HEARING AND VISION LOSS NEXT- GENERATION SEQUENCING … · Hearing and/or vision loss can result...

HEARING AND VISION LOSS NEXT- GENERATION SEQUENCING PANEL

Mail: One Gustave L. Levy Place, Box 1497 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 New York, NY 10029

CLIA #: 33D2097541 1 T: 800-298-6470

F: 212-241-0139 www.sema4genomics.com


CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139 www.sema4genomics.com

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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 10

RETINAL DISEASE SUBPANEL 14

ALBINISM, HERMANSKY-PUDLAK SYNDROME, AND WAARDENBURG SYNDROME SUBPANEL 24

DEVELOPMENTAL EYE SUBPANEL (ANOPHTHALMIA/MICROPHTHALMIA/ANIRIDIA) 27

STICKLER & CATARACT SUBPANEL 30

THE COMPREHENSIVE HEARING LOSS PANEL 35

BRANCHIO-OTO-RENAL SYNDROME SUBPANEL 40

USHER SYNDROME SUBPANEL 41

ZELLWEGER SYNDROME SUBPANEL 43

REFERENCES 45

DISCLAIMER 45



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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 genes 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),

Albinism, Hermansky-Pudlak Syndrome, and Waardenburg Syndrome (18), Developmental Eye Disorders (21), and Stickler

Disease and Cataracts (41). Customizable testing is available for ordering a hearing-specific or vision-specific gene 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 pregnancy. The parents of an affected child are most often

obligate carriers (heterozygotes) and each carry one mutant allele (unless a de novo mutation occurs). An X-linked

inheritance means that the risk of a male offspring with the disorder will be 50% if the mother carries an XL mutation.

Depending on the X-inactivation pattern of the gene, a mother and her daughters may rarely be affected. Although X-linked

diseases are normally transmitted from mother to son, transmission of an X-linked mutation will occur from an affected

father to each daughter, but will not occur from father to son.

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



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for known variant(s).

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 human 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 Medical Genetics

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.



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Sanger Sequencing

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;

<http://dgv.tcag.ca/>) and/or our internal laboratory CNV database

• Gains or losses of <500 kb that do not include any known genes (<http://www.ncbi.nlm.nih.gov/refseq/>)

• 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



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• Copy number gains and losses associated with genetic susceptibility, quantitative trait loci, pharmacogenetic

alleles, and cancer predisposition

• Copy number gains and losses that are < 1.0 Mb in size and that appear to be mosaic by aCGH due to atypical log2

ratios, unless the affected region is determined to be clinically significant based on gene content and/or coverage in the

DGV

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 mutations or small insertion/deletions below this array’s resolution that cause

frameshifts, imprinting defects or other epigenetic mutations, and may not detect low level mosaicism. The failure to detect

an alteration at any locus does not exclude the diagnosis of any of the disorders represented on the microarray.

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



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requested.

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

4 mg of direct CVS tissue, or 15 mL of direct amniotic fluid (AF) as well as 1 lavender-top (EDTA) 5-10mL tube of blood

from the pregnant patient and her partner are required. Note: parental blood samples are requested for confirmation

studies necessary in some cases; maternal blood is also used for maternal cell contamination studies. Please note,

prenatal analysis will only be performed for known parental variants.

Extracted DNA samples: We request 20 µL DNA (50-250 ng/µL) or at minimum require 10 µL DNA (50-250 ng/µL).

Causes for rejection include impurities in the test or reference DNA samples, including NaCl or KCl (>40 mM) and other

salts, phenol, ethanol, heparin, EDTA (>1.5 mM), and Fe, contaminated DNA, and low concentration of DNA (<20 ng/µL).

Saliva samples: We can accept saliva specimens upon request. Saliva samples should be collected in Oragene DNA (OG-

500) kits by DNA Genotek. Please contact our laboratory to obtain saliva kits.

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

1428 Madison Avenue, Atran Bldg, Room 2-25

New York, NY 10029

Contact:

[email protected]

Tel: 212-241-7518

Fax: 212-241-0139



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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.

Disease Category Gene ID Mim No. OMIM: Prevalent Phenotype(s) Inheritance Proportion of

Disease*

Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

HESX1

601802

182230: Growth hormone deficiency with pituitary anomalies 182230: Pituitary hormone deficiency, combined 182230: Septooptic dysplasia Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

AD, AR

MAC: Less common (<1%)

Congenital nystagmus FRMD7 300628 310700: Nystagmus, congenital, infantile periodic alternating (FIN) XL FIN: Only known gene

Congenital stationary night blindness CABP4 608965 610427: Cone-rod synaptic disorder, congenital nonprogressive AR Retinal dystrophy:

<1% (1/170 patients)

Congenital stationary night blindness

GNAT1

139330

610444: AD Night blindness, congenital stationary (CSNB) 616389: AR Night blindness, congenital stationary, type 1G **

AD, AR

Nougaret CSNB: One family reported with >135 cases


NYX

300278 310500: Night blindness, congenital

stationary (complete) (XL CSNB)

XLR

XL CSNB: 45% cCSNB: 43% (69/161 cases)

Glaucoma CYP1B1 601771 231300: AR Glaucoma, primary open angle, congenital, juvenile, or adult onset AR PCG: 20-100%,

familial; 10-15%,



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Disease* (PCG)

604229: Peters anomaly (PA) simplex

PA: Reported in association with CYP1B1

Glaucoma

MYOC

601652

137750: Glaucoma, primary open angle (PAOG) Juvenile onset open angle glaucoma (JOAG)

AD

PAOG: 2-4%, JOAG: ~33%

Macular degeneration

EFEMP1

601548

126600: Doyne honeycomb degeneration of retina Cuticular drusen (CD)

AD Doyne: 37 families

CD: 12.5% (1/8 cases)


ELOVL4

605512

614457: AR Ichthyosis, spastic quadriplegia, and mental retardation 133190: AD ?Spinocerebellar ataxia 600110: AD Stargardt disease

AD, AR

Stargardt: 17% (1/6 cases) not caused by ABCA4

Neuronal ceroid lipofuscinosis

CLN3

607042

204200: Ceroid lipofuscinosis, neuronal (NCL, Batten disease) Juvenile Neuronal Ceroid Lipofucsinosis (JNCL)

AR

Batten: Only known gene JNCL: Rare; Italian: 73% (16/22 patients) NCL: Rare; Italian 12.9% (16/124 patients)


CLN5

608102

256731: Ceroid lipofuscinosis, neuronal (NCL) Late-infantile Neuronal Ceroid Lipofuscinosis (LINCL)

AR

LINCL: Major in Finland; minor elsewhere; Finnish: 21% (10/47 patients), Italian: 7% (7/94 patients) NCL: Rare; Italian 5.6% (7/124 patients)


CLN6

606725

601780: Ceroid lipofuscinosis, neuronal 204300: Ceroid lipofuscinosis, neuronal, Kufs type, adult onset Juvenile Neuronal Ceroid Lipofucsinosis (JNCL) Late-infantile Neuronal Ceroid Lipofuscinosis (LINCL)

AR

JNCL: Italian: ~14% (3/22 patients) LINCL: Variant: Minor; Italian: 19% (18/94 patients) NCL: Rare; Italian: 16.9% (21/124 patients)


CLN8

607837

600143: Ceroid lipofuscinosis, neuronal (NCL) 610003: Ceroid lipofuscinosis, neuronal, Northern epilepsy variant Late-infantile Neuronal Ceroid Lipofuscinosis (LINCL)

AR

LINCL: Variant: Rare; Italian: 7% (7/94 patients) NCL: Italian: 5.6% (7/124 patients)


CTSD

116840

610127: AR Ceroid lipofuscinosis, neuronal Late-infantile Neuronal Ceroid Lipofuscinosis (LINCL)

AR

LINCL: Italian: 1% (1/94 patients as CLN10) NCL: Italian: 0.8% (1/124 patients) ID: <0.1% (0/986 patients) Congenital NCL: Minor


DNAJC5

611203

162350: Ceroid lipofuscinosis, neuronal, Parry type Adult-onset neuronal ceroid lipofuscinosis (AONCL)

AD

Parry: Only known gene NCL: Unknown AONCL: 10% (2/20 families/individuals)


MFSD8

611124

610951: Ceroid lipofuscinosis, neuronal (NCL) 616170: Macular dystrophy with central cone involvement Late-infantile Neuronal Ceroid Lipofuscinosis (LINCL)

AR

LINCL: Variant: Minor; Italian: 15% (14/94 patients as CLN7) NCL: Italian: 11.3% (14/124 patients)


PPT1

600722

256730: Ceroid lipofuscinosis, neuronal Infantile Neuronal Ceroid Lipofuscinosis (INCL) Juvenile Neuronal Ceroid Lipofucsinosis (JNCL)

AR

INCL: Major; Italian: 75% (6/8 patients as CLN1) JNCL: Minor; Italian: 9% (2/22 patients)



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Disease* Late-infantile Neuronal Ceroid

Lipofuscinosis (LINCL) LINCL: Minor; Italian:

10% (9/94 patients) Adult NCL: Rare; Italian: 13.7% (17/124 patients) ID: <0.1% (0/986 patients) Epilepsy: <1% (1/293 patients)


TPP1

607998

204500: Ceroid lipofuscinosis, neuronal (NCL) Late-infantile Neuronal Ceroid Lipofuscinosis (LINCL) 609270: Spinocerebellar ataxia

AR

LINCL: Italian: 31% (29/94 patients as CLN2) NCL: Italian: 23.5% (31/124 patients) Classic late-infantile NCL: Major Variant Juvenile NCL: Rare Epilepsy: <1% (2/293 patients)

Retinopathy-related gene

TGFBI

601692

607541: AD Corneal dystrophy, Avellino type 121900: AD Corneal dystrophy, Groenouw type I 608470: Corneal dystrophy, Reis-Bucklers type 602082: AD Corneal dystrophy, Thiel- Behnke type 121820: AD Corneal dystrophy, epithelial basement membrane 122200: AD Corneal dystrophy, lattice type I (LCD) 608471: AD Corneal dystrophy, lattice type IIIA

