**8. Conclusion**

HL is the most common sensory defect affecting human beings. It is categorized on the basis of several criteria. Genetic factors can be traced in half of the cases. Nonsyndromic HL can follow any of the Mendelian inheritance patterns, but the majority are ARNSHL. Approximately fifty genes have been reported to be involved in HL, and based on an estimation nearly 200 to 250 genes may cause HL. Genetic understanding of the causes of HL and finding the molecular mechanism of hearing process are valuable for genetic counseling, prevention and development of new therapeutic approaches. Many studies have been published about finding new genes causing prelingual nonsyndromic HL. Presbycusis is very common among eldely people and research on this phenotype needs more attention.

Genetics of Hearing Loss 231

Bacino C, Prezant TR, Bu X, Fournier P & Fischel-Ghodsian N. Susceptibility mutations in

Baldwin CT, Lipsky NR, Hoth CF, Cohen T, Mamuya W & Milunsky A. Mutations in *PAX3* associated with Waardenburg syndrome type I. Hum Mutat. 1994;3(3):205-11. Baldwin CT, Weiss S, Farrer LA, De Stefano AL, Adair R, Franklyn B, Kidd KK,

Belyantseva IA, Boger ET & Friedman TB. Myosin XVa localizes to the tips of inner ear

Bespalova IN, Van Camp G, Bom SJ, Brown DJ, Cryns K, DeWan AT, Erson AE, Flothmann

Bolz H, von Brederlow B, Ramírez A, Bryda EC, Kutsche K, Nothwang HG, Seeliger M, del

Bondurand N, Dastot-Le Moal F, Stanchina L, Collot N, Baral V, Marlin S, Attie-Bitach T,

Bonné-Tamir B, DeStefano AL, Briggs CE, Adair R, Franklyn B, Weiss S, Korostishevsky M,

Bork JM, Peters LM, Riazuddin S, Bernstein SL, Ahmed ZM, Ness SL, Polomeno R, Ramesh

Boughman JA, Vernon M & Shaver KA. Usher syndrome: definition and estimate of prevalence from two high-risk populations. J Chronic Dis. 1983;36(8):595-603.

Eastern Druze population. Hum Mol Genet. 1995;4(9):1637-42.

Proc Natl Acad Sci U S A. 2003;100(24):13958-63.

syndrome type 1D. Nat Genet. 2001;27(1):108-12.

impairment DFNB42. Am J Hum Genet. 2011;88(2):127-37.

2001;10(22):2501-8.

2007;81(6):1169-85.

Genet. 2001;68(1):26-37.

Pharmacogenetics. 1995 Jun;5(3):165-72.

the mitochondrial small ribosomal RNA gene in aminoglycoside induced deafness.

Korostishevsky M & Bonné-Tamir B. Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle

sensory cell stereocilia and is essential for staircase formation of the hair bundle.

K, Kunst HP, Kurnool P, Sivakumaran TA, Cremers CW, Leal SM, Burmeister M & Lesperance MM. Mutations in the Wolfram syndrome 1 gene (*WFS1*) are a common cause of low frequency sensorineural hearing loss. Hum Mol Genet.

C-Salcedó Cabrera M, Vila MC, Molina OP, Gal A & Kubisch C. Mutation of *CDH23*, encoding a new member of the cadherin gene family, causes Usher

Giurgea I, Skopinski L, Reardon W, Toutain A, Sarda P, Echaieb A, Lackmy-Port-Lis M, Touraine R, Amiel J, Goossens M & Pingault V. Deletions at the *SOX10* gene locus cause Waardenburg syndrome types 2 and 4. Am J Hum Genet.

Frydman M, Baldwin CT & Farrer LA. Linkage of congenital recessive deafness (gene DFNB10) to chromosome 21q22.3. Am J Hum Genet. 1996;58(6):1254-9. Borck G, Ur Rehman A, Lee K, Pogoda HM, Kakar N, von Ameln S, Grillet N, Hildebrand

MS, Ahmed ZM, Nürnberg G, Ansar M, Basit S, Javed Q, Morell RJ, Nasreen N, Shearer AE, Ahmad A, Kahrizi K, Shaikh RS, Ali RA, Khan SN, Goebel I, Meyer NC, Kimberling WJ, Webster JA, Stephan DA, Schiller MR, Bahlo M, Najmabadi H, Gillespie PG, Nürnberg P, Wollnik B, Riazuddin S, Smith RJ, Ahmad W, Müller U, Hammerschmidt M, Friedman TB, Riazuddin S, Leal SM, Ahmad J & Kubisch C. Loss-of-function mutations of *ILDR1* cause autosomal-recessive hearing

A, Schloss M, Srisailpathy CR, Wayne S, Bellman S, Desmukh D, Ahmed Z, Khan SN, Kaloustian VM, Li XC, Lalwani A, Riazuddin S, Bitner-Glindzicz M, Nance WE, Liu XZ, Wistow G, Smith RJ, Griffith AJ, Wilcox ER, Friedman TB & Morell RJ. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene *CDH23*. Am J Hum

New technology and strategies such as next generation sequencing can help to discover new genes for deafness in future.

