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ARNSHL gene identification: past, present and future

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Abstract

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common hereditary deafness. It is genetically highly heterogeneous and about 89 gene loci and 76 gene’s mutations have been implicated in the etiology of ARNSHL. Molecular basis of ARNSHL remains unresolved in 60% of cases and gene mutations are unknown for 23 of 89 reported loci. Techniques used to identify reported ARNSHL gene mutations can be divided into position-dependent and position-independent approaches. The localization of the loci has been facilitated by homozygosity mapping or linkage studies using STR or SNP genotyping in large consanguineous families. First few genes identified for hearing loss exhibited such wide diversity of function and expression patterns that candidate gene approach was not a viable option. The mapping of the disorder to a chromosomal location has been followed by Sanger sequencing of all genes in the target region or confining of the massively parallel sequencing data analyses to the linkage region. Sometimes genes located in the linkage interval were prioritized because there was a reported orthologs with mutations causing hearing loss in mouse or when mutations in the gene caused a related disorder. Position-independent approaches involving use of mouse subtractive cochlear libraries, forward genetic screening, and position-independent analyses of massively parallel sequencing data have helped identify 17 of 68 reported ARNSHL gene mutations. A thorough study of the strategies used in the identification of reported ARNSHL genes and of their relative success can help increase the success rate of future studies.

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References

  • Ahmed ZM, Morell RJ, Riazuddin S, Gropman A, Shaukat S, Ahmad MM, Mohiddin SA, Fananapazir L, Caruso RC, Husnain T, Khan SN, Riazuddin S, Griffith AJ, Friedman TB, Wilcox ER (2003a) Mutations of MYO6 are associated with recessive deafness, DFNB37. Am J Hum Genet 72:1315–1322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmed ZM, Riazuddin S, Ahmad J, Bernstein SL, Guo Y, Sabar MF, Sieving P, Riazuddin S, Griffith AJ, Friedman TB, Belyantseva IA, Wilcox ER (2003b) PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. Hum Molec Genet 12:3215–3223

    Article  CAS  PubMed  Google Scholar 

  • Ahmed ZM, Masmoudi S, Kalay E, Belyantseva IA, Mosrati MA, Collin RWJ, Riazuddin S, Hmani-Aifa M, Venselaar H, Kawar MN, Tlili A, van der Zwaag B et al (2008) Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans. Nat Genet 40:1335–1340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmed ZM, Yousaf R, Lee BC, Khan SN, Lee S, Lee K, Husnain T, Rehman AU, Bonneux S, Ansar M, Ahmad W, Leal SM, Gladyshev VN, Belyantseva IA, Van Camp G, Riazuddin S, Friedman TB, Riazuddin S (2011) Functional null mutations of MSRB3 encoding methionine sulfoxide reductase are associated with human deafness DFNB74. Am J Hum Genet 88:19–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Behlouli A, Bonnet C, Abdi S, Bouaita A, Lelli A, Hardelin J-P, Schietroma C, Rous Y, Louha M, Cheknane A, Lebdi H, Boudjelida K, Makrelouf M, Zenati A, Petit C (2014) EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness. Orphanet J Rare Dis 9:55

    Article  PubMed  PubMed Central  Google Scholar 

  • Booth KT, Azaiez H, Kahrizi K, Simpson AC, Tollefson WT, Sloan CM, Meyer NC, Babanejad M, Ardalani F, Arzhangi S, Schnieders MJ, Najmabadi H, Smith RJ (2015) PDZD7 and hearing loss: more than just a modifier. Am J Med Genet A 167A(12):2957–2965

    Article  PubMed  CAS  Google Scholar 

  • Booth KT, Kahrizi K, Najmabadi H, Azaiez H, Smith RJ (2018) Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment. J Med Genet 55(8):555–560

    Article  CAS  PubMed  Google Scholar 

  • Borck G, Ur Rehman A, Lee K, Pogoda H-M, Kakar N, von Ameln S, Grillet N, Hildebrand MS, Ahmed ZM, Nurnberg G, Ansar M, Basit S et al (2011) Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42. Am J Hum Genet 88:127–137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bork JM, Peters LM, Riazuddin S, Bernstein SL, Ahmed ZM, Ness SL, Polomeno R, Ramesh A, Schloss M, Srisailpathy CRS, Wayne S, Bellman S et al (2001) 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

