UKGTN Testing Criteria Test name: Syndromic and Non Syndromic Hearing Loss 95 Gene Panel

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1 UKGTN Testing Criteria Test name: Syndromic and Non Syndromic Hearing Loss 95 Gene Panel Approved name and symbol of disorder/condition(s): See Appendix 1 Approved name and symbol of gene(s): See Appendix 1 OMIM number(s): OMIM number(s): Patient name: Patient postcode: Date of birth: NHS number: Name of referrer: Title/Position: Lab ID: Referrals will only be accepted from one of the following: Referrer Consultant Clinical Geneticist Consultant Audiologist Consultant Paediatrician Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Early onset hearing loss that is moderate or severe or profound AND no GJB2 or GJB6 mutations found Additional Information: For panel tests: A pro forma is required to be completed that is available from the laboratory website Tick if this patient meets criteria At risk family members where familial mutation is known do not require a full panel test but should be offered analysis of the known mutation If the sample does not fulfil the clinical criteria or you are not one of the specified types of referrer and you still feel that testing should be performed please contact the laboratory to discuss testing of the sample. A

2 Appendix 1 Genes in panel test and associated conditions Rows where the genes are currently being fully analysed in the context of a single separate UKGTN test are highlighted yellow. HGNC standard name and symbol of the gene actin, gamma 1 (ACTG1) ATPase, Ca++ transporting, plasma membrane 2 (ATP2B2) B double prime 1, subunit of rna polymerase iii transcription initiation factor iiib (BDP1) cadherin related 23 (CDH23) HGNC number OMIM number OMIM standard name of condition and symbol DEAFNESS, DOMINANT 20 (DFNA20) DEAFNESS, RECESSIVE 12 (DFNB12) Mode of inherit ance OMIM number Evidence of association between gene(s) and condition AD Mutations in the gammaactin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26). Am. J. Hum. Genet. 73: , 2003 AD/M od Modification of human hearing loss by plasmamembrane calcium pump PMCA2. New Eng. J. Med. 352: , N/A AR N/A Linkage Study and Exome Sequencing Identify a BDP1 Mutation Associated with Hereditary Hearing Loss. PLoS ONE 8(12): e USHER SYNDROME, TYPE ID (USH1D); DEAFNESS, RECESSIVE 12 (DFNB12) AR ; Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin like gene CDH23. Am. J. Hum. Genet. 68: 26 37, 2001 % of MLPA horizontal coverage of gene N Comments

3 calcium and integrin binding family member 2 (CIB2) calcium binding protein 2 (CABP2) carcinoembryonic antigen related cell adhesion molecule 16 (CEACAM16) caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) DEAFNESS, RECESSIVE 48 (DFNB48); USHER SYNDROME, TYPE IJ (USH1J) DEAFNESS, RECESSIVE 93 (DFNB93) DEAFNESS, DOMINANT 4B (DFNA4B) PERRAULT SYNDROME 3 (PRLTS3) clarin 1 (CLRN1) USHER SYNDROME, TYPE IIIA (USH3A) AR ; Alterations of the CIB2 calcium and integrinbinding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. Nature Genet. 44: , 2012 AR A mutation in CABP2, expressed in cochlear hair cells, causes autosomalrecessive hearing impairment. Am. J. Hum. Genet. 91: , 2012 AD Carcinoembryonic antigenrelated cell adhesion molecule 16 interacts with alpha tectorin and is mutated in autosomal dominant hearing loss (DFNA4). Proc. Nat. Acad. Sci. 108: , 2011 AR Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP dependent chambered protease. Am. J. Hum. Genet. 92: , 2013 AR Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3. Am. J. Hum. Genet. 69: , 2001