#### **9. References**


New technology and strategies such as next generation sequencing can help to discover new

Abdelhak S, Kalatzis V, Heilig R, Compain S, Samson D, Vincent C, Levi-Acobas F, Cruaud C,

Ahmad NN, Ala-Kokko L, Knowlton RG, Jimenez SA, Weaver EJ, Maguire JI, Tasman W &

Ahmed ZM, Li XC, Powell SD, Riazuddin S, Young TL, Ramzan K, Ahmad Z, Luscombe S,

deafness in Newfoundland and Pakistan. BMC Med Genet. 2004;5:24. Ahmed ZM, Masmoudi S, Kalay E, Belyantseva IA, Mosrati MA, Collin RW, Riazuddin S,

nonsyndromic deafness in humans. Nat Genet. 2008;40(11):1335-40. Ahmed ZM, Riazuddin S, Ahmad J, Bernstein SL, Guo Y, Sabar MF, Sieving P, Riazuddin S,

both USH1F and DFNB23. Hum Mol Genet. 2003;12(24):3215-23.

Usher syndrome type 1F. Am J Hum Genet. 2001;69(1):25-34.

responsible in Japanese. J Hum Genet. 2001;46(7):355-61.

DFNB74. Am J Hum Genet. 2011;88(1):19-29.

populations. Eur J Hum Genet. 2006;14(6):773-9.

Ahmed ZM, Riazuddin S, Bernstein SL, Ahmed Z, Khan S, Griffith AJ, Morell RJ, Friedman

Ahmed ZM, Yousaf R, Lee BC, Khan SN, Lee S, Lee K, Husnain T, Rehman AU, Bonneux S,

Akita J, Abe S, Shinkawa H, Kimberling WJ & Usami S. Clinical and genetic features of

Albert S, Blons H, Jonard L, Feldmann D, Chauvin P, Loundon N, Sergent-Allaoui A,

Le Merrer M, Mathieu M, König R, Vigneron J, Weissenbach J, Petit C & Weil D. Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of *EYA1*. Hum Mol Genet. 1997;6(13):2247-55.

Prockop DJ. Stop codon in the procollagen II gene (*COL2A1*) in a family with the Stickler syndrome (arthro-ophthalmopathy). Proc Natl Acad Sci U S A.

Dhillon K, MacLaren L, Ploplis B, Shotland LI, Ives E, Riazuddin S, Friedman TB, Morell RJ & Wilcox ER. Characterization of a new full length *TMPRSS3* isoform and identification of mutant alleles responsible for nonsyndromic recessive

Hmani-Aifa M, Venselaar H, Kawar MN, Tlili A, van der Zwaag B, Khan SY, Ayadi L, Riazuddin SA, Morell RJ, Griffith AJ, Charfedine I, Caylan R, Oostrik J, Karaguzel A, Ghorbel A, Riazuddin S, Friedman TB, Ayadi H & Kremer H. Mutations of *LRTOMT*, a fusion gene with alternative reading frames, cause

Griffith AJ, Friedman TB, Belyantseva IA & Wilcox ER. *PCDH15* is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for

TB, Riazuddin S & Wilcox ER. Mutations of the protocadherin gene *PCDH15* cause

Ansar M, Ahmad W, Leal SM, Gladyshev VN, Belyantseva IA, Van Camp G, Riazuddin S, Friedman TB & Riazuddin S. Functional null mutations of *MSRB3* encoding methionine sulfoxide reductase are associated with human deafness

nonsyndromic autosomal dominant sensorineural hearing loss: *KCNQ4* is a gene

Houang M, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Dollfus H, Eliot MM, David A, Calais C, Drouin-Garraud V, Obstoy MF, Tran Ba Huy P, Lacombe D, Duriez F, Francannet C, Bitoun P, Petit C, Garabédian EN, Couderc R, Marlin S & Denoyelle F. *SLC26A4* gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian

genes for deafness in future.

1991;88(15):6624-7.

**9. References** 


Genetics of Hearing Loss 233

de Grey ADNJ. Life Span Extension Research and Public Debate: Societal Considerations. Studies in Ethics, Law, and Technology 1 2007.doi:10.2202/1941-6008.1011. de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, Huber I, Monaco AP, Malcolm S,

del Castillo FJ, Rodríguez-Ballesteros M, Alvarez A, Hutchin T, Leonardi E, de Oliveira CA,

del Castillo I, Villamar M, Moreno-Pelayo MA, del Castillo FJ, Alvarez A, Tellería D,

Delmaghani S, del Castillo FJ, Michel V, Leibovici M, Aghaie A, Ron U, Van Laer L, Ben-Tal

pathway, cause DFNB59 auditory neuropathy. Nat Genet. 2006;38(7):770-8. Di Palma F, Pellegrino R & Noben-Trauth K. Genomic structure, alternative splice forms and normal and mutant alleles of cadherin 23 (*CDH23*). Gene. 2001;281(1-2):31-41. Donaudy F, Ferrara A, Esposito L, Hertzano R, Ben-David O, Bell RE, Melchionda S, Zelante

nonsyndromic hearing impairment. N Engl J Med. 2002;346(4):243-9. del Castillo I, Villamar M, Sarduy M, Romero L, Herraiz C, Hernández FJ, Rodríguez M,

1995;267(5198):685-8.

Med Genet. 2005;42(7):588-94.

Genet. 1996;5(9):1383-7.

Annu Rev Genet. 2009;43:411-37.

2010;120(6):1812-23.