    Article  CAS  PubMed  Google Scholar 

  • Buniello A, Ingham NJ, Lewis MA, Huma SC, Martinez-Vega R, Varela-Nieto I, Vizcay-Barrena G, Fleck RA, Houston O, Bardhan T, Johnson SL, White JK, Yuan H, Marcotti W, Steel KP (2016) Wbp2 is required for normal glutamatergic synapses in the cochlea and is crucial for hearing. EMBO Mol Med 8:191–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charizopoulou N, Lelli A, Schraders M, Ray K, Hildebrand MS, Ramesh A, Srisailapathy CR, Oostrik J, Admiraal RJ, Neely HR, Latoche JR, Smith RJ, Northup JK, Kremer H, Holt JR, Noben-Trauth K (2011) GIPC3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat Commun 2:201

    Article  PubMed  CAS  Google Scholar 

  • Chen W, Kahrizi K, Meyer NC, Riazalhosseini Y, Van Camp G, Najmabadi H, Smith RJH (2005) Mutation of COL11A2 causes autosomal recessive non-syndromic hearing loss at the DFNB53 locus. J Med Genet 42:e61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen T, Rohacek AM, Caporizzo M, Nankali A, Smits JJ, Oostrik J, Lanting CP, Kücük E, Gilissen C, van de Kamp JM, Pennings RJE, Rakowiecki SM, Kaestner KH, Ohlemiller KK, Oghalai JS, Kremer H, Prosser BL, Epstein DJ (2021) Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing. Dev Cell 56(10):1526-1540.e7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collin RWJ, Kalay E, Tariq M, Peters T, van der Zwaag B, Venselaar H, Oostrik J, Lee K, Ahmed ZM, Caylan R, Li Y, Spierenburg HA et al (2008) Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35. Am J Hum Genet 82:125–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dahmani M, Ammar-Khodja F, Bonnet C, Lefevre GM, Hardelin J-P, Ibrahim H, Mallek Z, Petit C (2015) EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss. Orphanet J Rare Dis 10:96

    Article  PubMed  PubMed Central  Google Scholar 

  • Delmaghani S, del Castillo FJ, Michel V, Leibovici M, Aghaie A, Ron U, Van Laer L, Ben-Tal N, Van Camp G, Weil D, Langa F, Lathrop M, Avan P, Petit C (2006) Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nature Genet 38:770–778

    Article  CAS  PubMed  Google Scholar 

  • Delmaghani S, Aghaie A, Michalski N, Bonnet C, Weil D, Petit C (2012) Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness. Hum Mol Genet 21:3835–3844

    Article  CAS  PubMed  Google Scholar 

  • Diaz-Horta O, Subasioglu-Uzak A, Grati M, DeSmidt A, Foster J II, Cao L, Bademci G, Tokgoz-Yilmaz S, Duman D, Cengiz FB, Abad C, Mittal R, Blanton S, Liu XZ, Farooq A, Walz K, Lu Z, Tekin M (2014) FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing. Proc Nat Acad Sci 111:9864–9868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du X, Schwander M, Moresco EMY, Viviani P, Haller C, Hildebrand MS, Pak K, Tarantino L, Roberts A, Richardson H, Koob G, Najmabadi H, Ryan AF, Smith RJH, Muller U, Beutler B (2008) A catechol-O-methyltransferase that is essential for auditory function in mice and humans. Proc Nat Acad Sci 105:14609–14614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedman LM, Dror AA, Avraham KB (2007) Mouse models to study inner ear development and hereditary hearing loss. Int J Dev Biol 51(6–7):609–631

    Article  CAS  PubMed  Google Scholar 

  • Girotto G, Abdulhadi K, Buniello A, Vozzi D, Licastro D, d’Eustacchio A, Vuckovic D, Alkowari MK, Steel KP, Badii R, Gasparini P (2013) Linkage study and exome sequencing identify a bdp1 mutation associated with hereditary hearing loss. PLoS One 8:e80323