4 claudin 14 (CLDN14) DEAFNESS, RECESSIVE 29 (DFNB29) cochlin (COCH) DEAFNESS, DOMINANT 9 (DFNA9) coiled coil domain containing 50 (CCDC50) collagen, type IV, alpha 6 (COL4A6) collagen, type XI, alpha 2 (COL11A2) DEAFNESS, DOMINANT 44 (DFNA44) AR Mutations in the gene encoding tight junction claudin 14 cause recessive deafness DFNB29. Cell 104: , 2001 AD Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Nature Genet. 20: , 1998 AD A mutation in CCDC50, a gene encoding an effector of epidermal growth factor mediated cell signaling, causes progressive hearing loss. Am. J. Hum. Genet. 80: , N/A XL N/A Novel form of X linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6. Eur J Hum Genet May DEAFNESS, DOMINANT 13 (DFNA13); DEAFNESS, RECESSIVE 53 (DFNB53) AD;AR ; Mutations in COL11A2 cause non syndromic hearing loss (DFNA13). Nature Genet. 23: , 1999; Mutation of COL11A2 causes autosomal recessive non syndromic hearing loss at the DFNB N

5 crystallin, mu (CRYM) deafness, autosomal dominant 5 (DFNA5) deafness, autosomal recessive 31 (DFNB31) deafness, autosomal recessive 59 (DFNB59) DEAFNESS, DOMINANT 40 (DFNA40) DEAFNESS, DOMINANT 5 (DFNA5) DEAFNESS, RECESSIVE 31 (DFNB31); USHER SYNDROME, TYPE IID (USH2D) DEAFNESS, RECESSIVE 59 (DFNB59) locus. J. Med. Genet. 42: e61, 2005 AD No Identification of CRYM as a number candidate responsible for nonsyndromic deafness, through cdna microarray analysis of human cochlear and vestibular tissues. Am. J. Hum. Genet. 72: 73 82, 2003 AD Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nature Genetics 20: , 1998 AR ; Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nature Genet. 34: , 2003; A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss. Hum. Genet. 121: , 2007 AR Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central

6 diablo, IAP binding mitochondrial protein (DIABLO) diaphanous related formin 1 (DIAPH1) diaphanous related formin 3 (DIAPH3) DEAFNESS, DOMINANT 64 (DFNA64) DEAFNESS, DOMINANT 1 (DFNA1) Auditory neuropathy, autosomal dominant 1 (AUNA1) endothelin 3 (EDN3) WAARDENBURG SYNDROME, TYPE 4B (WS4B) endothelin receptor type B (EDNRB) WAARDENBURG SYNDROME, TYPE 4A (WS4A) vestibular dysfunction. Hum. Mutat. 28: , 2007 AD Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64. Am. J. Hum. Genet. 89: 56 66, 2011 AD Nonsyndromic deafness DFNA1 associated with mutation of the human homolog of the Drosophila gene diaphanous. Science 278: , 1997 AD Increased activity of Diaphanous homolog 3 (DIAPH3)/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila. Proc. Nat. Acad. Sci. 107: , 2010 AR/AD Mutation of the endothelin 3 gene in the Waardenburg Hirschsprung disease (Shah Waardenburg syndrome). Nature Genet. 12: , 1996 AR/AD A missense mutation of the endothelin B receptor gene in multigenic N

7 espin (ESPN) DEAFNESS, RECESSIVE 36 (DFNB36) estrogen related receptor beta (ESRRB) eyes absent homolog 1 (Drosophila) (EYA1) eyes absent homolog 4 (Drosophila) (EYA4) G protein coupled receptor 98 (GPR98) DEAFNESS, RECESSIVE 35 (DFNB35) BRANCHIOOTIC SYNDROME 1 (BOS1) DEAFNESS, DOMINANT 10 (DFNA10) USHER SYNDROME, TYPE IIC (USH2C) Hirschsprung's disease. Cell 79: , 1994 AR Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction. J. Med. Genet. 41: , 2004 AR Mutations of ESRRB encoding estrogen related receptor beta cause autosomal recessive nonsyndromic hearing impairment DFNB35. Am. J. Hum. Genet. 82: , 2008 AR BOR and BO syndromes are allelic defects of EYA1. Europ. J. Hum. Genet. 5: , 1997 AD Nonsyndromic hearing loss DFNA10 and a novel mutation of EYA4: evidence for correlation of normal cardiac phenotype with truncating mutations of the Eya domain. Am. J. Med. Genet. 143A: , 2007 AR Mutations in the VLGR1 gene implicate G protein signaling in the pathogenesis of Usher 100 Y N.B. some mutations in EYA4 cause dilated cardiomyopathy: Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nature Genet. 37: , N