Pembrey ME, Ropers HH & Cremers FP. Association between X-linked mixed deafness and mutations in the POU domain gene *POU3F4*. Science

Azaiez H, Brownstein Z, Avenarius MR, Marlin S, Pandya A, Shahin H, Siemering KR, Weil D, Wuyts W, Aguirre LA, Martín Y, Moreno-Pelayo MA, Villamar M, Avraham KB, Dahl HH, Kanaan M, Nance WE, Petit C, Smith RJ, Van Camp G, Sartorato EL, Murgia A, Moreno F & del Castillo I. A novel deletion involving the connexin-30 gene, del(*GJB6*-d13s1854), found in trans with mutations in the *GJB2* gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment. J

Menéndez I & Moreno F. A deletion involving the connexin 30 gene in

Borrás I, Montero A, Bellón J, Tapia MC & Moreno F. A novel locus for nonsyndromic sensorineural deafness (DFN6) maps to chromosome Xp22. Hum Mol

N, Van Camp G, Weil D, Langa F, Lathrop M, Avan P & Petit C. Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory

L, Avraham KB & Gasparini P. Multiple mutations of *MYO1A*, a cochlearexpressed gene, in sensorineural hearing loss. Am J Hum Genet. 2003;72(6):1571-7. Donaudy F, Snoeckx R, Pfister M, Zenner HP, Blin N, Di Stazio M, Ferrara A, Lanzara C,

Ficarella R, Declau F, Pusch CM, Nürnberg P, Melchionda S, Zelante L, Ballana E, Estivill X, Van Camp G, Gasparini P & Savoia A. Nonmuscle myosin heavy-chain gene *MYH14* is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4). Am J Hum Genet. 2004;74(4):770-6. Dossena S, Rodighiero S, Vezzoli V, Nofziger C, Salvioni E, Boccazzi M, Grabmayer E, Bottà

G, Meyer G, Fugazzola L, Beck-Peccoz P & Paulmichl M. Functional characterization of wild-type and mutated pendrin (*SLC26A4*), the anion transporter involved in Pendred syndrome. J Mol Endocrinol. 2009;43(3):93-103. Dror AA & Avraham KB. Hearing loss: mechanisms revealed by genetics and cell biology.

AF, Dafinger C, Bernd A, Zrenner E, Claustres M, Blanco B, Nürnberg G, Nürnberg P, Ruland R, Westerfield M, Benzing T & Bolz HJ. *PDZD7* is a modifier of retinal disease and a contributor to digenic Usher syndrome. J Clin Invest.

Ebermann I, Phillips JB, Liebau MC, Koenekoop RK, Schermer B, Lopez I, Schäfer E, Roux


Chaib H, Place C, Salem N, Dodé C, Chardenoux S, Weissenbach J, el Zir E, Loiselet J &

deafness, to chromosome 10q21-22. Hum Mol Genet. 1996;5(7):1061-4. Charizopoulou N, Lelli A, Schraders M, Ray K, Hildebrand MS, Ramesh A, Srisailapathy

syndrome. Am J Med Genet. 1995;58(4):365-70.

2008;82(1):125-38.

2006;16(2):204-12.

the DFNB53 locus. J Med Genet. 2005 Oct;42(10):e61.

Petit C. Mapping of DFNB12, a gene for a non-syndromal autosomal recessive

CR, Oostrik J, Admiraal RJ, Neely HR, Latoche JR, Smith RJ, Northup JK, Kremer H, Holt JR & Noben-Trauth K. *GIPC3* mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat Commun. 2011;2:201. Chen A, Francis M, Ni L, Cremers CW, Kimberling WJ, Sato Y, Phelps PD, Bellman SC,

Wagner MJ & Pembrey M. Phenotypic manifestations of branchio-oto-renal

Mutation of *COL11A2* causes autosomal recessive non-syndromic hearing loss at

Zhai S, Han D, Zhang MQ, Li W, Liu X, Li H, Chen ZY & Yuan H. Functional mutation of *SMAC*/*DIABLO*, encoding a mitochondrial proapoptotic protein, causes

Griffith AJ & Friedman TB. Identities and frequencies of mutations of the otoferlin gene (OTOF) causing DFNB9 deafness in Pakistan. Clin Genet. 2009;75(3):237-43. Collin RW, Kalay E, Tariq M, Peters T, van der Zwaag B, Venselaar H, Oostrik J, Lee K,

Ahmed ZM, Caylan R, Li Y, Spierenburg HA, Eyupoglu E, Heister A, Riazuddin S, Bahat E, Ansar M, Arslan S, Wollnik B, Brunner HG, Cremers CW, Karaguzel A, Ahmad W, Cremers FP, Vriend G, Friedman TB, Riazuddin S, Leal SM & Kremer H. Mutations of *ESRRB* encoding estrogen-related receptor beta cause autosomalrecessive nonsyndromic hearing impairment DFNB35. Am J Hum Genet.

Identification of a novel *COCH* mutation, G87W, causing autosomal dominant

Dallapiccola B. Molecular detection of novel *WFS1* mutations in patients with

Ensink RJ, Verstreken M, Declau F, Marres H, Kastury K, Bhasin S, McGuirt WT, Smith RJ, Cremers CW, Van de Heyning P, Willems PJ, Smith SD & Van Camp G. Mutations in the *KCNQ4* gene are responsible for autosomal dominant deafness in

K, Young TL, Smith RJ, Lesperance MM & Van Camp G. Mutational spectrum of the *WFS1* gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes

Chen W, Kahrizi K, Meyer NC, Riazalhosseini Y, Van Camp G, Najmabadi H & Smith RJ.