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grati M, Chakchouk I, Ma Q, Bensaid M, Desmidt A, Turki N, Yan D, Baanannou A, Mittal R, Driss N, Blanton S, Farooq A, Lu Z, Liu XZ, Masmoudi S (2015) A missense mutation in DCDC2 causes human recessive deafness DFNB66, likely by interfering with sensory hair cell and supporting cell cilia length regulation. Hum Molec Genet 24:2482–2491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grillet N, Schwander M, Hildebrand MS, Sczaniecka A, Kolatkar A, Velasco J, Webster JA, Kahrizi K, Najmabadi H, Kimberling WJ, Stephan D, Bahlo M, Wiltshire T, Tarantino LM, Kuhn P, Smith RJ, Muller U (2009) 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 85:328–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horn HF, Brownstein Z, Lenz DR, Shivatzki S, Dror AA, Dagan-Rosenfeld O, Friedman LM, Roux KJ, Kozlov S, Jeang K-T, Frydman M, Burke B, Stewart CL, Avraham KB (2013) The LINC complex is essential for hearing. J Clin Investig 123:740–750

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hosoya M, Fujioka M, Ogawa K et al (2016) Distinct expression patterns of causative genes responsible for hereditary progressive hearing loss in non-human primate cochlea. Sci Rep 6:22250. https://doi.org/10.1038/srep22250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imtiaz A, Kohrman DC, Naz S (2014) A frameshift mutation in GRXCR2 causes recessively inherited hearing loss. Hum Mutat 35:618–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imtiaz A, Belyantseva IA, Beirl AJ, Fenollar-Ferrer C, Bashir R, Bukhari I, Bouzid A, Shaukat U, Azaiez H, Booth KT, Kahrizi K, Najmabadi H, Maqsood A, Wilson EA, Fitzgerald TS, Tlili A, Olszewski R, Lund M, Chaudhry T, Rehman AU, Starost MF, Waryah AM, Hoa M, Dong L, Morell RJ, Smith RJH, Riazuddin S, Masmoudi S, Kindt KS, Naz S, Friedman TB (2018) CDC14A phosphatase is essential for hearing and male fertility in mouse and human. Hum Mol Genet 27(5):780–798

    Article  CAS  PubMed  Google Scholar 

  • Ingham NJ, Pearson SA, Vancollie VE, Rook V, Lewis MA, Chen J, Buniello A, Martelletti E, Preite L, Lam CC, Weiss FD, Powis Z, Suwannarat P, Lelliott CJ, Dawson SJ, White JK, Steel KP (2019) Mouse screen reveals multiple new genes underlying mouse and human hearing loss. PLoS Biol 17:e3000194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaworek TJ, Richard EM, Ivanova AA, Giese APJ, Hoo DI, Khan SN, Riazuddin S, Kahn RA, Riazuddin S (2013) An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans. PLoS Genet 9:e1003774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jenkinson EM, Rehman AU, Walsh T, Clayton-Smith J, Lee K, Morell RJ, Drummond MC, Khan SN, Naeem MA, Rauf B et al (2013) Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet 92:605–613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM (1997) Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387:80–83

    Article  CAS  PubMed  Google Scholar 

  • Khan SY, Ahmed ZM, Shabbir MI, Kitajiri S, Kalsoom S, Tasneem S, Shayiq S, Ramesh A, Srisailpathy S, Khan SN, Smith RJH, Riazuddin S, Friedman TB, Riazuddin S (2007) Mutations of the RDX gene cause nonsyndromic hearing loss at the DFNB24 locus. Hum Mutat 28:417–423

    Article  CAS  PubMed  Google Scholar 

  • Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, Arnaud D, Drury S, Mo J, Makishima T, Ghosh M, Menon PSN et al (2002) Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet 30:277–284

    Article  PubMed  Google Scholar 

  • Li XC, Everett LA, Lalwani AK, Desmukh D, Friedman TB, Green ED, Wilcox ER (1998) A mutation in PDS causes non-syndromic recessive deafness (letter). Nat Genet 18:215–217

    Article  CAS  PubMed  Google Scholar 

  • Li J, Zhao X, Xin Q, Shan S, Jiang B, Jin Y, Yuan H, Dai P, Xiao R, Zhang Q, Xiao J, Shao C, Gong Y, Liu Q (2015) Whole-exome sequencing identifies a variant in TMEM132E causing autosomal-recessive nonsyndromic hearing loss DFNB99. Hum Mutat 36:98–105