8 gap junction protein, beta 2 (GJB2) gap junction protein, beta 3 (GJB3) gap junction protein, beta 6 (GJB6) DEAFNESS, RECESSIVE 1A (DFNB1A); DEAFNESS, DOMINANT 3A (DFNA3A) ERYTHROKERATODE RMIA VARIABILIS ET PROGRESSIVA (EKVP); DEAFNESS, DOMINANT 2B (DFNA2B) DEAFNESS, RECESSIVE 1B (DFNB1B); DEAFNESS, DOMINANT 3A (DFNA3A) AR/AD ; AD ; AR;AD ; syndrome type II. Am. J. Hum. Genet. 74: , 2004 Connexin 26 mutations in hereditary non syndromic sensorineural deafness. Nature 387: 80 83, 1997; Functional analysis of R75Q mutation in the gene coding for connexin 26 identified in a family with nonsyndromic hearing loss. Clin. Genet. 68: , 2005 Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nature Genet. 20: , Mutations in the gene encoding gap junction protein beta 3 associated with autosomal dominant hearing impairment. Nature Genet. 20: , 1998 A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. New Eng. J. Med. 346: , 2002; Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nature

9 Genet. 23: 16 18, 1999 GIPC PDZ domain DEAFNESS, AR Gipc3 mutations associated containing family, member 3 (GIPC3) RECESSIVE 15 (DFNB15) with audiogenic seizures and sensorineural hearing loss in mouse and human. Nature Commun. 2: 201, 2011 glutaredoxin, DEAFNESS, AR Homozygosity mapping cysteine rich 1 (GRXCR1) RECESSIVE 25 (DFNB25) reveals mutations of GRXCR1 as a cause of autosomal recessive nonsyndromic hearing impairment. Am. J. Hum. Genet. 86: , 2010 G protein signaling Chudley McCullough AR Whole exome sequencing modulator 2 (GPSM2) syndrome (CMCS) and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82. Am. J. Hum. Genet. 87: 90 94, 2010 grainyhead like DEAFNESS, AD Mutation of a transcription 99.6 N (Drosophila) (GRHL2) DOMINANT 28 (DFNA28) factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28. Hum. Molec. Genet. 11: , 2002 hepatocyte growth DEAFNESS, AR Noncoding mutations of factor (hepapoietin A; scatter factor) (HGF) RECESSIVE 39 (DFNB39) HGF are associated with nonsyndromic hearing loss, DFNB39. Am. J. Hum. Genet. 85: 25 39, 2009 histidyl trna USHER SYNDROME, AR Genetic mapping and N

10 synthetase (HARS) TYPE IIIB (USH3B) exome sequencing identify variants associated with five novel diseases. PLoS One 7: e28936, 2012 histidyl trna synthetase 2, mitochondrial (HARS2) hydroxysteroid (17 beta) dehydrogenase 4 (HSD17B4) immunoglobulinlike domain containing receptor 1 (ILDR1) leucine rich transmembrane and O methyltransferase domain containing (LRTOMT) leucyl trna synthetase 2, mitochondrial PERRAULT SYNDROME 2 (PRLTS2) PERRAULT SYNDROME 1 (PRLTS1) DEAFNESS, RECESSIVE 42 (DFNB42) DEAFNESS, RECESSIVE 63 (DFNB63) PERRAULT SYNDROME 4 (PRLTS4) AR Mutations in mitochondrial histidyl trna synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc. Nat. Acad. Sci. 108: , 2011 AR Mutations in the DBPdeficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault syndrome. Am. J. Hum. Genet. 87: , 2010 AR Loss of function mutations of ILDR1 cause autosomalrecessive hearing impairment DFNB42. Am. J. Hum. Genet. 88: , 2011 AR Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans. Nature Genet. 40: , 2008 AR Mutations in LARS2, encoding mitochondrial leucyl trna synthetase, N N