Cheng J, Zhu Y, He S, Lu Y, Chen J, Han B, Petrillo M, Wrzeszczynski KO, Yang S, Dai P,

human progressive hearing loss DFNA64. Am J Hum Genet. 2011;89(1):56-66. Choi BY, Ahmed ZM, Riazuddin S, Bhinder MA, Shahzad M, Husnain T, Riazuddin S,

Collin RW, Pauw RJ, Schoots J, Huygen PL, Hoefsloot LH, Cremers CW & Kremer H.

Wolfram syndrome by a DHPLC-based assay. Hum Mutat. 2003;21(6):622-9. Coucke PJ, Van Hauwe P, Kelley PM, Kunst H, Schatteman I, Van Velzen D, Meyers J,

Craig R & Woodhead JL. Structure and function of myosin filaments. Curr Opin Struct Biol.

Cryns K, Sivakumaran TA, Van den Ouweland JM, Pennings RJ, Cremers CW, Flothmann

Davletov BA & Südhof TC. A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding. J Biol Chem 1993;268(35):26386-90.

mellitus, and psychiatric disease. Hum Mutat. 2003;22(4):275-87.

hearing impairment (DFNA9). Am J Med Genet A. 2006;140(16):1791-4. Colosimo A, Guida V, Rigoli L, Di Bella C, De Luca A, Briuglia S, Stuppia L, Salpietro DC &

four DFNA2 families. Hum Mol Genet. 1999;8(7):1321-8.


Genetics of Hearing Loss 235

Gal A, Pentelenyi K, Remenyi V, Pal Z, Csanyi B, Tomory G, Rasko I & Molnar MJ. Novel

Gómez-Zaera M, Strom TM, Rodríguez B, Estivill X, Meitinger T & Nunes V. Presence of a

Gorlin RJ. Genetic hearing loss—a brief history. Toriello HV, Reardon W, Gorlin RJ. In:

Goto Y, Nonaka I & Horai S. A mutation in the tRNALeu(UUR) gene associated with the

Greinwald JH Jr, Scott DA, Marietta JR, Carmi R, Manaligod J, Ramesh A, Zbar RI, Kraft

Grifa A, Wagner CA, D'Ambrosio L, Melchionda S, Bernardi F, Lopez-Bigas N, Rabionet R,

Grillet N, Schwander M, Hildebrand MS, Sczaniecka A, Kolatkar A, Velasco J, Webster JA,

Guan MX. Mitochondrial 12S rRNA mutations associated with aminoglycoside ototoxicity.

Gubler MC, Heidet L & Antignac C. Alport's syndrome, thin basement membrane

pericentromeric region of chromosome 13q. Nat Genet. 1994;6(1):24-8. Guipponi M, Antonarakis SE & Scott HS. *TMPRSS3*, a type II transmembrane serine

Guipponi M, Vuagniaux G, Wattenhofer M, Shibuya K, Vazquez M, Dougherty L, Scamuffa

2010;122(4):252-6.

2001;72(1):72-81.

Baltimore 2004.

Genet. 1999;23(1):16-8.

2008;13:1557-67.

2002;11(23):2829-36.

Mitochondrion. 2011;11(2):237-45.

653.

heteroplasmic mutation in the anticodon stem of mitochondrial tRNA(Lys) associated with dystonia and stroke-like episodes. Acta Neurol Scand.

major *WFS1* mutation in Spanish Wolfram syndrome pedigrees. Mol Genet Metab.

Hereditary Hearing Loss and Its Syndromes. Second Edition, Oxf University Press,

MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990; 348:651-

ML, Elbedour K, Yairi Y, Musy M, Skvorak AB, Van Camp G, Srisailapathy CR, Lovett M, Morton CC, Sheffield VC & Smith RJ. Construction of P1-derived artificial chromosome and yeast artificial chromosome contigs encompassing the DFNB7 and DFNB11 region of chromosome 9q13-21. Genome Res. 1997;7(9):879-86.

Arbones M, Monica MD, Estivill X, Zelante L, Lang F & Gasparini P. Mutations in *GJB6* cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat

Kahrizi K, Najmabadi H, Kimberling WJ, Stephan D, Bahlo M, Wiltshire T, Tarantino LM, Kuhn P, Smith RJ & Müller U. 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. 2009;85(3):328-37.

nephropathy, nail-patella syndrome, and type III collagen glomerulopathy. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. Heptinstall's Pathology of the Kidney. 6th ed. Philadelphia, Pa: LippincottWilliams & Wilkins; 2007:487–515. Guilford P, Ben Arab S, Blanchard S, Levilliers J, Weissenbach J, Belkahia A & Petit C. A

non-syndrome form of neurosensory, recessive deafness maps to the

protease mutated in non-syndromic autosomal recessive deafness. Front Biosci.

N, Guida E, Okui M, Rossier C, Hancock M, Buchet K, Reymond A, Hummler E, Marzella PL, Kudoh J, Shimizu N, Scott HS, Antonarakis SE & Rossier BC. The transmembrane serine protease (*TMPRSS3*) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro. Hum Mol Genet.