    Article  PubMed  CAS  Google Scholar 

  • Li C, Bademci G, Subasioglu A, Diaz-Horta O, Zhu Y, Liu J, Mitchell TG, Abad C, Seyhan S, Duman D, Cengiz FB, Tokgoz-Yilmaz S, Blanton SH, Farooq A, Walz K, Zhai RG, Tekin M (2019) Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss. Proc Nat Acad Sci 116:1347–1352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu X-Z, Xia XJ, Xu LR, Pandya A, Liang CY, Blanton SH, Brown SDM, Steel KP, Nance WE (2000) Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss. Hum Molec Genet 9:63–67

    Article  CAS  PubMed  Google Scholar 

  • Liu XZ, Ouyang XM, Xia XJ, Zheng J, Pandya A, Li F, Du LL, Welch KO, Petit C, Smith RJH, Webb BT, Yan D, Arnos KS, Corey D, Dallos P, Nance WE, Chen ZY (2003) Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Hum Molec Genet 12:1155–1162

    Article  CAS  PubMed  Google Scholar 

  • Mburu P, Mustapha M, Varela A, Weil D, El-Amraoui A, Holme RH, Rump A, Hardisty RE, Blanchard S, Coimbra RS, Perfettini I, Parkinson N et al (2003) Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nat Genet 34:421–428

    Article  CAS  PubMed  Google Scholar 

  • Mujtaba G, Schultz JM, Imtiaz A, Morell RJ, Friedman TB, Naz S (2015) A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss. J Med Genet 52:548–552

    Article  CAS  PubMed  Google Scholar 

  • Mustapha M, Weil D, Chardenoux S, Elias S, El-Zir E, Beckmann JS, Loiselet J, Petit C (1999) An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21. Hum Molec Genet 8:409–412

    Article  CAS  PubMed  Google Scholar 

  • Naz S, Giguere CM, Kohrman DC, Mitchem KL, Riazuddin S, Morell RJ, Ramesh A, Srisailpathy S, Deshmukh D, Riazuddin S, Griffith AJ, Friedman TB, Smith RJH, Wilcox ER (2002) Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus. Am J Hum Genet 71:632–636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naz S, Griffith AJ, Riazuddin S, Hampton LL, Battey JF Jr, Khan SN, Riazuddin S, Wilcox ER, Friedman TB (2004) Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction. J Med Genet 41:591–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ouyang XM, Xia XJ, Verpy E, Du LL, Pandya A, Petit C, Balkany T, Nance WE, Liu XZ (2002) Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness. Hum Genet 111:26–30

    Article  CAS  PubMed  Google Scholar 

  • Rehman AU, Morell RJ, Belyantseva IA, Khan SY, Boger ET, Shahzad M, Ahmed ZM, Riazuddin S, Khan SN, Riazuddin S, Friedman TB (2010) Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79. Am J Hum Genet 86:378–388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rehman AU, Gul K, Morell RJ, Lee K, Ahmed ZM, Riazuddin S, Ali RA, Shahzad M, Jaleel AU, Andrade PB, Khan SN, Khan S, Brewer CC, Ahmad W, Leal SM, Riazuddin S, Friedman TB (2011) Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p. Hum Genet 130:759–765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riazuddin S, Khan SN, Ahmed ZM, Ghosh M, Caution K, Nazli S, Kabra M, Zafar AU, Chen K, Naz S, Antonellis A, Pavan WJ, Green ED, Wilcox ER, Friedman PL, Morell RJ, Riazuddin S, Friedman TB (2006) Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness. Am J Hum Genet 78:137–142

    Article  CAS  PubMed  Google Scholar 

  • Riazuddin S, Belyantseva IA, Giese AP, Lee K, Indzhykulian AA, Nandamuri SP, Yousaf R, Sinha GP, Lee S, Terrell D, Hegde RS, Ali RA, Anwar S, Andrade-Elizondo PB, Sirmaci A, Parise LV, Basit S, Wali A, Ayub M, Ansar M, Ahmad W, Khan SN, Akram J, Tekin M, Riazuddin S, Cook T, Buschbeck EK, Frolenkov GI, Leal SM, Friedman TB, Ahmed ZM (2012) Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. Nat Genet 44:1265–1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson PN, Krawitz P, Mundlos S (2011) Strategies for exome and genome sequence data analysis in disease-gene discovery projects. Clin Genet 80:127–132