AD

CD: 100% in Chinese (21 families), Korean 86.5% (77/89 patients)

Retinopathy-related gene TIMP3 188826 136900: Sorsby fundus dystrophy (SFD) AD SFD: Only known gene

Retinopathy-related gene UBIAD1 611632 121800: Corneal dystrophy, Schnyder type (SCD) AD SCD: 10 families


CDH3

114021

225280: Ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM) 601553: Hypotrichosis, congenital, with juvenile macular dystrophy

AR

EEM: Only known gene

Retinopathy-related gene FZD4 604579 133780: Exudative vitreoretinopathy, Retinopathy of prematurity (ADFEVR) AD ADFEVR: 4-40%


PGK1

311800

300653: Phosphoglycerate kinase 1 deficiency (PGK1D)

XLR

PGK1D: Only known gene ID: <0.1% (0/986 patients) XLID: >5 total mutations


RGS9

604067

608415: Bradyopsia

None

Bradyopsia: One of two genes with RGS9BP

Retinopathy-related gene RGS9BP 607814 608415: Bradyopsia None Bradyopsia: One of two genes with RGS9


RS1

300839

312700: Retinoschisis

XLD

XL Juvenile retinoschisis: Only known gene

Retinopathy-related gene TSPAN12 613138 613310: Exudative vitreoretinopathy (ADFEVR) AD ADFEVR: 3-10%

Retinopathy-related gene (syndromic)

TREX1

606609

225750: AR, AD Aicardi-Goutieres syndrome (AGS) 610448: AD Chilblain lupus 152700: AD {Systemic lupus erythematosus, susceptibility to} 192315: AD Vasculopathy, retinal, with cerebral leukodystrophy

AD, AR

AGS: 23%



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Disease*

Syndromic hearing and vision loss: Mohr- Tranebjaerg syndrome

TIMM8A

300356

304700: Mohr-Tranebjaerg syndrome

XLR

Only known gene ID: <0.1% (0/986 patients) XL: >5 total mutations

Syndromic vision loss related gene (with retinopathy) MTTP 157147 200100: AR Abetalipoproteinemia (ABL)

605552: AD Metabolic syndrome ** AD, AR ABL: Only known gene

Syndromic vision loss: Axenfeld-Rieger syndrome

PITX2

601542

180500: AD Axenfeld-Rieger syndrome, type 1 (ARS) 137600: AD Iridogoniodysgenesis, type 2 604229: Peters anomaly 180550: AD Ring dermoid of cornea

AD

ARS: 55% (21/38 probands) of all ARS and 78% (21/27 probands) of ARS with dental and/or umbilical defects

Syndromic vision loss: Chediak-Higashi syndrome LYST 606897 214500: Chediak-Higashi syndrome

(CHS) AR CHS: 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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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 retinitis

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 ciliopathies, diseases caused by dysfunctional cilia. These diseases include Leber

congenital amaurosis (LCA), Bardet-Biedl syndrome (BBS), Joubert syndrome (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, kidney 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, brain 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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Disease Category Gene ID Mim No. OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease*

Achromatopsia CNGA3 600053 216900: Achromatopsia AR Achomatopsia: 5-23% in European; 28% in Israeli and Palestinian; 80% in Chinese

Achromatopsia

CNGB3

605080

262300: Achromatopsia 248200: Macular degeneration, juvenile

AR Achromatopsia: 47-87% in European; 72%

in Israeli and Palestinian Achromatopsia GNAT2 139340 613856: Achromatopsia AR Achromatopsia: Rare

Achromatopsia PDE6C 600827 613093: Cone dystrophy Achromatopsia AR Achromatopsia: Rare

Achromatopsia PDE6H 601190 610024: Achromatopsia 610024: Retinal cone dystrophy AD, AR Achromatopsia: Rare

Bardet-Biedl syndrome

ARL6

608845

209900: AR, DR {Bardet-Biedl syndrome, modifier of} 600151: AR Bardet-Biedl syndrome (BBS) 613575: AR Retinitis pigmentosa (ARRP)**

AR

BBS: <1% ARRP: 1%

Bardet-Biedl syndrome BBS1 209901 209900: Bardet-Biedl syndrome (BBS) AR, DR BBS: ~23%

Bardet-Biedl syndrome BBS10 610148 615987: Bardet-Biedl syndrome (BBS) AR BBS: ~20%



BBS2

606151

615981: Bardet-Biedl syndrome (BBS) 616562: Retinitis pigmentosa

AR

BBS: ~8%




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Bardet-Biedl syndrome BBS5 603650 615983: Bardet-Biedl syndrome (BBS) AR BBS: ~0.5%

Bardet-Biedl syndrome BBS7 607590 615984: Bardet-Biedl syndrome (BBS) AR BBS: ~1.5%


Bardet-Biedl syndrome LZTFL1 606568 615994: Bardet-Biedl syndrome (BBS) AR BBS: Two families


MKKS

604896

605231: Bardet-Biedl syndrome (BBS) 236700: McKusick-Kaufman syndrome

AR

BBS: ~6%


MKS1

609883

615990: Bardet-Biedl syndrome (BBS) 617121: Joubert syndrome 249000: Meckel syndrome

AR

BBS: ~4.5% Joubert: 2.1% (8/375 families)


SDCCAG8

613524

615993: AR Bardet-Biedl syndrome 613615: Senior-Loken syndrome Nephronophthisis (NPH)

AR

NPH: <1%


TTC8

608132

615985: Bardet-Biedl syndrome (BBS) 613464: Retinitis pigmentosa (ARRP)**

AR

BBS: ~1% ARRP: 1%

Bardet-Biedl syndrome, Limb Girdle Muscular Dystrophy

TRIM32

602290

615988: Bardet-Biedl syndrome 254110: Muscular dystrophy, limb- girdle (LGMD), type 2H

AR

AR LGMD: Italy: <1% (1 / 198 patients)

Colorblindness-related gene OPN1SW 613522 190900: Colorblindness, tritan AD Tritan: Only known gene

Cone or cone-rod dystrophy

ABCA4

601691

604116: Cone-rod dystrophy 248200: AR Fundus flavimaculatus 153800: AD {Macular degeneration, age-related} (AMD) 248200: AR Retinal dystrophy, early-onset severe 601718: AR Retinitis pigmentosa (ARRP) 248200: AR Stargardt disease

AD, AR

Stargardt: Primary cause ARRP: 2-5%

Cone or cone-rod dystrophy ADAM9 602713 612775: Cone-rod dystrophy (CRD) None CRD: Four consanguineous families


C8ORF37

614477

614500: Cone-rod dystrophy 614500: Retinitis pigmentosa (ARRP)

AR

ARRP: 1%


CACNA1F

300110

300600: Aland Island eye disease 300476: Cone-rod dystrophy 300071: Night blindness, congenital stationary (incomplete) (CSNB)

XLR

XL CSNB: 55%

Cone or cone-rod dystrophy CACNA2D4 608171 610478: Retinal cone dystrophy None Inherited retinal dystrophy: <1% (1/179

Chinese patients, 2/222 unrelated patients) Cone or cone-rod dystrophy CDHR1 609502 613660: Cone-rod dystrophy

613660: Retinitis pigmentosa AR Retinal dystrophy: ~1% (3/292 families)

Cone or cone-rod dystrophy CERKL 608381 608380: Retinitis pigmentosa

(ARRP) AR ARRP: 3-4% in Spain


CNNM4

607805 217080: Jalili syndrome

Neurofibromatosis 1 (NF1)

AR

Jalili: Only known gene NF1: Identified in one child with concomitant NF1 and Jalili syndrome

Cone or cone-rod dystrophy KCNV2 607604 610356: Retinal cone dystrophy

Cone-rod dystrophy (CRD) AR CRD: 4% (4/90 probands)

Cone or cone-rod dystrophy RAB28 612994 615374: Cone-rod dystrophy (CRD) AR CRD: Four families


RAX2

610362

610381: AD Cone-rod dystrophy (CRD) 613757: Macular degeneration, age- related **

AD

AD CRD: One family Retinal degeneration: Three individuals


RDH5

601617 136880: Fundus albipunctatus (FA)

Leber congenital amaurosis (LCA)

AD, AR

FA: Primary cause with RLBP1 and RPE65 secondary (~89%, 40/45 cases, ~7%, 3/45 cases, and 4%, 2/45 cases, respectively)



17


LCA: 1.8% (1/56 patients)


RPGRIP1

605446

608194: Cone-rod dystrophy 613826: Leber congenital amaurosis (LCA)

None

LCA: ~5%

Cone-rod retinal dystrophy GUCA1A 600364 602093: Cone dystrophy (CD)

602093: Cone-rod dystrophy (CRD) AD CD/CRD: ~3% (6/216 patients)

Cone-rod retinal dystrophy PITPNM3 608921 600977: Cone-rod dystrophy AD Inherited retinal dystrophy: <1% (1/179

Chinese patients)

Cone-rod retinal dystrophy

PROM1

604365

612657: Cone-rod dystrophy 608051: AD Macular dystrophy, retinal 612095: AR Retinitis pigmentosa (ARRP) 603786: Stargardt disease

AD, AR

ARRP: 1%

Cone-rod retinal dystrophy RIMS1 606629 603649: Cone-rod dystrophy None Retinal dystrophy: <1% (1/170 patients)


RPGR

312610

304020: Cone-rod dystrophy 300834: Macular degeneration, atrophic 300029: Retinitis pigmentosa (XLRP) 300455: Retinitis pigmentosa, and sinorespiratory infections, with or without deafness

XLR

XLRP: 70-90%


SEMA4A

607292

610283: AR Cone-rod dystrophy 610282: AR, AD Retinitis pigmentosa (ADRP)

