Whole exome sequencing Gene package Hearing impairment version 2,

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1 Whole Exome Sequencing Gene package Hearing impairment, version 2, Technical information After DNA was enriched using Agilent Sureselect Clinical Research Exome (CRE) Capture, samples were run on the Illumina Hiseq platform. The aim is to obtain 50 million total reads per exome with a mapped fraction >0.98. The average coverage of the exome is ~50x. Data are demultiplexed by Illumina software bcl2fastq. Reads are mapped to the genome using BWA (reference: bwa.sourceforge.net/). Variant detection is performed by Genome Analysis Toolkit (reference: Analysis is performed in Cartagenia using The Variant Calling File (VCF) followed by filtering. It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all types of sequence changes). HGNC approved Phenotype description including phenotype ID(s) median depth ACTB?Dystonia, juvenile onset, Baraitser Winter syndrome 1, ACTG1 Deafness, autosomal dominant 20/26, Baraitser Winter syndrome 2, ADCY1?Deafness, autosomal recessive 44, AIFM1 Combined oxidative phosphorylation deficiency 6, Cowchock syndrome, Deafness, X linked 5, APOPT1 Mitochondrial complex IV deficiency, ATP1A2 Migraine, familial hemiplegic, 2, Alternating hemiplegia of childhood, Migraine, familial basilar, ATP6V1B1 Renal tubular acidosis with deafness, BDP1 No phenotype BSND Bartter syndrome, type 4a, Sensorineural deafness with mild renal dysfunction, C10orf2 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), Perrault syndrome 5, CABP2 Deafness, autosomal recessive 93,

2 Phenotype description including phenotype ID(s) median depth CACNA1D Sinoatrial node dysfunction and deafness, Primary aldosteronism, seizures, and neurologic abnormalities, CC2D2A Joubert syndrome 9, Meckel syndrome 6, COACH syndrome, CCDC50?Deafness, autosomal dominant 44, CD164 No phenotype CDH23 Usher syndrome, type 1D, Deafness, autosomal recessive 12, Usher syndrome, type 1D/F digenic, CEACAM16?Deafness, autosomal dominant 4B, CIB2 Deafness, autosomal recessive 48, Usher syndrome, type IJ, CLDN14 Deafness, autosomal recessive 29, CLIC5?Deafness, autosomal recessive 103, CLPP Perrault syndrome 3, CLRN1 Usher syndrome, type 3A, Retinitis pigmentosa 61, COCH Deafness, autosomal dominant 9, COL11A1 Stickler syndrome, type II, Marshall syndrome, {Lumbar disc herniation, susceptibility to}, Fibrochondrogenesis 1, COL11A2 Stickler syndrome, type III, Otospondylomegaepiphyseal dysplasia, Weissenbacher Zweymuller syndrome, Deafness, autosomal dominant 13, Deafness, autosomal recessive 53, Fibrochondrogenesis 2,

3 Phenotype description including phenotype ID(s) median depth COL2A1 Stickler syndrome, type I, Kniest dysplasia, Achondrogenesis, type II or hypochondrogenesis, SED congenita, SMED Strudwick type, Epiphyseal dysplasia, multiple, with myopia and deafness, Spondyloperipheral dysplasia, Osteoarthritis with mild chondrodysplasia, Vitreoretinopathy with phalangeal epiphyseal dysplasia Platyspondylic skeletal dysplasia, Torrance type, Otospondylomegaepiphyseal dysplasia, Avascular necrosis of the femoral head, Legg Calve Perthes disease, Stickler sydrome, type I, nonsyndromic ocular, Czech dysplasia, Spondyloepiphyseal dysplasia, Stanescu type, COL4A3 Alport syndrome, autosomal recessive, Hematuria, benign familial, Alport syndrome, autosomal dominant, COL4A4 Alport syndrome, autosomal recessive, Hematuria, familial benign COL4A5 Alport syndrome, COL4A6?Deafness, X linked 6, COL9A1?Epiphyseal dysplasia, multiple, 6, Stickler syndrome, type IV, COL9A2 Epiphyseal dysplasia, multiple, 2, {Intervertebral disc disease, susceptibility to}, ?Stickler syndrome, type V, CRYM Deafness, autosomal dominant 40, DCDC2 Nephronophthisis 19, ?Deafness, autosomal recessive 66, DFNA5 Deafness, autosomal dominant 5, DFNB59 Deafness, autosomal recessive 59, DIAPH1 Deafness, autosomal dominant 1, Seizures, cortical blindness, microcephaly syndrome, DIAPH3 Auditory neuropathy, autosomal dominant, 1,