11 (LARS2) lipoma HMGIC fusion partner like 5 (LHFPL5) lipoxygenase homology domains 1 (LOXHD1) lysyl trna synthetase (KARS) MARVEL domain containing 2 (MARVELD2) DEAFNESS, RECESSIVE 67 (DFNB67) DEAFNESS, RECESSIVE 77 (DFNB77) DEAFNESS, RECESSIVE 89 (DFNB89) DEAFNESS, RECESSIVE 49 (DFNB49) lead to premature ovarian failure and hearing loss in Perrault syndrome. Am. J. Hum. Genet. 92: , 2013 AR Mutations in the lipoma HMGIC fusion partner like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss. Hum. Mutat. 27: , 2006 AR Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans. Am. J. Hum. Genet. 85: , 2009 AR Mutations in KARS, encoding lysyl trna synthetase, cause autosomal recessive nonsyndromic hearing impairment DFNB89. Am. J. Hum. Genet. 93: , 2013 AR Splice site mutations in the TRIC gene underlie autosomal recessive nonsyndromic hearing impairment in Pakistani families. J. Hum. Genet. 53: , N N

12 methionine sulfoxide reductase B3 (MSRB3) microphthalmiaassociated transcription factor (MITF) microrna 96 (MIR96) DEAFNESS, RECESSIVE 74 (DFNB74) WAARDENBURG SYNDROME, TYPE 2A (WS2A) DEAFNESS, DOMINANT 50 (DFNA50) myosin IA (MYO1A) DEAFNESS, DOMINANT 48 (DFNA48) myosin IIIA (MYO3A) DEAFNESS, RECESSIVE 30 (DFNB30) myosin VI (MYO6) DEAFNESS, DOMINANT 22 AR Functional null mutations of MSRB3 encoding methionine sulfoxide reductase are associated with human deafness DFNB74. Am. J. Hum. Genet. 88: 19 29, 2011 AD Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nature Genet. 8: , 1994 AD Mutations in the seed region of human mir 96 are responsible for nonsyndromic progressive hearing loss. Nature Genet. 41: , 2009 AD Multiple mutations of MYO1A, a cochlearexpressed gene, in sensorineural hearing loss. Am. J. Hum. Genet. 72: , 2003 AR From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc. Nat. Acad. Sci. 99: , 2002 AD ; MYO6, the human homologue of the gene responsible for deafness in 100 Y N Co association of hypertrophic cardiomyopathy:

13 myosin VIIA (MYO7A) myosin XVA (MYO15A) myosin, heavy chain 14, non muscle (MYH14) (DFNA22); DEAFNESS, RECESSIVE 37 (DFNB37) USHER SYNDROME, TYPE I (USH1); DEAFNESS, DOMINANT 11 (DFNA11); DEAFNESS, RECESSIVE 2 (DFNB2) DEAFNESS, RECESSIVE 3 (DFNB3) DEAFNESS, DOMINANT 4A (DFNA4A) AR/AD ; ; Snell's Waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss. Am. J. Hum. Genet. 69: , 2001; Mutations of MYO6 are associated with recessive deafness, DFNB37. Am. J. Hum. Genet. 72: , 2003 Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 374: 60 61, 1995; Autosomal dominant nonsyndromic deafness caused by a mutation in the myosin VIIA gene. (Letter) Nature Genet. 17: , 1997; Mutations in the myosin VIIA gene cause non syndromic recessive deafness. Nature Genet. 16: , 1997 AR Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness. Europ. J. Hum. Genet. 16: 89 96, 2008 AD Nonmuscle myosin heavychain gene MYH14 is expressed in cochlea and mutated in patients N N Novel association of hypertrophic cardiomyopathy, sensorineural deafness, and a mutation in unconventional myosin VI (MYO6). (Letter) J. Med. Genet. 41: , 2004