AD, AR

ADRP: 3%-4% in Pakistan

Congenital stationary night blindness GPR179 614515 614565: Night blindness, congenital

stationary (complete) (cCSNB) AR cCSNB: ~3-9%% (5/160 patients, 14/161 cases)

Congenital stationary night blindness GRK1 180381 613411: Oguchi disease AR Oguchi: One of two genes with SAG


GRM6

604096

257270: AR Night blindness, congenital stationary (complete) (cCSNB)

AR

cCSNB: ~14% (22/161 cases)

Congenital stationary night blindness LRIT3 615004 615058: Night blindness, congenital

stationary (complete) (cCSNB) AR cCSNB: ~3% (5/161 cases)


PDE6B

180072

163500: AD Night blindness, congenital stationary 613801: AR Retinitis pigmentosa (ARRP)

AD, AR

ARRP: 2-5%


RHO

180380

610445: Night blindness, congenital stationary 613731: AR, AD Retinitis pigmentosa (ADRP, ARRP) 136880: AR, AD Retinitis punctata albescens

AD, AR

ADRP: 20-30% ARRP: 1%


SAG

181031

258100: Oguchi disease 613758: Retinitis pigmentosa (ARRP)

AR Oguchi: One of two genes with GRK1

ARRP: 2-3% in Japan

Congenital stationary night blindness SLC24A1 603617 613830: Night blindness, congenital

stationary (complete) AR CSNB with a Riggs- typeERG: 10% (1/10 cases)

Congenital stationary night blindness TRPM1 603576 613216: Night blindness, congenital

stationary (complete) AR cCSNB: ~31% (51/161 cases)

Joubert syndrome

AHI1

608894

608629: Joubert syndrome

AR

Joubert: 7-10%; 6.9% (26/375 families) 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%

Joubert syndrome

INPP5E

613037

213300: Joubert syndrome 610156: Mental retardation, truncal obesity, retinal dystrophy, and micropenis

AR

Joubert: 2.4% (9/375 families)

Joubert syndrome

KIF7

611254

200990: Acrocallosal syndrome 607131: Al-Gazali-Bakalinova syndrome ** 614120: Hydrolethalus syndrome ** 200990: Joubert syndrome

AR




18


Joubert syndrome TCTN1 609863 614173: Joubert syndrome AR Joubert: 0.2% (1/375 families)

Joubert syndrome TCTN2 613846 616654: Joubert syndrome 613885: Meckel syndrome ** AR Joubert: 1.3% (5/375 families)

Joubert syndrome TCTN3 613847 614815: Joubert syndrome 258860: Orofaciodigital syndrome IV AR Joubert: 0.2% (1/375 families)

Joubert syndrome TMEM216 613277 608091: Joubert syndrome 603194: Meckel syndrome AR Joubert: ~3%; 2.9% (11/375 families)

Joubert syndrome TMEM231 614949 614970: Joubert syndrome 615397: Meckel syndrome AR Joubert: N. European 2% (1/51 cases)

Meckel: 10 cases Joubert syndrome TMEM237 614423 614424: Joubert syndrome AR Joubert: <1%; 0.2% (1/375 families)

Joubert syndrome

TMEM67

609884

615991: {Bardet-Biedl syndrome, modifier of} 216360: COACH syndrome 610688: Joubert syndrome 607361: Meckel syndrome 613550: Nephronophthisis (NPH)

AR

Joubert: ~10%; 6.1% (23/375 families) NPH: 2-3%

Joubert syndrome

TTC21B

612014

613820: AR, AD Nephronophthisis 613819: AR Short-rib thoracic dysplasia with or without polydactyly

AD, AR

Joubert: Unknown NPH: Detected in 7 families w/NPH w/ or w/out extrarenal features, 3 families w/Jeune asphyxiating thoracic dystrophy, & additional families w/a NPH-related ciliopathy. Also identified in persons w/familial primary focal segmental glomerulosclerosis. Two families had infantile NPH w/extrarenal features. Estimated <1%

Joubert syndrome and orofaciodigital syndrome

C5ORF42

614571 614615: Joubert syndrome

277170: Orofaciodigital syndrome VI

AR


Joubert syndrome and orofaciodigital syndrome

OFD1

300170

300804: XLR Joubert syndrome 311200: XLD Orofaciodigital syndrome I 300424: XLR Retinitis pigmentosa ** 300209: XLR Simpson-Golabi- Behmel syndrome, type 2

XLD, XLR

Joubert: 1% (4/375 families) XLID: <1% (0/150 male patients); >5 total mutations ID: 0.1% (1/986 patients)

Joubert syndrome and other ciliopathies

CC2D2A

612013

216360: COACH syndrome 612285: Joubert syndrome 612284: Meckel syndrome

AR

COACH: One of three genes Joubert: ~10%; 8.2% (31/375 families) Meckel: One of 11 genes


CEP290

610142

615991: AR Bardet-Biedl syndrome ** 610188: AR Joubert syndrome 611755: Leber congenital amaurosis (LCA) 611134: AR Meckel syndrome 610189: AR Senior-Loken syndrome Nephronophthisis (NPH)

AR

Joubert: ~10%; 7.2% (27/375 families) LCA: 20% NPH: 2-3%


NPHP1

607100

609583: Joubert syndrome 256100: Nephronophthisis, juvenile (NPH) 266900: Senior-Loken syndrome

AR

NPH: 20-25% Joubert: 1-2%; 1.3% (5/375 families)

Leber congenital amaurosis

AIPL1

604392

604393: AR Cone-rod dystrophy 604393: AR Leber congenital amaurosis (LCA) 604393: AD Retinitis pigmentosa, juvenile (ADRP)

AD, AR

LCA: 4-8% ADRP: Rare


CRB1

604210

613835: Leber congenital amaurosis (LCA) 172870: AD Pigmented paravenous chorioretinal atrophy 600105: AR Retinitis pigmentosa (ARRP)

AD, AR

LCA: Unknown ARRP: 6-7% in Spain


CRX

602225

120970: AD Cone-rod retinal dystrophy 613829: Leber congenital amaurosis (LCA) Retinitis Pigmentosa (ADRP)

AD

LCA: 3% ADRP: 1%


GUCY2D

600179

601777: AD Cone-rod dystrophy 204000: AR Leber congenital amaurosis (LCA)

AD, AR

LCA: 6-21%



19



IFT140

614620

266920: Short-rib thoracic dysplasia with or without polydactyly Non-syndromic retinal dystrophy (NSRD)

AR

NSRD: ~1%


IMPDH1

146690

613837: Leber congenital amaurosis 180105: AD Retinitis pigmentosa (ADRP)

AD LCA: Rare

ADRP: 2-3%


IQCB1

609237

609254: Senior-Loken syndrome Leber Congenital Amaurosis (LCA) Nephronophthisis (NPH)

AR LCA: Unknown

NPH: 2-3%


KCNJ13

603208

614186: AR Leber congenital amaurosis (LCA) 193230: AD Snowflake vitreoretinal degeneration

AD, AR

LCA: Unknown

Leber congenital amaurosis LCA5 611408 604537: Leber congenital amaurosis

(LCA) None LCA: ~1-2%


LRAT

604863

613341: Leber congenital amaurosis (LCA) 613341: Retinal dystrophy, early- onset severe 613341: Retinitis pigmentosa, juvenile (ARRP)

AR

LCA: Unknown ARRP: 1%

Leber congenital amaurosis NMNAT1 608700 608553: Leber congenital amaurosis

(LCA) AR LCA: Unknown

Leber congenital amaurosis RD3 180040 610612: Leber congenital amaurosis

(LCA) AR LCA: Unknown


RDH12

608830

612712: AR Leber congenital amaurosis AD Retinitis Pigmentosa (ADRP)

AD, AR LCA: ~4%

ADRP: Unknown


RPE65

180069

204100: Leber congenital amaurosis (LCA) 613794: Retinitis pigmentosa (ARRP) Fundus albipunctatus (FA)

AR

LCA: 3-16% ARRP: 2-5% FA: 4% (2/45 cases)


RPGRIP1L

610937

216360: COACH syndrome 611560: Joubert syndrome 611561: Meckel syndrome Nephronophthisis (NPH)

AR

Joubert: 2-4%; 2.1% (8/375 families) NPH: <1%


SPATA7

609868

604232: Leber congenital amaurosis (LCA) 604232: AR Retinitis pigmentosa, juvenile (ARRP)

AR


Leber congenital amaurosis, cone-rod retinal dystrophy

PRPH2

179605

613105: AD Choriodal dystrophy, central areolar 608133: AR, AD Leber congenital amaurosis 169150: AD Macular dystrophy, patterned 608161: AD Macular dystrophy, vitelliform 608133: AR, AD Retinitis pigmentosa and digenic (ADRP) 136880: AR, AD Retinitis punctata albescens

AD, AR

ADRP: 5-10%

Leber congenital amaurosis, retinitis pigmentosa

TULP1

602280

613843: Leber congenital amaurosis (LCA) 600132: Retinitis pigmentosa (ARRP)

AR



BEST1

607854

611809: AR Bestrophinopathy (ARB) 153700: AD Macular dystrophy, Best vitelliform (VMD2) 193220: AD Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma, Vitreoretinochoroidopathy Age-related macular degeneration (AMD)

AD, AR

ARB, VMD2: Only known gene AMD, ADRP: Rare



20


613194: AD Retinitis pigmentosa, concentric (ADRP)

Macular degeneration FSCN2 607643 607921: Retinitis pigmentosa (ADRP) AD ADRP: 3% of Japanese; otherwise rare

Macular degeneration GUCA1B 602275 613827: Retinitis pigmentosa (ADRP) AD ADRP: 4%-5% in Japan; rare in UK

Macular degeneration RP1L1 608581 613587: Occult macular dystrophy (OCMD) AD OCMD: ~36% (10/28 cases), Japanese:

57% (12/21 families)

Non-syndromic hearing loss

WHRN

607928

607084: Deafness 611383: Usher syndrome, type 2D (USH2)

