) 166780: Otofaciocervical syndrome ** BOR/BOS: 2% Syndromic hearing loss: 608389: Branchiootic syndrome (BOS/BOR) Deafness (AD): SIX1 601205 AD Branchiootorenal syndrome 605192: Deafness (AD) <1.6% Deafness: <0.2% Syndromic hearing loss: SIX5 600963 610896: Branchiootorenal syndrome (BOR/BOS) None BOR/BOS: 2.5% Branchiootorenal syndrome

*Proportion of disease attributed to mutation of this gene. **The relationship between the phenotype and gene is provisional.

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USHER SYNDROME SUBPANEL

Usher syndrome is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 has an age of onset in childhood, whereas USH3 often begins in adolescence.

The Usher Syndrome Panel includes the following 11 genes.

Mim Disease Category Gene ID OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease* No. 607084: Deafness Usher syndrome, type 2D Non-syndromic hearing loss WHRN 607928 AR 611383: Usher syndrome, type 2D (USH2) : ~0-10% Syndromic hearing and vision 605472: AR, DD Usher syndrome, type 2C ADGRV1 602851 AR, DD Usher Type II: ~7-19% loss: Usher syndrome 605472: AR, DD Usher syndrome, type 2C 601386: AR Deafness Syndromic hearing and vision CDH23 605516 601067: AR, DR Usher syndrome, type 1D/F AR, DR USH1: 7-20% loss: Usher syndrome (USH1) Syndromic hearing and vision 609439: Deafness CIB2 605564 AR USH1: Unknown loss: Usher syndrome 614869: Usher syndrome, type IJ (USH1) ARRP: 1% Syndromic hearing and vision 614180: Retinitis pigmentosa (ARRP) CLRN1 606397 AR USH3: One of two genes loss: Usher syndrome 276902: Usher syndrome, type 3A (USH3) with HARS 616625: AD Charcot-Marie-Tooth disease, CMT2W: 5 families Syndromic hearing and vision HARS 142810 axonal, type 2W (CMT2W) AD, AR USH3: One of two genes loss: Usher syndrome 614504: AR Usher syndrome type 3B (USH3) with CLRN1 601317: AD Deafness Syndromic hearing and vision 600060: AR Deafness MYO7A 276903 AD, AR USH1: 53-63% loss: Usher syndrome 276900: AR Usher syndrome, type 1B (USH1) 609533: AR Deafness Syndromic hearing and vision 601067: AR, DR Usher syndrome, type 1D/F PCDH15 605514 AR, DR USH1: 7-12% loss: Usher syndrome (USH1) 602083: AR Usher syndrome, type 1F Syndromic hearing and vision 602092: Deafness USH1C 605242 AR USH1: 1-15% loss: Usher syndrome 276904: Usher syndrome, type 1C (USH1) Syndromic hearing and vision USH1G 607696 606943: Usher syndrome, type 1G (USH1) AR USH1: Rare (0-4%) loss: Usher syndrome 613809: Retinitis pigmentosa Syndromic hearing and vision USH2A 608400 276901: AR Usher syndrome, type 2A AR USH2: 57-79% loss: Usher syndrome (USH2) *Proportion of disease attributed to mutation of this gene. **The relationship between the phenotype and gene is provisional.

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ZELLWEGER SYNDROME SUBPANEL

Zellweger syndrome spectrum is a group of peroxisomal disorders arising from a failure of protein import into the peroxisomal membrane or matrix. These peroxisome biogenesis disorders are genetically heterogeneous with at least 14 distinct genetic groups as identified from complementation studies. Peroxisome biogenesis disorders include Zellweger syndrome (ZWS), neonatal (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes. While many of these patients present with severe disease in infancy, individuals diagnosed in childhood may first be identified through loss of hearing or vision.

The Zellweger Syndrome Panel includes the following nine genes.