Ebermann I, Scholl HP, Charbel Issa P, Becirovic E, Lamprecht J, Jurklies B, Millán JM, Aller

Edery P, Attié T, Amiel J, Pelet A, Eng C, Hofstra RM, Martelli H, Bidaud C, Munnich A &

Estivill X, Fortina P, Surrey S, Rabionet R, Melchionda S, D'Agruma L, Mansfield E,

sporadic and inherited sensorineural deafness. Lancet. 1998;351: 394-398. Eudy JD, Weston MD, Yao S, Hoover DM, Rehm HL, Ma-Edmonds M, Yan D, Ahmad I,

Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E,

Finsterer J & Fellinger J. Nuclear and mitochondrial genes mutated in nonsyndromic

Fonseca SG, Ishigaki S, Oslowski CM, Lu S, Lipson KL, Ghosh R, Hayashi E, Ishihara H,

stress signaling in rodent and human cells. J Clin Invest. 2010;120(3):744-55. Fraser Gr. Association of congenital deafness with gitre (Pendred's syndrome) a study of 207

Friedman RA, Van Laer L, Huentelman MJ, Sheth SS, Van Eyken E, Corneveaux JJ, Tembe

Friedman TB, Schultz JM, Ben-Yosef T, Pryor SP, Lagziel A, Fisher RA, Wilcox ER,

Fukuoka H, Kanda Y, Ohta S & Usami S. Mutations in the *WFS1* gene are a frequent cause of

impaired hearing. Int J Pediatr Otorhinolaryngol. 2005;69(5):621-47. Fischel-Ghodsian N. Mitochondrial deafness mutations reviewed. Hum Mutat. 1999;13:261-

disease (Shah-Waardenburg syndrome). Nat Genet. 1996;12(4):442-4. Emery A. Hereditary. Rimoin DL, Connor JM, Pyeritz RE, Korf BR. In: Emery and Rimom΄s

hearing loss. Hum Genet. 2007;121(2):203-11.

2003; 1:243-244.

22.

270.

2009;18(4):785-96

Genet. 2007;52(6):510-5.

Science. 1998;280(5370):1753-7.

families. Ann Hum Genet. 1965;28:201-49.

hearing loss. Med Genet. 1999;89:147-157.

E, Mitter D & Bolz H. A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural

Lyonnet S. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung

principles and practice of Medical Genetics. Churchill Livingstone, 5th edition.

Rappaport E, Govea N, Milà M, Zelante L & Gasparini P. Connexin-26 mutations in

Cheng JJ, Ayuso C, Cremers C, Davenport S, Moller C, Talmadge CB, Beisel KW, Tamayo M, Morton CC, Swaroop A, Kimberling WJ & Sumegi J. Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa.

Baxevanis AD, Sheffield VC & Green ED. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. 1997;17(4):411-

Oka Y, Permutt MA, Urano F. Wolfram syndrome 1 gene negatively regulates ER

WD, Halperin RF, Thorburn AQ, Thys S, Bonneux S, Fransen E, Huyghe J, Pyykkö I, Cremers CW, Kremer H, Dhooge I, Stephens D, Orzan E, Pfister M, Bille M, Parving A, Sorri M, Van de Heyning PH, Makmura L, Ohmen JD, Linthicum FH Jr, Fayad JN, Pearson JV, Craig DW, Stephan DA & Van Camp G. *GRM7* variants confer susceptibility to age-related hearing impairment. Hum Mol Genet.

Riazuddin S, Ahmed ZM, Belyantseva IA & Griffith AJ. Recent advances in the understanding of syndromic forms of hearing loss. Ear Hear 2003;24(4):289-302. Friedman TB, Sellers JR & Avraham KB. Unconventional myosins and the genetics of

autosomal dominant nonsyndromic low-frequency hearing loss in Japanese. J Hum


Genetics of Hearing Loss 237

Johnson KR, Yu H, Ding D, Jiang H, Gagnon LH & Salvi RJ. Separate and combined effects

Kalay E, Uzumcu A, Krieger E, Caylan R, Uyguner O, Ulubil-Emiroglu M, Erdol H,

novel motor domain mutation. Am J Med Genet A. 2007;143A(20):2382-9. Kameoka K, Isotani H, Tanaka K, et al. Novel mitochondrial DNA mutation in tRNA(Lys)

Kapur RP. Early death of neural crest cells is responsible for total enteric aganglionosis in *SOX10*(Dom)/*SOX10*(Dom) mouse embryos. Pediatr Dev Pathol. 1999;2(6):559-69. Kelley PM, Harris DJ, Comer BC, Askew JW, Fowler T, Smith SD & Kimberling WJ. Novel

Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF & Leigh IM.

Khan SY, Ahmed ZM, Shabbir MI, Kitajiri S, Kalsoom S, Tasneem S, Shayiq S, Ramesh A,

Kimberling WJ, Weston MD, Möller C, Davenport SL, Shugart YY, Priluck IA, Martini A,

Klein D. Historical background and evidence for dominant inheritance of the Klein-Waardenburg syndrome (type III). Am J Med Genet. 1983;14(2):231-9. Kopp P, Pesce L & Solis-S JC. Pendred syndrome and iodide transport in the thyroid. Trends

Kubisch C, Schroeder BC, Friedrich T, Lütjohann B, El-Amraoui A, Marlin S, Petit C &

Kumar NM & Gilula NB. The gap Junction communication channel. Cell. 1996; 84:381-388. Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, Arnaud D, Drury S, Mo J,

Lalwani AK, Goldstein JA, Kelley MJ, Luxford W, Castelein CM & Mhatre AN. Human

is mutated in dominant deafness. Cell 1999;96(3):437-46.

myosin *MYH9*. Am J Hum Genet. 2000;67(5):1121-8.