AR

Usher syndrome, type 2D : ~0-10%

Non-syndromic hearing loss or syndromic neuropathies, Charcot Marie Tooth Disease

PRPS1

311850

301835: Arts syndrome 311070: Charcot-Marie-Tooth disease (CMTX) 304500: Deafness (X-linked) 300661: Phosphoribosylpyrophosphate synthetase superactivity; Gout, PRPS-related

XLR

CMTX: Unknown Arts: Only known gene (4 families reported) ID: <0.1% (0/986 patients) XLID: >5 missense/regulatory mutations

Retinitis pigmentosa C2ORF71 613425 613428: Retinitis pigmentosa (ARRP) AR ARRP: 1%

Retinitis pigmentosa CA4 114760 600852: Retinitis pigmentosa (ADRP) AD ADRP: Rare

Retinitis pigmentosa CNGA1 123825 613756: Retinitis pigmentosa (ARRP) AR ARRP: 1-2%

Retinitis pigmentosa CNGB1 600724 613767: Retinitis pigmentosa (ARRP) AR ARRP: 1%

Retinitis pigmentosa CYP4V2 608614 210370: Bietti crystalline corneoretinal dystrophy (BCD) AR BCD: Only known gene

Retinitis pigmentosa DHDDS 608172 613861: Retinitis pigmentosa (ARRP) AR ARRP: 1%

CDG: <2 cases

Retinitis pigmentosa EYS 612424 602772: Retinitis pigmentosa (ARRP) AR ARRP: 10-30% in Spain; common in China

Retinitis pigmentosa FAM161A 613596 606068: Retinitis pigmentosa (ARRP) AR ARRP: 1%

Retinitis pigmentosa

IMPG2

607056

616152: AD Macular dystrophy, vitelliform 613581: AR Retinitis pigmentosa (ARRP)

AD, AR

ARRP: 1%


KLHL7

611119

617055: Cold-induced sweating syndrome 612943: AD Retinitis pigmentosa (ADRP)

AD

ADRP: 1-2%

Retinitis pigmentosa MAK 154235 614181: Retinitis pigmentosa (ARRP) AR ARRP: 1%

Retinitis pigmentosa MERTK 604705 613862: Retinitis pigmentosa (ARRP) AR ARRP: 1%


NR2E3

604485

268100: AR Enhanced S-cone syndrome 611131: AR, AD Retinitis pigmentosa (ADRP, ARRP)

AD, AR

ADRP: 1-2% ARRP: Rare; found in Sephardic Jews in Portugal


NRL

162080

AR Retinal degeneration, clumped pigment type 613750: AD Retinitis pigmentosa (ADRP, ARRP)

AD, AR

ARRP: 1% ADRP: Rare

Retinitis pigmentosa PDE6A 180071 613810: Retinitis pigmentosa (ARRP) AR ARRP: 2-5%

Retinitis pigmentosa PDE6G 180073 613582: Retinitis pigmentosa (ARRP) AR ARRP: 1%

Retinitis pigmentosa PRCD 610598 610599: Retinitis pigmentosa (ARRP) AR ARRP: 1%

Retinitis pigmentosa PRPF3 607301 601414: Retinitis pigmentosa (ADRP) AD ADRP: 1%

Retinitis pigmentosa PRPF31 606419 600138: Retinitis pigmentosa (ADRP) AD ADRP: 5-10%

Retinitis pigmentosa PRPF6 613979 613983: Retinitis pigmentosa (ADRP) AD ADRP: Rare



21


Retinitis pigmentosa PRPF8 607300 600059: Retinitis pigmentosa (ADRP) AD ADRP: 2-3%

Retinitis pigmentosa RBP3 180290 615233: Retinitis pigmentosa (ARRP) ** AR ARRP: 1%

Retinitis pigmentosa RGR 600342 613769: Retinitis pigmentosa (ARRP) AR ARRP: 1%


RLBP1

180090

607475: AR Bothnia retinal dystrophy 136880: AR, AD Fundus albipunctatus (FA) 607476: Newfoundland rod-cone dystrophy 136880: AR, AD Retinitis punctata albescens AR Retinitis Pigmentosa (ARRP)

AD, AR

FA: ~7% (3/45 casees) ARRP: 1%

Retinitis pigmentosa ROM1 180721 608133: AR, AD Retinitis pigmentosa, digenic (ADRP) AD, AR ADRP: Rare

Retinitis pigmentosa RP1 603937 180100: Retinitis pigmentosa AD, AR AD: 3-4%; AR: 1%

Retinitis pigmentosa RP2 300757 312600: Retinitis pigmentosa (XLRP) XLR XLRP: 10-20%

Retinitis pigmentosa SNRNP200 601664 610359: Retinitis pigmentosa (ADRP) AD ADRP: Unknown

Retinopathy-related gene CAPN5 602537 193235: Vitreoretinopathy,

neovascular inflammatory (ADNIV) AD ADNIV: Three families

Retinopathy-related gene CHM 300390 303100: Choroideremia (CHM) XLD CHM: Only known gene


MFRP

606227

611040: AR Microphthalmia, isolated 609549: Nanophthalmos Retinitis pigmentosa (ARRP)

AR

High hyperopia: Chinese: ~7% (3/46 probands) ARRP: ~2% (1/65 patients)


RBP4

180250

616428: AD Microphthalmia, isolated, with coloboma 615147: AR Retinal dystrophy, iris coloboma, and comedogenic acne syndrome

AD, AR

Retinal dystrophy: Three families

Retinopathy-related gene TOPORS 609507 609923: Retinitis pigmentosa

(ADRP) AD ADRP: 1%

Retinopathy-related gene (syndromic)

PANK2

606157

607236: HARP syndrome 234200: Neurodegeneration with brain iron accumulation (NBIA)

AR NBIA: 35-50%

Epilepsy: <1% (1/293 patients)

Syndromic hearing and vision loss: Alstrom syndrome

ALMS1

606844

203800: Alstrom syndrome

AR

Alstrom: Only known gene

Syndromic hearing and vision loss: optic atrophy with or without auditory neuropathy

TMEM126A

612988

612989: Optic atrophy (OPA7)

AR

OPA7: Rare

Syndromic hearing and vision loss: optic atrophy, auditory neuropathy, axonal sensorineural polyneuropathy

OPA1

605290

616896: Mitochondrial DNA depletion syndrome (encephalocardiomyopathic type) 210000: AR Behr syndrome 165500: AD Optic atrophy 125250: AD Optic atrophy plus syndrome

AD, AR

One of three genes in which mutations are known to cause mtDNA deletion or mtDNA depletion-related ataxia neuropathy syndromes

Syndromic hearing and vision loss: polyneuropathy hearing loss ataxia retinitis pigmentosa

ABHD12

613599

612674: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC)

AR

Cerebral ataxia: Reported in 1-5 families

Syndromic hearing and vision loss: Usher syndrome

ADGRV1

602851

605472: AR, DD Usher syndrome, type 2C 605472: AR, DD Usher syndrome, type 2C

AR, DD

Usher Type II: ~7-19%


CDH23

605516

601386: AR Deafness 601067: AR, DR Usher syndrome, type 1D/F (USH1)

AR, DR

USH1: 7-20%

Syndromic hearing and vision loss: Usher CIB2 605564 609439: Deafness

614869: Usher syndrome, type IJ AR USH1: Unknown



22


syndrome (USH1)


CLRN1

606397

614180: Retinitis pigmentosa (ARRP) 276902: Usher syndrome, type 3A (USH3)

AR

ARRP: 1% USH3: One of two genes with HARS


HARS

142810

616625: AD Charcot-Marie-Tooth disease, axonal, type 2W (CMT2W) 614504: AR Usher syndrome type 3B (USH3)

AD, AR

CMT2W: 5 families USH3: One of two genes with CLRN1


MYO7A

276903

601317: AD Deafness 600060: AR Deafness 276900: AR Usher syndrome, type 1B (USH1)

AD, AR

USH1: 53-63%


PCDH15

605514

609533: AR Deafness 601067: AR, DR Usher syndrome, type 1D/F (USH1) 602083: AR Usher syndrome, type 1F

AR, DR

USH1: 7-12%


USH1C

605242

602092: Deafness 276904: Usher syndrome, type 1C (USH1)

AR

USH1: 1-15%


USH1G

607696 606943: Usher syndrome, type 1G

(USH1)

AR

USH1: Rare (0-4%)


USH2A

608400

613809: Retinitis pigmentosa 276901: AR Usher syndrome, type 2A (USH2)

AR

USH2: 57-79%

Syndromic hearing and vision loss: Zellweger syndrome

PEX1

602136

234580: AR Heimler syndrome 214100: AR Peroxisome biogenesis disorder 1A (Zellweger) 601539: Peroxisome biogenesis disorder 1B (NALD/IRD)

AR

Zellweger: 57-68%


PEX10

602859

614870: Peroxisome biogenesis disorder 6A (Zellweger) 614871: Peroxisome biogenesis disorder 6B

AR

Zellweger: ~3-5%


PEX14

601791 614887: Peroxisome biogenesis

disorder 13A (Zellweger)

AR

Zellweger: <1%


PEX16

603360

614876: Peroxisome biogenesis disorder 8A, (Zellweger) 614877: Peroxisome biogenesis disorder 8B

None

Zellweger: 0.5-1%


PEX19

600279 614886: Peroxisome biogenesis

disorder 12A (Zellweger)

None

Zellweger: <1%


PEX2

170993


AR

Zellweger: 1-4%


PEX5

600414

214110: Peroxisome biogenesis disorder 2A (Zellweger) 202370: Peroxisome biogenesis disorder 2B 616716: Rhizomelic chondrodysplasia punctata, type 5

AR

Zellweger: 1.5-2%


PEX6

601498

616617: AR Heimler syndrome 614862: Peroxisome biogenesis disorder 4A (Zellweger) 614863: Peroxisome biogenesis disorder 4B

AR

Zellweger: ~11-16%

Syndromic hearing loss: Refsum disease PHYH 602026 266500: Refsum disease AR AR Ataxia: More common (>5 families)