Gene Mim Proportion of Disease Category OMIM: Prevalent Phenotype(s) Inheritance ID No. Disease* AR Ataxia:>5 614879: Peroxisome biogenesis disorder Syndromic hearing and vision loss: families reported PEX7 601757 215100: AR Rhizomelic chondrodysplasia AR rhizomelic chondrodysplasia punctata Refsum: <10% punctata, type 1 (RCDP1) Only known gene 234580: AR Heimler syndrome 214100: AR Peroxisome biogenesis Syndromic hearing and vision loss: PEX1 602136 disorder 1A (Zellweger) AR Zellweger: 57-68% Zellweger syndrome 601539: Peroxisome biogenesis disorder 1B (NALD/IRD) 614870: Peroxisome biogenesis disorder Syndromic hearing and vision loss: 6A (Zellweger) PEX10 602859 AR Zellweger: ~3-5% Zellweger syndrome 614871: Peroxisome biogenesis disorder 6B Syndromic hearing and vision loss: 614887: Peroxisome biogenesis disorder PEX14 601791 AR Zellweger: <1% Zellweger syndrome 13A (Zellweger) 614876: Peroxisome biogenesis disorder Syndromic hearing and vision loss: 8A, (Zellweger) PEX16 603360 None Zellweger: 0.5-1% Zellweger syndrome 614877: Peroxisome biogenesis disorder 8B Syndromic hearing and vision loss: 614886: Peroxisome biogenesis disorder PEX19 600279 None Zellweger: <1% Zellweger syndrome 12A (Zellweger) 614866: Peroxisome biogenesis disorder Syndromic hearing and vision loss: PEX2 170993 5A (Zellweger) AR Zellweger: 1-4% Zellweger syndrome 614867: Peroxisome biogenesis disorder

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Gene Mim Proportion of Disease Category OMIM: Prevalent Phenotype(s) Inheritance ID No. Disease* 5B 214110: Peroxisome biogenesis disorder 2A (Zellweger) Syndromic hearing and vision loss: 202370: Peroxisome biogenesis disorder PEX5 600414 AR Zellweger: 1.5-2% Zellweger syndrome 2B 616716: Rhizomelic chondrodysplasia punctata, type 5 616617: AR Heimler syndrome 614862: Peroxisome biogenesis disorder Syndromic hearing and vision loss: PEX6 601498 4A (Zellweger) AR Zellweger: ~11-16% Zellweger syndrome 614863: Peroxisome biogenesis disorder 4B

*Proportion of disease attributed to mutation of this gene. **The relationship between the phenotype and gene is provisional.

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References

1. Abdel-Salam GM et al., Am J Med Genet A. 2013 Aug; 161A (8):1875-81. Further delineation of the clinical spectrum in RNU4ATAC related microcephalic osteodysplastic primordial type I. 2. Alford RL ACMG Working Group on Update of Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss; Professional Practice and Guidelines Committee. Genet Med. 2014 Apr;16(4):347-55 3. Ashwal et al., Neurology 2009, 73: 887-897 Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. 4. Baldwin EL, et al. (2008) Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray. Genet Med. 10:415-429. 5. Cheung SW, et al. (2005) Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet Med. 7:422–432. 6. de Vries BB, et al. (2005) Diagnostic genome profiling in mental retardation. Am J Hum Genet. 77:606–616. 7. Dobyns WB, Das S. LIS1-Associated /Subcortical Band Heterotopia. 2009 Mar 3 [Updated 2014 Aug 14]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993- 2015. http://www.ncbi.nlm.nih.gov/books/NBK5189/ 8. Flore LA et al., Semin Pediatr Neurol. 2012 Dec;19(4):173-80. Updates in the genetic evaluation of the child with global developmental delay or intellectual disability. 9. Kaindl AM et al., Prog Neurobiol. 2010 Mar; 90(3):363-83. Many roads lead to primary autosomal recessive microcephaly. 10. Lu X, et al. (2007) Clinical Implementation of Chromosomal Microarray Analysis: Summary of 2513 Postnatal Cases. PLoS ONE. 28;2:e327. 11. Miller DT, et al. (2010) Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies. Am J Hum Genet. 86:749-64. 12. Shaffer LG, et al. (2007) Microarray analysis for constitutional cytogenetic abnormalities. Genet Med. 9:654-662. 13. Solomon BD, et al. Overview. 2000 Dec 27 [Updated 2013 Aug 29]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. http://www.ncbi.nlm.nih.gov/books/NBK1530/ 14. Tayeh MK, et al. (2009) Targeted comparative genomic hybridization array for the detection of single- and multiexon gene deletions and duplications. Genet Med. 2009 Apr;11(4):232-40. PMID: 19282776 15. Toriello HV, Reardon W, Gorlin RJ, 2nd eds. Hereditary Hearing Loss and Its Syndromes. New York: Oxford University Press; 2013. 16. Trunca Y, et al. Prenat Diagn 2006; 26: 449–453.Prenatal diagnosis of primary microcephaly in two consanguineous families by confrontation of morphometry with DNA data

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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