Genet. 2001;69(4):673-84.

527.

in C57BL/6J mice. Hear Res. 2010;268(1-2):85-92.

hearing loss. Am J Hum Genet. 1998; 62: 792-799.

Nature. 1997;387(6628):80-3.

Hum Mutat. 2007;28(5):417-23.

Endocrinol Metab. 2008;19(7):260-8.

Genomics. 1990;7(2):245-9.

Genet. 2002;30(3):277-84.

gene with transmembrane domains underlie Usher syndrome type 3. Am J Hum

of Sod1 and *CDH23* mutations on age-related hearing loss and cochlear pathology

Kayserili H, Hafiz G, Başerer N, Heister AJ, Hennies HC, Nürnberg P, Başaran S, Brunner HG, Cremers CW, Karaguzel A, Wollnik B & Kremer H. *MYO15A* (DFNB3) mutations in Turkish hearing loss families and functional modeling of a

(8296A→G) associated with diabetes. Biochem Biophys Res Commun. 1998;245:523-

mutations in the connexin 26 gene (*GJB2*) that cause autosomal recessive (DFNB1)

Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.

Srisailpathy S, Khan SN, Smith RJ, Riazuddin S, Friedman TB & Riazuddin S. Mutations of the *RDX* gene cause nonsyndromic hearing loss at the DFNB24 locus.

Milani M & Smith RJ. Localization of Usher syndrome type II to chromosome 1q.

Jentsch TJ. *KCNQ4*, a novel potassium channel expressed in sensory outer hair cells,

Makishima T, Ghosh M, Menon PS, Deshmukh D, Oddoux C, Ostrer H, Khan S, Riazuddin S, Deininger PL, Hampton LL, Sullivan SL, Battey JF Jr, Keats BJ, Wilcox ER, Friedman TB & Griffith AJ. Dominant and recessive deafness caused by mutations of a novel gene, *TMC1*, required for cochlear hair-cell function. Nat

nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle


Gumbiner BM. Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol

Hilgert N, Alasti F, Dieltjens N, Pawlik B, Wollnik B, Uyguner O, Delmaghani S, Weil D,

Hilgert N, Huentelman MJ, Thorburn AQ, Fransen E, Dieltjens N, Mueller-Malesinska M,

Hilgert N, Smith RJ & Van Camp G. Forty-six genes causing nonsyndromic hearing

Hofmann S, Philbrook C, Gerbitz KD & Bauer MF. Wolfram syndrome: structural and

Hofstra RM, Osinga J, Tan-Sindhunata G, Wu Y, Kamsteeg EJ, Stulp RP, van Ravenswaaij-

Holms RH & Steel KP. Genes involved in deafness. Curr opin Gene Dev. 1999; 9:309-314. Hope CI, Bundey S, Proops D & Fielder AR. Usher syndrome in the city of Birmingham- prevalence and clinical classification. Br J Ophthalmol. 1997;81(1):46-53. Hoskins BE, Cramer CH, Silvius D, Zou D, Raymond RM, Orten DJ, Kimberling WJ, Smith

Hu H, Wu L, Feng Y, Pan Q, Long Z, Li J, Dai H, Xia K, Liang D, Niikawa N & Xia J.

Huang Q & Tang J. Age-related hearing loss or presbycusis. Eur Arch Otorhinolaryngol.

Hudson BG, Tryggvason K, Sundaramoorthy M & Neilson EG. Alport's syndrome,

Jaksch M, Klopstock T, Kurlemann G, et al. Progressive myoclonus epilepsy and

Jamora C & Fuchs E. Intercellular adhesion, signalling and the cytoskeleton. Nat Cell Biol.

Joensuu T, Hämäläinen R, Yuan B, Johnson C, Tegelberg S, Gasparini P, Zelante L, Pirvola

Petit C, Danis E, Yang T, Pandelia E, Petersen MB, Goossens D, Favero JD, Sanati MH, Smith RJ & Van Camp G. Mutation analysis of *TMC1* identifies four new mutations and suggests an additional deafness gene at loci DFNA36 and

Pollak A, et al. Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene.

impairment: which ones should be analyzed in DNA diagnostics? Mutat Res

functional analyses of mutant and wild-type wolframin, the *WFS1* gene product.

Arts C, Majoor-Krakauer D, Angrist M, Chakravarti A, Meijers C, Buys CH. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg

RJ, Weil D, Petit C, Otto EA, Xu PX & Hildebrandt F. Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. Am J Hum Genet.

Molecular analysis of hearing loss associated with enlarged vestibular aqueduct in the mainland Chinese: a unique *SLC26A4* mutation spectrum. J Hum Genet.

Goodpasture's syndrome, and type IV collagen. N Engl J Med. 2003;348(25):2543-

mitochondrial myopathy associated with mutations in the tRNASer(UCN)) gene.