266500: >90% Syndromic vision loss related gene (with retinopathy)

CEP164

614848

614845: Nephronophthisis (NPH)

AR

NPH: Identified in a Saudi child and in in <1% (3/856) of families w/NPH-related ciliopathies; estimated <1%

Syndromic vision loss related gene (with FLVCR1 609144 609033: Ataxia, posterior column,

with retinitis pigmentosa AR Cerebellar Ataxia: Less common (1-5 families)



23


retinopathy)

Syndromic vision loss related gene (with retinopathy)

NPHP3

608002

267010: Meckel syndrome 604387: Nephronophthisis (NPH) 208540: Renal-hepatic-pancreatic dysplasia

AR

NPH: 1-2%


NPHP4

607215 606966: Nephronophthisis (NPH),

Senior-Loken syndrome

AR

NPH: 3-4%


WDR19

608151

614378: Cranioectodermal dysplasia** 614377: Nephronophthisis 616307: Senior-Loken syndrome 614376: Short-rib thoracic dysplasia with or without polydactyly**

AR

NPH: Biallelic pathogenic variants identified in families w/cranioectodermal dysplasia, Jeune syndrome, Senior-Lken syndrome, & isolated NPH. Eight individuals w/biallelic pathogenic variants had NPH & dilation of the intrahepatic bile ducts. Estimated <1%


ZNF423

604557

614844: Joubert syndrome, Nephronophthisis

AD, AR

NPH: <1% (Turkish siblings w/ infantile NPH, cerebellar vermis hypoplasia, & situs inversus; 2 individuals w/ Joubert syndrome).





24

ALBINISM, HERMANSKY-PUDLAK SYNDROME, AND WAARDENBURG SYNDROME SUBPANEL

Albinism refers to a set of disorders in which pigmentation of the skin, hair, and/or eyes are lighter than expected due to

deficiencies of the pigment melanin. 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 ocular

albinism 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.


Albinism GPR143 300808 300814: Nystagmus, congenital XL OA1: Only known gene



25


300500: Ocular albinism, type I, Nettleship-Falls type

Albinism

OCA2

611409

203200: Albinism, brown oculocutaneous, type II 227220: [Skin/hair/eye pigmentation, blond/brown hair], [Skin/hair/eye pigmentation, blue/nonblue eyes]

AR

OCA2: Only known gene

Albinism

SLC45A2

606202

606574: Albinism, oculocutaneous, type IV 227240: AR [Skin/hair/eye pigmentation, black/nonblack hair], [Skin/hair/eye pigmentation, dark/fair skin], [Skin/hair/eye pigmentation, dark/light eyes]

AR


Albinism

TYR

606933

203100: AR Albinism, oculocutaneous, type IA 606952: Albinism, oculocutaneous, type IB 601800: {Melanoma, cutaneous malignant, susceptibility to}, [Skin/hair/eye pigmentation, blue/green eyes], [Skin/hair/eye pigmentation, light/dark/freckling skin] 103470: AD Waardenburg syndrome/albinism, digenic

AD, AR


Albinism

TYRP1

115501

203290: AR Albinism, oculocutaneous, type III 612271: [Skin/hair/eye pigmentation, variation in, (Melanesian blond hair)]

AR



CACNA1F

300110

300600: Aland Island eye disease 300476: Cone-rod dystrophy 300071: Night blindness, congenital stationary (incomplete) (CSNB)

XLR

XL CSNB: 55%

Hermansky-Pudlak syndrome

AP3B1

603401

608233: Hermansky-Pudlak syndrome (HPS)

AR

HPS: Puerto Rican: 0%; Non-Puerto Rican: ~1- 10%

Hermansky-Pudlak syndrome BLOC1S6 604310 614171: Hermansky-Pudlak syndrome (HPS) AR HPS: Puerto Rican: 0%;

Non-Puerto Rican: 1%


HPS1

604982


AR

HPS: Puerto Rican: 0- 74%; Non-Puerto Rican: 0-43%


HPS3

606118


None

HPS: Puerto Rican: 0- 25%; Non-Puerto Rican: 0-~13%

Hermansky-Pudlak syndrome HPS4 606682 614073: Hermansky-Pudlak syndrome (HPS) None HPS: Puerto Rican: 0%;

Non-Puerto Rican: ~12% Hermansky-Pudlak syndrome HPS5 607521 614074: Hermansky-Pudlak syndrome (HPS) None HPS: Puerto Rican: 0%;

Non-Puerto Rican: ~9%


HPS6

607522


None

HPS: Puerto Rican: 0%; Non-Puerto Rican: ~0- 7%

Syndromic hearing loss: Waardenburg syndrome

EDN3

131242

209880: congenital central hypoventilation syndrome (CCHS) 613265: Waardenburg syndrome, type 4B (WS4) 613712: Hirschsprung disease (HSCR)**

AD, AR

CCHS: AD, Identified in a subset of individuals Nonsyndromic HSCR: 5% WS4: AR, Common with EDNRB


EDNRB

131244

600501: albinism, black lock, cell migration disorder of neurocytes of the gut and deafness (ABCD) syndrome 600155: Hirschsprung disease (HSCR)** 277580: AR, AD Waardenburg syndrome, type 4A (WS4)

AD, AR

ABCD syndrome: (AR), only known gene Nonsyndromic Hirschsprung disease: AR, 3-7% Waardenburg Type 4A: (AR, AD) Common with EDN3


MITF

156845

614456: cutaneous malignant melanoma ** 103500: AD Tietz albinism-deafness syndrome 193510: AD Waardenburg syndrome, type 2A (WS2) 103470: AD Waardenburg syndrome/ocular albinism, digenic

AD

Waardenburg Type 2A (AD): 10-20%


PAX3

606597

122880: AD craniofacial-deafness-hand syndrome 268220: AR alveolar rhabdomyosarcoma, 193500: AD Waardenburg syndrome, type 1 (WS1) 148820: AR, AD Waardenburg syndrome, type 3

AD, AR

Waardenburg Type 1 / 3 (AD, AR): Only known gene


SOX10

602229

609136: peripheral demyleinating neuropathy, central dysmelination, Waardenburg syndrome, and Hirschsprung disease (PCWH syndrome) 611584: Waardenburg syndrome, type 2E, with or without neurologic involvement 613266: Waardenburg syndrome, type 4C

AD

Waardenburg syndrome: 15%



26





27

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 optic nerve hypoplasia

(underdeveloped optic nerve).

The Developmental Eye Panel contains the following 21 genes.

Disease Category Gene ID Mim

No. OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease*


BCOR

300485

300166: Microphthalmia, syndromic Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

XLD

MAC: >1% ID: <0.1% (0/986 patients) XLID: >5 total mutations


BMP4

112262

607932: AD Microphthalmia, syndromic Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum 600625: Orofacial cleft

AD

MAC: 2%


FOXE3

601094

107250: AD Anterior segment mesenchymal dysgenesis 610256: AR Aphakia, congenital primary Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum Peters' Anomaly (PA)

AD, AR

MAC: 2.5% PA: One of six genes


HCCS

300056

309801: Linear skin defects with multiple congenital anomalies (MLS)

XLD

MLS: Only known gene ID: <0.1% (0/986 patients) XLID: 2-5 total mutations


OTX2

600037

610125: Microphthalmia, syndromic Microphthalmia/Anophthalmia/Coloboma (MAC) Spectrum 613986: Pituitary hormone deficiency, combined 610125: Retinal dystrophy, early-onset, with or without pituitary dysfunction

AD

MAC: 2-5%


PAX6

607108

106210: AD Aniridia, Cataract with late-onset corneal dystrophy 120430: AD Coloboma of optic nerve ** 120200: AD Coloboma, ocular ** 136520: AD Foveal hypoplasia 148190: AD Keratitis 120430: AD Morning glory disc anomaly **

AD

MAC: 2% ID: 0.1% (1/986 patients)



28


Disease* 165550: AD Optic nerve hypoplasia

604229: Peters anomaly Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum


PXDN

605158

269400: Corneal opacification and other ocular anomalies Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

AR



SMOC1

608488

206920: Microphthalmia with limb anomalies Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

AR MAC: Less

common (<1%)


SOX2

184429

206900: Microphthalmia, syndromic, Optic nerve hypoplasia and abnormalities of the central nervous system Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

AD

MAC: 15-20%


STRA6

610745

601186: Microphthalmia, isolated, with coloboma, syndromic Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

AR

MAC: >1%


VSX2

142993

610092: Microphthalmia with coloboma 610093: Microphthalmia, isolated Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

None


Cataract

PITX3

602669

107250: Anterior segment mesenchymal dysgenesis 610623: Cataract, multiple types, syndromic

AD

Eye anomolies: 2.5% (2/80 patients screened)


MFRP

606227

611040: AR Microphthalmia, isolated 609549: Nanophthalmos Retinitis pigmentosa (ARRP)

AR

High hyperopia: Chinese: ~7% (3/46 probands) ARRP: ~2% (1/65 patients)

Retinopathy-related gene PLA2G5 601192 228980: [Fleck retina, familial benign] (FRFB) AR FRFB: Only known gene

Syndromic hearing and vision loss: Axenfeld-Rieger syndrome

FOXC1

601090

602482: Rieger or Axenfeld anomalies, Axenfeld-Rieger syndrome, type 3 601631: Iris hypoplasia and glaucoma, Iridogoniodysgenesis, type 1 (Peters' Anomaly, PA) Primary Congenital Glaucoma (PCG)

AD

PA: One of six genes PCG: Limited

Syndromic hearing and vision loss: Fraser syndrome

FRAS1

607830

219000: Fraser syndrome

AR

Fraser: One of three genes with GRIP1 and FREM2


FREM2

608945


AR

Fraser: One of three genes with GRIP1 and FRAS1


GRIP1

604597


AR

Fraser: One of three genes with FRAS1 and FREM2

Syndromic hearing and vision loss: Norrie disesae

NDP

300658

305390: Exudative vitreoretinopathy 310600: Norrie disease

XLR

Norrie: Only known gene ID: <0.1% (0/986 patients) XLID: >5 total mutations

Syndromic vision loss related gene

FREM1

608944

608980: Bifid nose with or without anorectal and renal anomalies 248450: AR Manitoba oculotrichoanal syndrome 614485: AD Trigonocephaly

AD, AR

MOTA: Only known gene


KIF11

148760

152950: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (AD MCLMR)

AD

AD MCLMR: Only known gene



29





30

STICKLER & CATARACT SUBPANEL

Stickler syndrome is an inherited disorder that associates ocular signs with more or less complete forms of Pierre Robin

sequence, bone disorders and sensorineural deafness. Ocular disorders may include juvenile cataract, myopia, strabismus,

vitreoretinal or chorioretinal degeneration, retinal detachment, and chronic uveitis. Robin sequence includes an opening in

the roof of the mouth (a cleft palate), a large tongue (macroglossia), and a small lower jaw (micrognathia). Bones are

affected by slight platyspondylisis and large, often defective epiphyses. Juvenile joint 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 lens 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.