    Article  PubMed  Google Scholar 

  • Rohacek AM, Bebee TW, Tilton RK, Radens CM, McDermott-Roe C, Peart N, Kaur M, Zaykaner M, Cieply B, Musunuru K, Barash Y, Germiller JA, Krantz ID, Carstens RP, Epstein DJ (2017) ESRP1 mutations cause hearing loss due to defects in alternative splicing that disrupt cochlear development. Dev Cell 43:318–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santos-Cortez RLP, Lee K, Azeem Z, Antonellis PJ, Pollock LM, Khan S, Irfanullah, Andrade-Elizondo PB, Chiu I, Adams MD, Basit S, Smith JD, Nickerson DA, McDermott BM Jr, Ahmad W, Leal SM (2013) Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89. Am J Hum Genet 93:132–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santos-Cortez RLP, Lee K, Giese AP, Ansar M, Amin-Ud-Din M, Rehn K, Wang X, Aziz A, Chiu I, Ali RH, Smith JD, Shendure J, Bamshad M, Nickerson DA, Ahmed ZM, Ahmad W, Riazuddin S, Leal SM (2014) Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish. Hum. Molec. Genet. 23:3289–3298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schraders M, Lee K, Oostrik J, Huygen PLM, Ali G, Hoefsloot LH, Veltman JA, Cremers FPM, Basit S, Ansar M, Cremers CWRJ, Kunst HPM, Ahmad W, Admiraal RJC, Leal SM, Kremer H (2010a) Homozygosity mapping reveals mutations of GRXCR1 as a cause of autosomal-recessive nonsyndromic hearing impairment. Am J Hum Genet 86:138–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schraders M, Oostrik J, Huygen PL, Strom TM, van Wijk E, Kunst HP, Hoefsloot LH, Cremers CW, Admiraal RJ, Kremer H (2010b) Mutations in PTPRQ are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction. Am J Hum Genet 86:604–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schraders M, Ruiz-Palmero L, Kalay E, Oostrik J, del Castillo FJ, Sezgin O, Beynon AJ, Strom TM, Pennings RJE, Seco CZ, Oonk AMM, Kunst HPM et al (2012) Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment. Am J Hum Genet 91:883–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schrauwen I, Helfmann S, Inagaki A, Predoehl F, Tabatabaiefar MA, Picher MM, Sommen M, Seco CZ, Oostrik J, Kremer H, Dheedene A, Claes C, Fransen E, Chaleshtori MH, Coucke P, Lee A, Moser T, Camp GV (2012) A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment. Am J Hum Genet 91:636–645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schultz JM, Khan SN, Ahmed ZM, Riazuddin S, Waryah AM, Chhatre D, Starost MF, Ploplis B, Buckley S, Velasquez D, Kabra M, Lee K et al (2009) Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am J Hum Genet 85:25–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scott HS, Kudoh J, Wattenhofer M, Shibuya K, Berry A, Chrast R, Guipponi M, Wang J, Kawasaki K, Asakawa S, Minoshima S, Younus F, Mehdi SQ, Radhakrishna U, Papasavvas MP, Gehrig C, Rossier C, Korostishevsky M, Gal A, Shimizu N, Bonne-Tamir B, Antonarakis SE (2001) Insertion of betasatellite repeats repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Nat Genet 27:59–63

    Article  CAS  PubMed  Google Scholar 

  • Seco CZ, Oonk AM, Domínguez-Ruiz M, Draaisma JM, Gandía M, Oostrik J, Neveling K, Kunst HP, Hoefsloot LH, Del Castillo I, Pennings RJ, Kremer H, Admiraal RJ, Schraders M (2014) Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5. Eur J Hum Genet. https://doi.org/10.1038/ejhg.2014.83 (Epub ahead of print)