U, Pakarinen L, Lehesjoki AE, de la Chapelle A & Sankila EM. Mutations in a novel

Cell Biol 2005;6:622-634.

2009b;681(2-3):189-96.

2007;80(4):800-4.

2007;52(6):492-7.

2002;4(4):E101-8.

56.

2010;267(8):1179-91.

Ann Neurol. 1998; 44:635- 640.

DFNB7/11. Clin Genet. 2008;74(3):223-32.

Eur J Hum Genet. 2009a Apr;17(4):517-24.

Hum Mol Genet. 2003;12(16):2003-12.

syndrome). Nat Genet. 1996;12(4):445-7.

gene with transmembrane domains underlie Usher syndrome type 3. Am J Hum Genet. 2001;69(4):673-84.


Genetics of Hearing Loss 239

Mahdieh N, Rabbani B, Shirkavand A, Bagherian H, Movahed ZS, Fouladi P, Rahiminejad F,

Mahdieh N, Rabbani B, Wiley S, Akabari MT & Zeinali S. Genetic causes of nonsyndromic

Mahdieh N, Shirkavand A, Raeisi M, Akbari MT & Zeinali S. Unexpected heterogeneity due

Mburu P, Mustapha M, Varela A, Weil D, El-Amraoui A, Holme RH, Rump A, Hardisty RE,

McGuirt WT, Prasad SD, Griffith AJ, Kunst HP, Green GE, Shpargel KB, Runge C,

Melchionda S, Ahituv N, Bisceglia L, Sobe T, Glaser F, Rabionet R, Arbones ML,

Mencia A, Modamio-Høybjør S, Redshaw N, Morín M, Mayo-Merino F, Olavarrieta L,

Merchant SN, Burgess BJ, Adams JC, Kashtan CE, Gregory MC, Santi PA, Colvin R, Collins

Migliosi V, Modamio-Høybjør S, Moreno-Pelayo MA, Rodríguez-Ballesteros M, Villamar M,

prelingual non-syndromic hearing loss. J Med Genet. 2002;39(7):502-6. Mirghomizadeh F, Pfister M, Apaydin F, Petit C, Kupka S, Pusch CM, Zenner HP & Blin N.

Genet Test Mol Biomarkers. 2011;15(7-8):489-93.

2004;65(6):506-8.

2010a;55(10):639-48.

Genet. 2003;34(4):421-8.

1999 Dec;23(4):413-9.

2004;114(9):1609-18.

Am J Hum Genet. 2001;69(3):635-40.

progressive hearing loss. Nat Genet. 2009;41(5):609-13.

Res Commun 2010c;402(2):305-7.

mutations and the Delta (*GJB6*-D13S1830) deletion as a cause of autosomal recessive non-syndromic deafness in the Kurdish population. Clin Genet.

Masoudifard M, Akbari MT & Zeinali S. Impact of consanguineous marriages in *GJB2*-related hearing loss in the Iranian population: a report of a novel variant.

hearing loss in Iran in comparison with other populations. J Hum Genet.

to recessive and de novo dominant mutations of *GJB2* in an Iranian family with nonsyndromic hearing loss: implication for genetic counseling. Biochem Biophys

Blanchard S, Coimbra RS, Perfettini I, Parkinson N, Mallon AM, Glenister P, Rogers MJ, Paige AJ, Moir L, Clay J, Rosenthal A, Liu XZ, Blanco G, Steel KP, Petit C & Brown SD. Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nat

Huybrechts C, Mueller RF, Lynch E, King MC, Brunner HG, Cremers CW, Takanosu M, Li SW, Arita M, Mayne R, Prockop DJ, Van Camp G & Smith RJ. Mutations in *COL11A2* cause non-syndromic hearing loss (DFNA13). Nat Genet.

Notarangelo A, Di Iorio E, Carella M, Zelante L, Estivill X, Avraham KB & Gasparini P. *MYO6*, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss.

Aguirre LA, del Castillo I, Steel KP, Dalmay T, Moreno F & Moreno-Pelayo MA. Mutations in the seed region of human miR-96 are responsible for nonsyndromic

B & Nadol JB Jr.Temporal bone histopathology in alport syndrome. Laryngoscope.

Tellería D, Menéndez I, Moreno F & Del Castillo I. Q829X, a novel mutation in the gene encoding *OTOF*erlin (*OTOF*), is frequently found in Spanish patients with

Substitutions in the conserved C2C domain of *OTOF*erlin cause DFNB9, a form of nonsyndromic autosomal recessive deafness. Neurobiol Dis. 2002;10(2):157-64. Modamio-Hoybjor S, Mencia A, Goodyear R, del Castillo I, Richardson G, Moreno F &

Moreno-Pelayo MA. A mutation in *CCDC50*, a gene encoding an effector of


Lemmink HH, Mochizuki T, van den Heuvel LP, Schröder CH, Barrientos A, Monnens LA,

Leon PE, Raventos H, Lynch E, Morrow J & King MC. The gene for an inherited form of deafness maps to chromosome 5q31. Proc Natl Acad Sci U S A. 1992;89(11):5181-4.