Disease*


BCOR

300485

300166: Microphthalmia, syndromic Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

XLD

MAC: >1% ID: <0.1% (0/986 patients) XLID: >5 total mutations


OTX2

600037

610125: Microphthalmia, syndromic Microphthalmia/Anophthalmia/Coloboma (MAC) Spectrum 613986: Pituitary hormone deficiency, combined 610125: Retinal dystrophy, early-onset, with or without pituitary dysfunction

AD

MAC: 2-5%


PAX6

607108

106210: AD Aniridia, Cataract with late- onset corneal dystrophy 120430: AD Coloboma of optic nerve **

AD

MAC: 2% ID: 0.1% (1/986 patients)



31


Disease* 120200: AD Coloboma, ocular **

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


PXDN

605158

269400: Corneal opacification and other ocular anomalies Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

AR



VSX2

142993

610092: Microphthalmia with coloboma 610093: Microphthalmia, isolated Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum

None


Cataract AGK 610345 614691: Cataract 212350: Sengers syndrome AR Sengers: Only

known gene

Cataract

CRYAA

123580

604219: Cataract, multiple types Nonsyndromic congenital cataract (NCC)

AD

NCC: 39.4% (46 probands) with CRYAB, CRYBA4, CRYGC, CRYBB1, CRYBB2, CRYBB3, and CRYGD

Cataract

CRYAB

123590

615184: AD Cardiomyopathy, dilated 613763: AR,AD Cataract, multiple types 608810: AD Myopathy, myofibrillar (MFM) 613869: AR Myopathy, myofibrillar, fatal infantile hypertrophy, alpha-B crystallin- related

AD, AR

MFM: 3%

Cataract

CRYBB1

600929

611544: Cataract, multiple types Nonsyndromic congenital cataract (NCC)

None

NCC: 39.4% (46 probands) with CRYAA, CRYAB, CRYBA4, CRYGC, CRYBB2, CRYBB3, and CRYGD

Cataract

CRYBB3

123630

609741: Cataract Nonsyndromic congenital cataract (NCC)

AD, AR

NCC: 39.4% (46 probands) with CRYAA, CRYAB, CRYBA4, CRYGC, CRYBB1, CRYBB2, and CRYGD

Cataract

FYCO1

607182

610019: Cataract Nonsyndromic congenital cataract (NCC)

AR

NCC: 12 Pakistani families and one Arab Israeli family; 10% (2/20 patients)

Cataract

GCNT2

600429

110800: AD Adult i phenotype without cataract 110800: AD [Blood group, Ii] 116700: AR Cataract with adult i phenotype Nonsyndromic congenital cataract (NCC)

AD, AR

NCC: 4 distantly related Arab Israeli families; one consanguineous Pakistani family

Cataract

GJA8

600897 116200: Cataract, multiple types

Nonsyndromic congenital cataract (NCC)

AD

NCC: 21.2% (46 probands) with GJA3

Cataract HSF4 602438 116800: Cataract, multiple types Nonsyndromic congenital cataract (NCC) AD NCC: 5% (1/20

patients)

Cataract

PITX3

602669

107250: Anterior segment mesenchymal dysgenesis 610623: Cataract, multiple types, syndromic

AD

Eye anomolies: 2.5% (2/80 patients screened)

Cataract TDRD7 611258 613887: Cataract Sporadic Congenital Cataract (SCC) None SCC: ~4% (1/23

cases)


CRX

602225 120970: AD Cone-rod retinal dystrophy 613829: Leber congenital amaurosis (LCA) Retinitis Pigmentosa (ADRP)

AD LCA: 3%

ADRP: 1%


KCNJ13

603208

614186: AR Leber congenital amaurosis (LCA) 193230: AD Snowflake vitreoretinal

AD, AR

LCA: Unknown



32


Disease* degeneration


BEST1

607854

611809: AR Bestrophinopathy (ARB) 153700: AD Macular dystrophy, Best vitelliform (VMD2) 193220: AD Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma, Vitreoretinochoroidopathy Age-related macular degeneration (AMD) 613194: AD Retinitis pigmentosa, concentric (ADRP)

AD, AR

ARB, VMD2: Only known gene AMD, ADRP: Rare


MYH9

160775

603622: AD Deafness 153650: AD Epstein syndrome 153640: AD Fechtner syndrome 600208: AD Macrothrombocytopenia and progressive sensorineural deafness 155100: AD May-Hegglin anomaly 605249: AD Sebastian syndrome

AD

Epstein, Fechtner, May-Hegglin, Sebastian: Only known gene


WFS1

606201

116400: AD Cataract ** 600965: AD Deafnes 125853: AD {noninsulin-dependent diabetes mellitus, association} 222300: AR Wolfram syndrome 614296: AD Wolfram-like syndrome

AD, AR

Wolfram: Only known gene


RLBP1

180090

607475: AR Bothnia retinal dystrophy 136880: AR, AD Fundus albipunctatus (FA) 607476: Newfoundland rod-cone dystrophy 136880: AR, AD Retinitis punctata albescens AR Retinitis Pigmentosa (ARRP)

AD, AR

FA: ~7% (3/45 casees) ARRP: 1%

Retinopathy-related gene CAPN5 602537 193235: Vitreoretinopathy, neovascular inflammatory (ADNIV) AD ADNIV: Three

families

Retinopathy-related gene OAT 613349 258870: Gyrate atrophy of choroid and retina with or without ornithinemia AR Gyrate atrophy:

Only known gene

Syndromic hearing and vision loss: Cockayne syndrome

ERCC6

609413

214150: AR Cerebrooculofacioskeletal syndrome 133540: AR Cockayne syndrome, type B 278800: AR De Sanctis-Cacchione syndrome 211980: AR {Lung cancer, susceptibility to} 613761: {Macular degeneration, age- related, susceptibility to} 616946: AD Premature ovarian failure 600630: AR UV-sensitive syndrome

AD, AR

Cockayne: 65%

Syndromic hearing and vision loss: Norrie disesae

NDP

300658

305390: Exudative vitreoretinopathy 310600: Norrie disease

XLR

Norrie: Only known gene ID: <0.1% (0/986 patients) XLID: >5 total mutations

Syndromic hearing and vision loss: osteoporosis-pseudoglioma syndrome

LRP5

603506

601884: AD [Bone mineral density variability] 601813: AR, AD Exudative vitreoretinopathy (ADFEVR) 144750: AD Hyperostosis, endosteal 607634: AD Osteopetrosis 259770: AR Osteoporosis-pseudoglioma syndrome 166710: AD {Osteoporosis} 144750: AD Osteosclerosis 607636: AD van Buchem disease, type 2 Polycystic liver disease (PCD)

AD, AR

ARFEVR: 12-25% PCD: One of three genes with PRKCSH and SEC63

Syndromic hearing and vision loss: polyneuropathy hearing loss ataxia retinitis pigmentosa

ABHD12

613599

612674: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC)

AR

Cerebral ataxia: Reported in 1-5 families

Syndromic hearing and vision loss: rhizomelic chondrodysplasia punctata

PEX7

601757

614879: Peroxisome biogenesis disorder 215100: AR Rhizomelic chondrodysplasia punctata, type 1 (RCDP1)

AR

AR Ataxia:>5 families reported Refsum: <10% Only known gene



33


Disease*

Syndromic hearing and vision loss: Stickler syndrome

COL2A1

120140

200610: AD Achondrogenesis, type II or hypochondrogenesis 608805: AD Avascular necrosis of the femoral head 609162: AD Czech dysplasia (CD) 132450: AD Epiphyseal dysplasia, multiple, with myopia and deafness 156550: AD Kniest dysplasia 150600: AD Legg-Calve-Perthes disease (LCPD) 604864: AD Osteoarthritis 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

AD, AR

CD, Kniest, LCPD, PLDST, SEDC, SMED1, SEDSTN: Only known gene Stickler: 80-90%

Syndromic hearing and vision loss: Stickler syndrome

COL9A1

120210

614135: AD Multiple epiphyseal dysplasia ** 614134: Stickler syndrome, type IV

AD Stickler: Rare,

unknown

Syndromic hearing and vision loss: Stickler syndrome COL9A2 120260 600204: AD Multiple epiphyseal dysplasia

614284: AR ?Stickler syndrome, type V AD, AR Stickler: Rare, unknown


PEX16

603360


None

Zellweger: 0.5-1%

Syndromic hearing loss: Branchiootorenal syndrome

EYA1

601653

113650: Branchiootorenal syndrome, Anterior segment anomalies with or without cataract 602588: Branchiootic syndrome (BOR) 166780: Otofaciocervical syndrome **

AD

BOR: 40%

Syndromic hearing loss: Refsum disease

PHYH

602026

266500: Refsum disease

AR

AR Ataxia: More common (>5 families) 266500: >90%

Syndromic hearing loss: Stickler syndrome

COL11A1

120280

228520: AR Fibrochondrogenesis 603932: Lumbar disc herniation ** 154780: AD Marshall syndrome 604841: AD Stickler syndrome, type II

AD, AR

Stickler: 10-20%


COL11A2

120290

601868: AD Deafness 609706: AR Deafness 614524: AR, AD Fibrochondrogenesis 215150: AR Otospondylomegaepiphyseal dysplasia 184840: AD Stickler syndrome, type III 277610: AD Weissenbacher-Zweymuller syndrome

AD, AR

Stickler: Rare, unknown

Syndromic vision loss related gene (with retinopathy) GNPTG 607838 252605: Mucolipidosis III gamma AR MLIII_: Only known

gene


JAG1

601920

118450: AD Alagille syndrome (ALGS) Deafness, congenital heart defects, and posterior embryotoxon ** 187500: AD Tetralogy of Fallot Neonatal/infantile intrahepatic cholestasis (NIIC)

AD

ALGS: DelDup: ~5- 7%, Sequencing: 89% NIIC: Japanese 10% (11/109 patients)


OPA3

606580

258501: AR 3-methylglutaconic aciduria, type III 165300: AD Optic atrophy with cataract

AD, AR 3-MGC: Only known

gene



34


Disease*

Syndromic vision loss: Wagner syndrome VCAN 118661 143200: Wagner syndrome AD Wagner, ERVR: Only known gene





35

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.