14 myosin, heavy chain 9, non muscle (MYH9) DEAFNESS, DOMINANT 17 (DFNA17) otoancorin (OTOA) DEAFNESS, RECESSIVE 22 (DFNB22) otoferlin (OTOF) DEAFNESS, RECESSIVE 9 (DFNB9); AUDITORY NEUROPATHY, RECESSIVE, 1 (AUNB1) affected by autosomal dominant hearing impairment (DFNA4). Am. J. Hum. Genet. 74: , 2004 AD Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am. J. Hum. Genet. 67: , 2000 AR Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22. Proc. Nat. Acad. Sci. 99: , 2002 AR A mutation in OTOF, encoding otoferlin, a FER 1 like protein, causes DFNB9, a nonsyndromic form of deafness. Nature Genet. 21: , Non syndromic recessive auditory neuropathy is the result of mutations in the otoferlin (OTOF) gene. J. Med. Genet. 40: 45 50, otogelin (OTOG) DEAFNESS, AR Mutations of the gene

15 RECESSIVE 18B (DFNB18B) paired box 3 (PAX3) WAARDENBURG SYNDROME, TYPE 1 (WS1); WAARDENBURG SYNDROME, TYPE 3 (WS3) PDZ domain containing 7 (PDZD7) phosphoribosyl pyrophosphate synthetase 1 (PRPS1) polyribonucleotide nucleotidyltransfera se 1 (PNPT1) potassium inwardlyrectifying channel, subfamily J, member USHER SYNDROME, TYPE IIC (USH2C) DEAFNESS, X LINKED 1 (DFNX1) DEAFNESS, RECESSIVE 70 (DFNB70) SEIZURES, SENSORINEURAL DEAFNESS, ATAXIA, MENTAL AR/AD ; Mod/d igenic encoding otogelin are a cause of autosomalrecessive nonsyndromic moderate hearing impairment. Am. J. Hum. Genet. 91: , 2012 Waardenburg syndrome patients have mutations in the human homologue of the Pax 3 paired box gene. Nature 355: , PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome. J. Clin. Invest. 120: , 2010 XL Loss of function mutations in the PRPS1 gene cause a type of nonsyndromic X linked sensorineural deafness, DFN2. Am. J. Hum. Genet. 86: 65 71, 2010 AR A mutation in PNPT1, encoding mitochondrial RNA import protein PNPase, causes hereditary hearing loss. Am. J. Hum. Genet. 91: , 2012 AR Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME / EAST 100 Y N N

16 (KCNJ10) potassium voltagegated channel, KQTlike subfamily, member 4 (KCNQ4) POU class 3 homeobox 4 (POU3F4) POU class 4 homeobox 3 (POU4F3) protein tyrosine phosphatase, receptor type, Q (PTPRQ) protocadherinrelated 15 (PCDH15) RETARDATION, AND ELECTROLYTE IMBALANCE (SESAMES / EAST) DEAFNESS, DOMINANT 2A (DFNA2A) DEAFNESS, X LINKED 2 (DFNX2) DEAFNESS, DOMINANT 15 (DFNA15) DEAFNESS, RECESSIVE 84A (DFNB84A) USHER SYNDROME, TYPE IF (USH1F); DEAFNESS, syndrome) caused by mutations in KCNJ10. Proc. Nat. Acad. Sci. 106: , 2009 AD Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum. Molec. Genet. 8: , 1999 XL Association between X linked mixed deafness and mutations in the POU domain gene POU3F4. Science 267: , 1995 AD Missense mutations in POU4F3 cause autosomal dominant hearing impairment DFNA15 and affect subcellular localization and DNA binding. Hum. Mutat. 29: , 2008 AR Mutations in PTPRQ are a cause of autosomalrecessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction. Am. J. Hum. Genet. 86: , 2010 AR ; PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are 100 Y 94 N