4 Phenotype description including phenotype ID(s) median depth DSPP Dentinogenesis imperfecta, Shields type II, Deafness, autosomal dominant 39, with dentinogenesis, Dentinogenesis imperfecta, Shields type III, Dentin dysplasia, type II, EDN3 Waardenburg syndrome, type 4B, Central hypoventilation syndrome, congenital, {Hirschsprung disease, susceptibility to, 4}, EDNRB {Hirschsprung disease, susceptibility to, 2}, ABCD syndrome, Waardenburg syndrome, type 4A, ELMOD3?Deafness, autosomal recessive 88, EPS8?Deafness, autosomal recessive 102, ESPN Deafness, autosomal recessive 36, Deafness, neurosensory, without vestibular involvement, autosomal dominant ESRRB Deafness, autosomal recessive 35, EYA1 Branchiootorenal syndrome 1, with or without cataracts, Anterior segment anomalies with or without cataract, Branchiootic syndrome 1, ?Otofaciocervical syndrome, EYA4 Deafness, autosomal dominant 10, Cardiomyopathy, dilated, 1J, FAM65B?Deafness, autosomal recessive 104, FGF3 Deafness, congenital with inner ear agenesis, microtia, and microdontia, FOXI1 Enlarged vestibular aqueduct, GIPC3 Deafness, autosomal recessive 15, GJB2 Deafness, autosomal recessive 1A, Deafness, autosomal dominant 3A, Vohwinkel syndrome, Keratoderma, palmoplantar, with deafness, Keratitis ichthyosis deafness syndrome, Hystrix like ichthyosis with deafness, Bart Pumphrey syndrome, GJB3 Erythrokeratodermia variabilis et progressiva, Deafness, autosomal dominant 2B, Deafness, autosomal recessive Deafness, autosomal dominant, with peripheral neuropathy Deafness, digenic, GJB2/GJB3,

5 Phenotype description including phenotype ID(s) median depth GJB6 Deafness, autosomal dominant 3B, Deafness, autosomal recessive 1B, Deafness, digenic GJB2/GJB6, Ectodermal dysplasia 2, Clouston type, GPR98 Febrile seizures, familial, 4, Usher syndrome, type 2C, Usher syndrome, type 2C, GPR98/PDZD7 digenic, GPSM2 Chudley McCullough syndrome, GRHL2 Deafness, autosomal dominant 28, Ectodermal dysplasia/short stature syndrome, GRXCR1 Deafness, autosomal recessive 25, GRXCR2?Deafness, autosomal recessive 101, HARS Usher syndrome type 3B, Charcot Marie Tooth disease, axonal, type 2W, HARS2?Perrault syndrome 2, HGF Deafness, autosomal recessive 39, HOMER2?Deafness, autosomal dominant 68, HSD17B4 D bifunctional protein deficiency, Perrault syndrome 1, ILDR1 Deafness, autosomal recessive 42, KARS?Charcot Marie Tooth disease, recessive intermediate, B, Deafness, autosomal recessive 89, KCNE1 Jervell and Lange Nielsen syndrome 2, Long QT syndrome 5, KCNJ10 SESAME syndrome, Enlarged vestibular aqueduct, digenic, KCNQ1 Long QT syndrome 1, Jervell and Lange Nielsen syndrome, Atrial fibrillation, familial, 3, Short QT syndrome 2, {Long QT syndrome 1, acquired, susceptibility to}, KCNQ4 Deafness, autosomal dominant 2A, KITLG [Skin/hair/eye pigmentation 7, blond/brown hair], Hyperpigmentation with or without hypopigmentation, Deafness, congenital, unilateral or asymmetric, LARS2 Perrault syndrome 4, LHFPL5 Deafness, autosomal recessive 67, LOXHD1 Deafness, autosomal recessive 77, LRTOMT Deafness, autosomal recessive 63,

6 Phenotype description including phenotype ID(s) median depth MARVELD2 Deafness, autosomal recessive 49, MCM2 No phenotype MIR96 Deafness, autosomal dominant 50, No coverage data MITF Waardenburg syndrome, type 2A, Waardenburg syndrome/ocular albinism, digenic, Tietz albinism deafness syndrome, {Melanoma, cutaneous malignant, susceptibility to, 8}, MSRB3 Deafness, autosomal recessive 74, MYH14 Deafness, autosomal dominant 4A, ?Peripheral neuropathy, myopathy, hoarseness, and hearing loss, MYH9 May Hegglin anomaly, Fechtner syndrome, Sebastian syndrome, Deafness, autosomal dominant 17, Epstein syndrome, Macrothrombocytopenia and progressive sensorineural deafness, MYO15A Deafness, autosomal recessive 3, MYO3A Deafness, autosomal recessive 30, MYO6 Deafness, autosomal dominant 22, Deafness, autosomal recessive 37, Deafness, autosomal dominant 22, with hypertrophic cardiomyopathy, MYO7A Usher syndrome, type 1B, Deafness, autosomal recessive 2, Deafness, autosomal dominant 11, NARS2 Combined oxidative phosphorylation deficiency 24, NLRP3 Familial cold induced inflammatory syndrome 1, Muckle Wells syndrome, CINCA syndrome, OPA1 Optic atrophy 1, {Glaucoma, normal tension, susceptibility to}, Optic atrophy plus syndrome, OSBPL2 Deafness, autosomal dominant 67, OTOA Deafness, autosomal recessive 22, OTOF Deafness, autosomal recessive 9, Auditory neuropathy, autosomal recessive, 1, OTOGL Deafness, autosomal recessive 84B, P2RX2 Deafness, autosomal dominant 41,