ACTG1

102560

614583: Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF) 604717: Deafness

AD

BWCFF: >20% AD Deafness: 6.3% Deafness: 0.9% MCPH: 1 family with intermediatephenotype

Non-syndromic hearing loss CCDC50 611051 607453: Deafness ** AD AD Deafness: <1.6% Deafness: <0.2%

Non-syndromic hearing loss CEACAM16 614591 614614: Deafness AD Deafness: 3 families Non-syndromic hearing loss CLDN14 605608 614035: Deafness AR AR Deafness: 0.5%



36


Deafness: 0.5%

Non-syndromic hearing loss COCH 603196 601369: Deafness AD AD Deafness: 3.2% Deafness: 0.5%

Non-syndromic hearing loss DFNA5 608798 600994: Deafness AD AD Deafness: <1.6% Deafness: <0.2%

Non-syndromic hearing loss DFNB59 610219 610220: Deafness AR AR Deafness: 0.3% Deafness: 0.2%

Non-syndromic hearing loss DIABLO 605219 614152: Deafness AD AD Deafness: 1.6% Deafness: 0.2%


DIAPH1

602121

124900: AD Deafness 616632: AR Seizures, cortical blindness, microcephaly syndrome

AD, AR

AD Deafness: One family


ESPN

606351

609006: AR Deafness AD Deafness, neurosensory, without vestibular involvement

AD, AR

AR Deafness: <0.3% AD Deafness: 3.2% Deafness: 0.5%

Non-syndromic hearing loss ESRRB 602167 608565: Deafness AR AR Deafness: <0.3% Deafness: <0.2%


EYA4

603550

605362: familial dilated cardiomyopathy, (FDC) 601316: AD Deafness

AD

FDC: Unknown (two families)


GIPC3

608792 601869: Deafness

Non-syndromic Deafness (NSD)

AR AR Deafness: ~1% (2/160 families from Turkey, Iran, Mexico, Ecuador, and Puerto Rico)


GJB2

121011

149200: AD Bart-Pumphrey syndrome 601544: AD Deafness 220290: AR, DD Deafness 602540: AD Hystrix-like ichthyosis with deafness 148210: AD Keratitis-ichthyosis-deafness syndrome 148350: AD Keratoderma, palmoplantar, with deafness 124500: AD Vohwinkel syndrome

AD, AR, DD

AR Deafness: 50% with GJB6


GJB6

604418

612643: AD Deafness 612645: AR Deafness 220290: AR, DD Deafness, digenic GJB2/GJB6 129500: AD Ectodermal dysplasia, Clouston type

AD, AR, DD

AR Deafness: 50% with GJB2


GPSM2

609245 604213: Chudley-McCullough syndrome

(CMCS)

AR

Chudley-McCullough syndrome: Only known gene AR Deafness: <50%


GRHL2

608576

608641: AD Deafness 616029: AR Ectodermal dysplasia/short stature syndrome

AD, AR AD Deafness: <1.6%

Deafness: <0.2%

Non-syndromic hearing loss GRXCR1 613283 613285: Deafness AR AR Deafness: 0.3% Deafness: 0.2%

Non-syndromic hearing loss HGF 142409 608265: AR Deafness AR AR Deafness: <0.3% Deafness: <0.2%


ILDR1

609739

609646: Deafness

AR

AR Deafness: ~3% (5/160 families from Turkey, Iran, Mexico, Ecuador, and Puerto Rico)


KARS

601421

613641: Charcot-Marie-Tooth disease, intermediate, B 613916: Deafness

AR

hearing loss: Three unrelated, consanguineous Pakistani families

Non-syndromic hearing loss KCNQ4 603537 600101: Deafness AD DFNA2: Only known gene

Non-syndromic hearing loss LHFPL5 609427 610265: Deafness AR AR Deafness: 0.3% Deafness: 0.2%

Non-syndromic hearing loss LOXHD1 613072 613079: Deafness AR AR Deafness: 2.2% Deafness: 1.8%

Non-syndromic hearing loss LRTOMT 612414 611451: Deafness AR AR Deafness: 0.5% Deafness: 0.5%

Non-syndromic hearing loss MARVELD2 610572 610153: Deafness AR AR Deafness: <0.3% Deafness: <0.2%


MSRB3

613719

613718: Deafness

AR

hearing loss: Pakistani: 3% without GJB2 or MYO15A (1/30 families); six other unrelated



37


families reported


MT-RNR1

561000

580000: Aminoglycoside-Induced Deafness, Mitochondrial 500008: Nonsyndromic hearing loss, Mitochondrial

Prevalence is population dependent (e.g. NSHL detected 0.1% European, 15-20% Spanish, 3-11% Asian)


MYH14

608568

600652: Deafness 614369: Peripheral neuropathy, myopathy, hoarseness, and hearing loss **

AD

AD Deafness: 7.9% Deafness: 1.1%


MYH9

160775

603622: AD Deafness 153650: AD Epstein syndrome 153640: AD Fechtner syndrome 600208: AD Macrothrombocytopenia and progressive sensorineural deafness 155100: AD May-Hegglin anomaly 605249: AD Sebastian syndrome

AD

Epstein, Fechtner, May-Hegglin, Sebastian: Only known gene

Non-syndromic hearing loss MYO15A 602666 600316: Deafness AR AR Deafness: 5.6% Deafness: 4.8%

Non-syndromic hearing loss MYO3A 606808 607101: Deafness AR AR Deafness: <0.3% Deafness: <0.2%


MYO6

600970

606346: AD Deafness 606346: AD Deafness, with hypertrophic cardiomyopathy 607821: AR Deafness

AD, AR

AR Deafness:<0.3% AD Deafness: 6.3% Deafness: 1.1%

Non-syndromic hearing loss OTOA 607038 607039: Deafness AR AR Deafness: 2.2% Deafness: 1.8%

Non-syndromic hearing loss OTOF 603681 601071: Auditory neuropathy 601071: Deafness AR DFNB9: Only known gene

Non-syndromic hearing loss OTOG 604487 614945: Deafness AR Deafness: Two families (Dutch, Spanish)


OTOGL

614925

614944: Deafness

AR

ARNSD: ~1% (2/160 families from Turkey, Iran, Mexico, Ecuador, and Puerto Rico)

Non-syndromic hearing loss P2RX2 600844 608224: Deafness AD AD Deafness: <1.6% Deafness: <0.2%

Non-syndromic hearing loss POU3F4 300039 304400: Deafness XLR XL or Mitochondrial Deafness: 40% (2/5 cases)

Non-syndromic hearing loss POU4F3 602460 602459: Deafness AD hearing loss: <1% (1/342 families)

Non-syndromic hearing loss PTPRQ 603317 613391: Deafness AR AR Deafness: 1.1% Deafness: 0.9%

Non-syndromic hearing loss RDX 179410 611022: Deafness AR AR Deafness: <0.3% Deafness: <0.2%

Non-syndromic hearing loss SERPINB6 173321 613453: Deafness ** AR hearing loss: One Korean individual and one Turkish family

Non-syndromic hearing loss SMPX 300226 300066: Deafness XLD XL Nonsyndromic hearing loss: One of three genes

Non-syndromic hearing loss STRC 606440 603720: Deafness AR Deafness infertility syndrome: Only known gene


TECTA

602574 601543: AD Deafness

603629: AR Deafness

AD, AR

AR Deafness: 2.2% AD Deafness: 23.8% Deafness: 5.2%


TMC1

606706 606705: AD Deafness

600974: AR Deafness

AD, AR


Non-syndromic hearing loss TMIE 607237 600971: Deafness AR AR Deafness: <0.3% Deafness: <0.2%

Non-syndromic hearing loss TMPRSS3 605511 601072: Deafness AR AR Deafness: 2.4% Deafness: 2.0%


TPRN

613354

613307: Deafness

AR


Non-syndromic hearing loss TRIOBP 609761 609823: Deafness AR AR Deafness: 0.8% Deafness: 0.7%

Non-syndromic hearing loss TSPEAR 612920 614861: Deafness AR AR Deafness: 0.3% Deafness: 0.2%

Non-syndromic hearing loss WFS1 606201 116400: AD Cataract ** 600965: AD Deafnes AD, AR Wolfram: Only known gene



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125853: AD {noninsulin-dependent diabetes mellitus, association} 222300: AR Wolfram syndrome 614296: AD Wolfram-like syndrome

Non-syndromic hearing loss or syndromic neuropathies, Charcot Marie Tooth Disease

PRPS1

311850

301835: Arts syndrome 311070: Charcot-Marie-Tooth disease (CMTX) 304500: Deafness (X-linked) 300661: Phosphoribosylpyrophosphate synthetase superactivity; Gout, PRPS- related