17 purinergic receptor P2X, ligand gated ion channel, 2 (P2RX2) RECESSIVE 23 (DFNB23) DEAFNESS, DOMINANT 41 (DFNA41) radixin (RDX) DEAFNESS, RECESSIVE 24 (DFNB24) retinitis pigmentosa GTPase regulator (RPGR) serpin peptidase inhibitor, clade B (ovalbumin), member 6 (SERPINB6) SIX homeobox 1 (SIX1) RETINITIS PIGMENTOSA, X LINKED, AND SINORESPIRATORY INFECTIONS, WITH OR WITHOUT DEAFNESS DEAFNESS, RECESSIVE 91 (DFNB91) DEAFNESS, DOMINANT 23 (DFNA23); BRANCHIOOTIC SYNDROME 3 (BOS3) responsible for both USH1F and DFNB23. Hum. Molec. Genet. 12: , 2003 AD Mutation of the ATP gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise. Proc. Nat. Acad. Sci. 110: , 2013 AR Mutations of the RDX gene cause nonsyndromic hearing loss at the DFNB24 locus. Hum. Mutat. 28: , 2007 XL RPGR mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infections. J. Med. Genet. 40: , 2003 AR A truncating mutation in SERPINB6 is associated with autosomal recessive nonsyndromic sensorineural hearing loss. Am. J. Hum. Genet. 86: , 2010 AD ; SIX1 mutations cause branchio oto renal syndrome by disruption of EYA1 SIX1 DNA complexes. Proc. Nat. Acad. Sci. 101: , 2004

18 SIX homeobox 5 (SIX5) small muscle protein, X linked (SMPX) snail family zinc finger 2 (SNAI2) solute carrier family 17 (vesicular glutamate transporter), member 8 (SLC17A8) solute carrier family 26 (anion exchanger), member 4 (SLC26A4) BRANCHIOOTORENA L SYNDROME 2 (BOR2) DEAFNESS, X LINKED 4 (DFNX4) WAARDENBURG SYNDROME, TYPE 2D (WS2D); PIEBALD TRAIT (PBT) DEAFNESS, DOMINANT 25 (DFNA25) DEAFNESS, RECESSIVE 4 (DFNB4); PENDRED SYNDROME (PDS) AD Transcription factor SIX5 is mutated in patients with branchio oto renal syndrome. Am. J. Hum. Genet. 80: , 2007 XL Nonsense mutations in SMPX, encoding a protein responsive to physical force, result in X chromosomal hearing loss. Am. J. Hum. Genet. 88: , 2011 AR ; SLUG (SNAI2) deletions in patients with Waardenburg disease. Hum. Molec. Genet. 11: , 2002 AD Impairment of SLC17A8 encoding vesicular glutamate transporter 3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. Am. J. Hum. Genet. 83: , 2008 AR ; A mutation in PDS causes non syndromic recessive deafness. (Letter) Nature Genet. 18: , 1998; Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nature Genet. 17: , N