    Article  PubMed  PubMed Central  Google Scholar 

  • Shabbir MI, Ahmed ZM, Khan SY, Riazuddin S, Waryah AM, Khan SN, Camps RD, Ghosh M, Kabra M, Belyantseva IA, Friedman TB, Riazuddin S (2006) Mutations of human TMHS cause recessively inherited nonsyndromic hearing loss. J Med Genet 43:634–640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shahin H, Walsh T, Sobe T, Sa’ed JA, Rayan AA, Lynch ED, Lee MK, Avraham KB, King MC, Kanaan M (2006) Mutations in a novel isoform of TRIOBP that encodes a filamentous-acting binding protein are responsible for DFNB28 recessive nonsyndromic hearing loss. Am J Hum Genet 78:144–152

    Article  CAS  PubMed  Google Scholar 

  • Shahin H, Walsh T, Rayyan AA, Lee MK, Higgins J, Dickel D, Lewis K, Thompson J, Baker C, Nord AS, Stray S, Gurwitz D, Avraham KB, King MC, Kanaan M (2010) Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families. Eur J Hum Genet 18:407–413

    Article  CAS  PubMed  Google Scholar 

  • Shearer AE, DeLuca AP, Hildebrand MS, Taylor KR, Gurrola J 2nd, Scherer S, Scheetz TE, Smith RJ (2010) Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing. Proc Natl Acad Sci USA 107(49):21104–21109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simon M, Richard EM, Wang X, Shahzad M, Huang VH, Qaiser TA, Potluri P, Mahl SE, Davila A, Nazli S, Hancock S, Yu M et al (2015) Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase cause nonsyndromic deafness and Leigh syndrome. PLoS Genet 11:e1005097

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sineni CJ, Yildirim-Baylan M, Guo S, Camarena V, Wang G, Tokgoz-Yilmaz S, Duman D, Bademci G, Tekin M (2019) A truncating CLDN9 variant is associated with autosomal recessive nonsyndromic hearing loss. Hum Genet 138:1071–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sirmaci A, Erbek S, Price J, Huang M, Duman D, Cengiz FB, Bademci G, Tokgoz-Yilmaz S, Hismi B, Ozdag H, Ozturk B, Kulaksizoglu S, Yildirim E, Kokotas H, Grigoriadou M, Petersen MB, Shahin H, Kanaan M, King MC, Chen ZY, Blanton SH, Liu XZ, Zuchner S, Akar N, Tekin M (2010) A truncating mutation in SERPINB6 is associated with autosomal-recessive nonsyndromic sensorineural hearing loss. Am J Hum Genet 86:797–804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sommen M, Schrauwen I, Vandeweyer G, Boeckx N, Corneveaux JJ, van den Ende J, Boudewyns A, De Leenheer E, Janssens S, Claes K (2016) DNA diagnostics of hereditary hearing loss: a targeted resequencing approach combined with a mutation classification system. Hum Mutat 37:812–819

    Article  CAS  PubMed  Google Scholar 

  • Tabatabaiefar MA, Alasti F, Shariati L, Farrokhi E, Fransen E, Nooridaloii MR, Chaleshtori MH, Van Camp G (2011) DFNB93, a novel locus for autosomal recessive moderate-to-severe hearing impairment. Clin Genet 79:594–598

    Article  CAS  PubMed  Google Scholar 

  • Verpy E, Masmoudi S, Zwaenepoel I, Leibovici M, Hutchin TP, Del Castillo I, Nouaille S, Blanchard S, Laine S, Popot JL, Moreno F, Mueller RF, Petit C (2001) Mutations in a new gene encoding a protein of the hair bundle cause nonsyndromic deafness at the DFNB16 locus. Nat Genet 29:345–349

    Article  CAS  PubMed  Google Scholar 

  • von Ameln S, Wang G, Boulouiz R, Rutherford MA, Smith GM, Li Y, Pogoda HM, Nürnberg G, Stiller B, Volk AE, Borck G, Hong JS, Goodyear RJ, Abidi O, Nürnberg P, Hofmann K, Richardson GP, Hammerschmidt M, Moser T, Wollnik B, Koehler CM, Teitell MA, Barakat A, Kubisch C (2012) A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss. Am J Hum Genet 91:919–927