7 Phenotype description including phenotype ID(s) median depth PAX3 Waardenburg syndrome, type 1, Waardenburg syndrome, type 3, Craniofacial deafness hand syndrome, Rhabdomyosarcoma 2, alveolar, PCDH15 Usher syndrome, type 1F, Deafness, autosomal recessive 23, Usher syndrome, type 1D/F digenic, PDZD7 {Retinal disease in Usher syndrome type IIA, modifier of}, Usher syndrome, type IIC, GPR98/PDZD7 digenic, PEX1 Peroxisome biogenesis disorder 1A (Zellweger), Peroxisome biogenesis disorder 1B (NALD/IRD), Heimler syndrome 1, PEX6 Peroxisome biogenesis disorder 4A (Zellweger), Peroxisome biogenesis disorder 4B, Heimler syndrome 2, PNPT1 Combined oxidative phosphorylation deficiency 13, Deafness, autosomal recessive 70, POU3F4 Deafness, X linked 2, POU4F3 Deafness, autosomal dominant 15, PRPS1 Gout, PRPS related, Phosphoribosylpyrophosphate synthetase superactivity, Charcot Marie Tooth disease, X linked recessive, 5, Arts syndrome, Deafness, X linked 1, PTPRQ Deafness, autosomal recessive 84A, RDX Deafness, autosomal recessive 24, S1PR2 No phenotype SERPINB6?Deafness, autosomal recessive 91, SIX1 Brachiootic syndrome 3, Deafness, autosomal dominant 23, SIX5 Branchiootorenal syndrome 2, SLC17A8 Deafness, autosomal dominant 25, SLC26A4 Pendred syndrome, Deafness, autosomal recessive 4, with enlarged vestibular aqueduct, SLC26A5?Deafness, autosomal recessive 61, SLC33A1 Spastic paraplegia 42, autosomal dominant, Congenital cataracts, hearing loss, and neurodegeneration, SLITRK6 Deafness and myopia, SMPX Deafness, X linked 4,

8 Phenotype description including phenotype ID(s) median depth SNAI2 Waardenburg syndrome, type 2D, Piebaldism, SOX10 Waardenburg syndrome, type 4C, Waardenburg syndrome, type 2E, with or without neurologic involvement, PCWH syndrome, STRC Deafness, autosomal recessive 16, SYNE4 Deafness, autosomal recessive 76, TBC1D24 Myoclonic epilepsy, infantile, familial, Epileptic encephalopathy, early infantile, 16, DOOR syndrome, Deafness, autosomal recessive 86, Deafness, autosomal dominant 65, TECTA Deafness, autosomal dominant 8/12, Deafness, autosomal recessive 21, TIMM8A Mohr Tranebjaerg syndrome, Jensen syndrome, TJP2 Hypercholanemia, familial, Cholestasis, progressive familial intrahepatic 4, TMC1 Deafness, autosomal recessive 7, Deafness, autosomal dominant 36, TMEM132E No phenotype TMIE Deafness, autosomal recessive 6, TMPRSS3 Deafness, autosomal recessive 8/10, TNC Deafness, autosomal dominant 56, TPRN Deafness, autosomal recessive 79, TRIOBP Deafness, autosomal recessive 28, TSPEAR Deafness, autosomal recessive 98, TYR Albinism, oculocutaneous, type IA, Waardenburg syndrome/albinism, digenic, Albinism, oculocutaneous, type IB, [Skin/hair/eye pigmentation 3, light/dark/freckling skin], {Melanoma, cutaneous malignant, susceptibility to, 8}, [Skin/hair/eye pigmentation 3, blue/green eyes], USH1C Usher syndrome, type 1C, Deafness, autosomal recessive 18A, USH1G Usher syndrome, type 1G, USH2A Usher syndrome, type 2A, Retinitis pigmentosa 39,

9 Phenotype description including phenotype ID(s) WFS1 Wolfram syndrome, Deafness, autosomal dominant 6/14/38, Wolfram like syndrome, autosomal dominant, {Diabetes mellitus, noninsulin dependent, association with}, ?Cataract 41, WHRN Deafness, autosomal recessive 31, Usher syndrome, type 2D, YAP1 Coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or mental retardation, Coloboma, ocular, median depth No coverage data Gene symbols according HGCN release used: "No phenotypes" indicates a gene without a current association phenotypes between "[ ]", indicate "nondiseases," mainly genetic variations that lead to apparently abnormal laboratory test values phenotypes between "{}", indicate risk factors phenotypes with a question mark, "?", before the disease name indicates an unconfirmed or possibly spurious mapping. The statistics above are based on a set of 50 samples Median depth is the median of the mean sequence depth over the protein coding exons of the transcript % Covered 10x describes the percentage of a gene s coding sequence that is covered at least 10x % Covered 20x describes the percentage of a gene s coding sequence that is covered at least 20x