XLR

CMTX: Unknown Arts: Only known gene (4 families reported) ID: <0.1% (0/986 patients) XLID: >5 missense/regulatory mutations

Syndromic hearing and vision loss: Mohr- Tranebjaerg syndrome

TIMM8A

300356

304700: Mohr-Tranebjaerg syndrome

XLR

Only known gene ID: <0.1% (0/986 patients) XL: >5 total mutations

Syndromic hearing and vision loss: optic atrophy with or without auditory neuropathy

TMEM126A

612988

612989: Optic atrophy (OPA7)

AR

OPA7: Rare

Syndromic hearing and vision loss: optic atrophy, auditory neuropathy, axonal sensorineural polyneuropathy

OPA1

605290

616896: Mitochondrial DNA depletion syndrome (encephalocardiomyopathic type) 210000: AR Behr syndrome 165500: AD Optic atrophy 125250: AD Optic atrophy plus syndrome

AD, AR

One of three genes in which mutations are known to cause mtDNA deletion or mtDNA depletion-related ataxia neuropathy syndromes

Syndromic hearing loss: Cowchock syndrome, combined oxidative phosphorylation deficiency, deafness

AIFM1

300169

300816: Combined oxidative phosphorylation deficiency (Leigh syndrome, subacute necrotizing encephalomyelopathy) 310490: Cowchock syndrome (CMTX) 300614: Deafness (X-linked)

XLR

XL Leigh syndrome: One of three genes CMTX: Unknown

Syndromic hearing loss: Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation, and Seizures syndrome

TBC1D24

613577

220500: AR DOORS syndrome 614617: AR Deafness 616044: AD Deafness 615338: AR Epileptic encephalopathy, early infantile (EIEE) 605021: AR Myoclonic epilepsy, infantile, familial Epileptic encephalopathy (EE)

AD, AR

DOORS: Only known gene EIEE: One of 35 known genes NBIA: 1-2% Epilepsy: <1% (2/293 patients) ID: 2% (1/41 patients) EE: <1% (1/358 patients)

Syndromic hearing loss: Jervell & Lange-Nielsen syndrome

KCNQ1

607542

607554: AD Atrial fibrillation, familial 220400: AR Jervell and Lange-Nielsen syndrome 192500: AD Long QT syndrome, and acquired susceptibility to LQTS 609621: Short QT syndrome

AD, AR

LQTS: 30-35%

Syndromic hearing loss: Pendred syndrome

SLC26A4

605646

600791: Deafness, with enlarged vestibular aqueduct 274600: Pendred syndrome (PDS)

AR

PDS: 50%

Syndromic hearing loss: Refsum disease

PHYH

602026

266500: Refsum disease

AR

AR Ataxia: More common (>5 families) 266500: >90%

Syndromic hearing loss: SANDD Sydrome, Sinoatrial node dysfunction and deafness

CACNA1D

114206

615474: AD Primary aldosteronism, seizures, and neurologic abnormalities 614896: AR Sinoatrial node dysfunction and deafness

AD, AR

Deafness: Two consanguineous families


COL11A2

120290

601868: AD Deafness 609706: AR Deafness 614524: AR, AD Fibrochondrogenesis 215150: AR Otospondylomegaepiphyseal dysplasia 184840: AD Stickler syndrome, type III 277610: AD Weissenbacher-Zweymuller syndrome

AD, AR

Stickler: Rare, unknown


EDN3

131242

209880: congenital central hypoventilation syndrome (CCHS) 613265: Waardenburg syndrome, type 4B (WS4) 613712: Hirschsprung disease (HSCR)**

AD, AR

CCHS: AD, Identified in a subset of individuals Nonsyndromic HSCR: 5% WS4: AR, Common with EDNRB

Syndromic hearing loss: EDNRB 131244 600501: albinism, black lock, cell AD, AR ABCD syndrome: (AR), only



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Waardenburg syndrome migration disorder of neurocytes of the gut and deafness (ABCD) syndrome 600155: Hirschsprung disease (HSCR)** 277580: AR, AD Waardenburg syndrome, type 4A (WS4)

known gene Nonsyndromic Hirschsprung disease: AR, 3-7% Waardenburg Type 4A: (AR, AD) Common with EDN3


MITF

156845

614456: cutaneous malignant melanoma ** 103500: AD Tietz albinism-deafness syndrome 193510: AD Waardenburg syndrome, type 2A (WS2) 103470: AD Waardenburg syndrome/ocular albinism, digenic

AD

Waardenburg Type 2A (AD): 10- 20%


PAX3

606597

122880: AD craniofacial-deafness-hand syndrome 268220: AR alveolar rhabdomyosarcoma, 193500: AD Waardenburg syndrome, type 1 (WS1) 148820: AR, AD Waardenburg syndrome, type 3

AD, AR

Waardenburg Type 1 / 3 (AD, AR): Only known gene


SOX10

602229

609136: peripheral demyleinating neuropathy, central dysmelination, Waardenburg syndrome, and Hirschsprung disease (PCWH syndrome) 611584: Waardenburg syndrome, type 2E, with or without neurologic involvement 613266: Waardenburg syndrome, type 4C

AD

Waardenburg syndrome: 15%





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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.

Disease Category Gene

ID Mim No. OMIM: Prevalent Phenotype(s) Inheritance Proportion of

Disease*


EYA1

601653

113650: Branchiootorenal syndrome, Anterior segment anomalies with or without cataract 602588: Branchiootic syndrome (BOR) 166780: Otofaciocervical syndrome **

AD

BOR: 40%


SIX1

601205

608389: Branchiootic syndrome (BOS/BOR) 605192: Deafness (AD)

AD

BOR/BOS: 2% Deafness (AD): <1.6% Deafness: <0.2%

Syndromic hearing loss: Branchiootorenal syndrome SIX5 600963 610896: Branchiootorenal syndrome (BOR/BOS) None BOR/BOS: 2.5%





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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.

Disease Category Gene ID Mim

No. OMIM: Prevalent Phenotype(s) Inheritance Proportion of Disease*

Non-syndromic hearing loss WHRN 607928 607084: Deafness 611383: Usher syndrome, type 2D (USH2) AR Usher syndrome, type 2D

: ~0-10% Syndromic hearing and vision loss: Usher syndrome ADGRV1 602851 605472: AR, DD Usher syndrome, type 2C

605472: AR, DD Usher syndrome, type 2C AR, DD Usher Type II: ~7-19%


CDH23

605516

601386: AR Deafness 601067: AR, DR Usher syndrome, type 1D/F (USH1)

AR, DR

USH1: 7-20%

Syndromic hearing and vision loss: Usher syndrome CIB2 605564 609439: Deafness

614869: Usher syndrome, type IJ (USH1) AR USH1: Unknown


CLRN1

606397 614180: Retinitis pigmentosa (ARRP)

276902: Usher syndrome, type 3A (USH3)

AR

ARRP: 1% USH3: One of two genes with HARS


HARS

142810

616625: AD Charcot-Marie-Tooth disease, axonal, type 2W (CMT2W) 614504: AR Usher syndrome type 3B (USH3)

AD, AR

CMT2W: 5 families USH3: One of two genes with CLRN1


MYO7A

276903

601317: AD Deafness 600060: AR Deafness 276900: AR Usher syndrome, type 1B (USH1)

AD, AR

USH1: 53-63%


PCDH15

605514

609533: AR Deafness 601067: AR, DR Usher syndrome, type 1D/F (USH1) 602083: AR Usher syndrome, type 1F

AR, DR

USH1: 7-12%

Syndromic hearing and vision loss: Usher syndrome USH1C 605242 602092: Deafness

276904: Usher syndrome, type 1C (USH1) AR USH1: 1-15%

Syndromic hearing and vision loss: Usher syndrome USH1G 607696 606943: Usher syndrome, type 1G (USH1) AR USH1: Rare (0-4%)


USH2A

608400

613809: Retinitis pigmentosa 276901: AR Usher syndrome, type 2A (USH2)

AR

USH2: 57-79%



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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 adrenoleukodystrophy (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.

Disease Category Gene ID

Mim No. OMIM: Prevalent Phenotype(s) Inheritance Proportion of

Disease*

Syndromic hearing and vision loss: rhizomelic chondrodysplasia punctata

PEX7

601757

614879: Peroxisome biogenesis disorder 215100: AR Rhizomelic chondrodysplasia punctata, type 1 (RCDP1)

AR

AR Ataxia:>5 families reported Refsum: <10% Only known gene


PEX1

602136

234580: AR Heimler syndrome 214100: AR Peroxisome biogenesis disorder 1A (Zellweger) 601539: Peroxisome biogenesis disorder 1B (NALD/IRD)

AR

Zellweger: 57-68%


PEX10

602859


AR

Zellweger: ~3-5%

Syndromic hearing and vision loss: Zellweger syndrome PEX14 601791 614887: Peroxisome biogenesis disorder

13A (Zellweger) AR Zellweger: <1%


PEX16

603360


None

Zellweger: 0.5-1%


12A (Zellweger) None Zellweger: <1%


5A (Zellweger) AR Zellweger: 1-4%



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Disease Category Gene ID

Mim No. OMIM: Prevalent Phenotype(s) Inheritance Proportion of

Disease* 614867: Peroxisome biogenesis disorder

5B


PEX5

600414

214110: Peroxisome biogenesis disorder 2A (Zellweger) 202370: Peroxisome biogenesis disorder 2B 616716: Rhizomelic chondrodysplasia punctata, type 5

AR

Zellweger: 1.5-2%


PEX6

601498

616617: AR Heimler syndrome 614862: Peroxisome biogenesis disorder 4A (Zellweger) 614863: Peroxisome biogenesis disorder 4B

AR

Zellweger: ~11-16%





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References

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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.

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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 Lissencephaly/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.

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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.

HEARING AND VISION LOSS NEXT- GENERATION SEQUENCING … · Hearing and/or vision loss can result...

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