    Article  CAS  Google Scholar 

  • Vona B, Mazaheri N, Lin S-J, Dunbar LA, Maroofian R, Azaiez H, Booth KT, Vitry S, Rad A, Ruschendorf F, Varshney P, Fowler B et al (2021) A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans. Hum Genet 140:915–931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walsh T, Shahin H, Elkan-Miller T, Lee MK, Thornton AM, Roeb W, Abu Rayyan A, Loulus S, Avraham KB, King M-C, Kanaan M (2010) Whole exome sequencing 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang A, Liang Y, Fridell RA, Probst FJ, Wilcox ER, Touchman JW, Morton CC, Morell RJ, Noben-Trauth K, Camper SA, Friedman TB (1998) Association of unconventional myosin MYO15A mutations with human nonsyndromic deafness DFNB3. Science 280:1447–1451

    Article  CAS  PubMed  Google Scholar 

  • Weil D, Kussel P, Blanchard S, Levy G, Levi-Acobas F, Drira M, Ayadi H, Petit C (1997) The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nat Genet 16:191–193

    Article  CAS  PubMed  Google Scholar 

  • Wesdorp M, Murillo-Cuesta S, Peters T, Celaya AM, Oonk A, Schraders M, Oostrik J, Gomez-Rosas E, Beynon AJ, Hartel BP, Okkersen K, Koenen HJPM et al (2018) MPZL2, encoding the epithelial junctional protein myelin protein zero-like 2, is essential for hearing in man and mouse. Am J Hum Genet 103:74–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilcox ER, Burton QL, Naz S, Riazuddin S, Smith TN, Ploplis B, Belyatseva I, Ben-Yosef T, Liburd NA, Morell RJ, Kachar B, Wu DK, Griffith AJ, Riazuddin S, Friedman TB (2001) Mutations in the gene encoding tight junction claudin-14 cause recessive deafness DFNB29. Cell 104:165–172

    Article  CAS  PubMed  Google Scholar 

  • Yan D, Tekin D, Bademci G, Foster J 2nd, Cengiz FB, Kannan-Sundhari A, Guo S, Mittal R, Zou B, Grati M (2016) Spectrum of DNA variants for non-syndromic deafness in a large cohort from multiple continents. Hum Genet 135:953–961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yariz KO, Duman D, Seco CZ, Dallman J, Huang M, Peters TA, Sirmaci A, Lu N, Schraders M, Skromne I, Oostrik J, Diaz-Horta O et al (2012) Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss. Am J Hum Genet 91:872–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yasunaga S, Grati M, Cohen-Salmon M, El-Amraoui A, Mustapha M, Salem N, El-Zir E, Loiselet J, Petit C (1999) A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat Genet 21:363–369

    Article  CAS  PubMed  Google Scholar 

  • Yousaf R, Ahmed ZM, Giese APJ, Morell RJ, Lagziel A, Dabdoub A, Wilcox ER, Riazuddin S, Friedman TB, Riazuddin S (2018a) Modifier variant of METTL13 suppresses human GAB1-associated profound deafness. J Clin Investig 128:1509–1522

    Article  PubMed  PubMed Central  Google Scholar 

  • Yousaf R, Gu C, Ahmed ZM, Khan SN, Friedman TB, Riazuddin S, Shears SB, Riazuddin S (2018b) Mutations in diphosphoinositol-pentakisphosphate kinase PPIP5K2 are associated with hearing loss in human and mouse. PLoS Genet 14:e1007297

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zheng L, Zheng J, Whitlon DS, García-Añoveros J, Bartles JR (2010) Targeting of the hair cell proteins cadherin 23, harmonin, myosin XVa, espin, and prestin in an epithelial cell model. J Neurosci 30:7187–7201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zwaenepoel I, Mustapha M, Leibovici M, Verpy E, Goodyear R, Liu XZ, Nouaille S, Nance WE, Kanaan M, Avraham KB, Tekaia F, Loiselet J, Lathrop M, Richardson G, Petit C (2002) 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 Natl Acad Sci USA 99:6240–6245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The author is thankful to Dr. Thomas B. Friedman and Dr. Sadaf Naz for reading initial version of this manuscript. She is also grateful to Dr. Karen Federici for suggesting to publish this review.

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  1. School of Biological Sciences, University of the Punjab, Lahore, 54590, Pakistan

    Ayesha Imtiaz

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Imtiaz, A. ARNSHL gene identification: past, present and future. Mol Genet Genomics 297, 1185–1193 (2022). https://doi.org/10.1007/s00438-022-01926-x

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