19 solute carrier family 26 (anion exchanger), member 5 (SLC26A5) solute carrier family 4, sodium borate transporter, member 11 (SLC4A11) SRY (sex determining region Y) box 10 (SOX10) DEAFNESS, RECESSIVE 61 (DFNB61) CORNEAL DYSTROPHY AND PERCEPTIVE DEAFNESS (CDPD) WAARDENBURG SYNDROME, TYPE 2E (WS2E); WAARDENBURG SYNDROME, TYPE 4C (WS4C) stereocilin (STRC) DEAFNESS, RECESSIVE 16 (DFNB16) taperin (TPRN) DEAFNESS, RECESSIVE 79 (DFNB79) tectorin alpha (TECTA) DEAFNESS, RECESSIVE 8 (DFNB8); DEAFNESS, 1997 AR Prestin, a cochlear motor protein, is defective in nonsyndromic hearing loss. Hum. Molec. Genet. 12: , 2003 AR Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non syndromic corneal endothelial dystrophy. J. Med. Genet. 44: , 2007 AD ; Deletions at the SOX gene locus gene Waardenburg syndrome types 2 and 4. Am. J. Hum. Genet. 81: , 2007 AR Mutations in a new gene encoding a protein of the hair bundle cause nonsyndromic deafness at the DFNB16 locus. Nature Genet. 29: , 2001 AR Mutations in TPRN cause a progressive form of autosomal recessive nonsyndromic hearing loss. Am. J. Hum. Genet. 86: , 2010 AR;AD ; Mutations in the human alpha tectorin gene cause autosomal dominant nonsyndromic hearing 100 Y N

20 tight junction protein 2 (TJP2) transmembrane channel like 1 (TMC1) transmembrane inner ear (TMIE) transmembrane protease, serine 3 DOMINANT 21 (DFNA21) DEAFNESS, DOMINANT 51 (DFNA51) DEAFNESS, DOMINANT 36 (DFNA36); DEAFNESS, RECESSIVE 7 (DFNB7) DEAFNESS, RECESSIVE 6 (DFNB6) DEAFNESS, impairment. Nature Genet. 19: 60 62, 1998; An alphatectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre lingual non syndromic deafness, DFNB21. Hum. Molec. Genet. 8: , 1999 AD Genomic duplication and overexpression of TJP2/ZO 2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51. Am. J. Hum. Genet. 87: , 2010 AD;AR ; Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair cell function. Nature Genet. 30: , 2002 AR Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus. Am. J. Hum. Genet. 71: , 2002 AR Mutations in the TMPRSS3 gene are a rare cause of Mutations in TJP2 are associated with familial hypercholanemia: Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nature Genet. 34: 91 96, N

21 (TMPRSS3) RECESSIVE 8 (DFNB8) childhood nonsyndromic deafness in Caucasian patients. J. Molec. Med. 80: , 2002 TRIO and F actin binding protein (TRIOBP) USH1C gene (USH1C) USH1G gene (USH1G) USH2A gene (USH2A) DEAFNESS, RECESSIVE 28 (DFNB28) USHER SYNDROME, TYPE IC (USH1C); DEAFNESS, RECESSIVE 18A (DFNB18A) USHER SYNDROME, TYPE IG (USH1G) USHER SYNDROME, TYPE IIA (USH2A) AR Mutations in a novel isoform of TRIOBP that encodes a filamentousacting binding protein are responsible for DFNB28 recessive nonsyndromic hearing loss. Am. J. Hum. Genet. 78: , 2006 AR ; A defect in harmonin, a PDZ domain containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nature Genet. 26: 51 55, 2000; Mutations in the alternatively spliced exons of USH1C cause nonsyndromic recessive deafness. Hum. Genet. 111: 26 30, 2002 AR Usher syndrome type IG (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin. Hum. Molec. Genet. 12: , 2003 AR Mutation of a gene encoding a protein with extracellular matrix motifs 100 Y

22 v kit Hardy Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) Wolfram syndrome 1 (wolframin) (WFS1) in Usher syndrome type IIa. Science 280: , PIEBALD TRAIT (PBT) AD Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. Proc. Nat. Acad. Sci. 88: , DEAFNESS, DOMINANT 6 (DFNA6); WOLFRAM SYNDROME 1 (WFS1) AD ; Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum. Molec. Genet. 10: , 2001; Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Hum. Molec. Genet. 7: , 1998 Included due to overlap with Waardenburg phenotype