Lezirovitz K, PardonoE, de Mello Auricchio MTB, de Carvalho e Silva FL, Lopes JJ, Abreu-

Li XC, Everett LA, Lalwani AK, Desmukh D, Friedman TB, Green ED & Wilcox ER. A

Li Z, Li R, Chen J, et al. Mutational analysis of the mitochondrial 12S rRNA gene in Chinese

Liang Y, Wang A, Belyantseva IA, Anderson DW, Probst FJ, Barber TD, Miller W,

Liu X, Han D, Li J, Han B, Ouyang X, Cheng J, Li X, Jin Z, Wang Y, Bitner-Glindzicz M,

Liu XZ, Ouyang XM, Xia XJ, Zheng J, Pandya A, Li F, Du LL, Welch KO, Petit C, Smith RJ,

Liu XZ, Walsh J, Tamagawa Y, Kitamura K, Nishizawa M, Steel KP & Brown SD. Autosomal

Loikkanen I, Toljamo K, Hirvikoski P, Väisänen T, Paavonen TK & Vaarala MH. Myosin VI

Lynch ED, Lee MK, Morrow JE, Welcsh PL, León PE & King MC. Nonsyndromic deafness

Mahdieh N & Rabbani B. Statistical study of 35delG mutation of *GJB2* gene: a meta-analysis

Mahdieh N, Bagherian H, Shirkavand A, Sharafi M & Zeinali S. High level of intrafamilial

Mahdieh N, Nishimura C, Ali-Madadi K, Riazalhosseini Y, Yazdan H, Arzhangi S, Jalalvand

Mol Genet. 1994;3(8):1269-73.

Eur J Hum Genet. 2008;16:89–96.

Hum Genet. 2005; 117:9-15.

shaker 2. Genomics. 1999;61:243-258.

Am J Hum Genet. 2010;86(1):65-71.

Genet. 2003;12(10):1155-62.

Nat Genet. 1997;17(3):268-9.

diaphanous. Science. 1997;278(5341):1315-8.

of carrier frequency. Int J Audiol. 2009;48(6):363-70.

5.

1998;18(3):215-7.

van Oost BA, Brunner HG, Reeders ST & Smeets HJ. Mutations in the type IV collagen alpha 3 (*COL4A3*) gene in autosomal recessive Alport syndrome. Hum

Silva RS, Romanos J, Batissoco AC & Mingroni-Netto RC. Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness.

mutation in PDS causes non-syndromic recessive deafness. Nat Genet.

pediatric subjects with aminoglycoside- induced and nonsyndromic hearing loss.

Touchman JW, Jin L, Sullivan SL, Sellers JR, Camper SA, Lloyd RV, Kachar B, Friedman TB & Fridell RA. Characterization of the human and mouse unconventional myosin XV genes responsible for hereditary deafness DFNB3 and

Kong X, Xu H, Kantardzhieva A, Eavey RD, Seidman CE, Seidman JG, Du LL, Chen ZY, Dai P, Teng M, Yan D & Yuan H. Loss-of-function mutations in the *PRPS1* gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2.

Webb BT, Yan D, Arnos KS, Corey D, Dallos P, Nance WE & Chen ZY. Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Hum Mol

dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene.

is a modulator of androgen-dependent gene expression. Oncol Rep. 2009;22(5):991-

DFNA1 associated with mutation of a human homolog of the Drosophila gene

phenotypic variability of non-syndromic hearing loss in a Lur family due to delE120 mutation in *GJB2* gene. Int J Pediatr Otorhinolaryngol. 2010b;74:1089-1091.

K, Ebrahimi A, Kazemi S, Smith RJ & Najmabadi H. The frequency of *GJB2*

mutations and the Delta (*GJB6*-D13S1830) deletion as a cause of autosomal recessive non-syndromic deafness in the Kurdish population. Clin Genet. 2004;65(6):506-8.


Genetics of Hearing Loss 241

Pallares-Ruiz N, Blanchet P, Mondain M, Claustres M & Roux AF. A large deletion

Pandya A, Xia XJ, Erdenetungalag R, et al. Heterogenous point mutations in the

Pingault V, Bondurand N, Kuhlbrodt K, Goerich DE, Préhu MO, Puliti A, Herbarth B,

Rehman AU, Gul K, Morell RJ, Lee K, Ahmed ZM, Riazuddin S, Ali RA, Shahzad M, Jaleel

Rehman AU, Morell RJ, Belyantseva IA, Khan SY, Boger ET, Shahzad M, Ahmed ZM,

Riazuddin S, Anwar S, Fischer M, Ahmed ZM, Khan SY, Janssen AG, Zafar AU, Scholl U,

Riazuddin S, Khan SN, Ahmed ZM, Ghosh M, Caution K, Nazli S, Kabra M, Zafar AU, Chen

Richards AJ, Yates JR, Williams R, Payne SJ, Pope FM, Scott JD & Snead MP.A family with

Richardson GP, Lukashkin AN & Russell IJ. The tectorial membrane: one slice of a complex cochlear sandwich. Curr Opin Otolaryngol Head Neck Surg. 2008;16(5):458-64.

or Bartter syndrome. Am J Hum Genet. 2009;85(2):273-80.

deafness. Am J Hum Genet. 2006;78(1):137-43.

nonsyndromic deafness DFNB79. Am J Hum Genet. 2010;86(3):378-88. Riazuddin S, Ahmed ZM, Fanning AS, Lagziel A, Kitajiri S, Ramzan K, Khan SN, Chattaraj

Read AP & Newton VE. Waardenburg syndrome. J Med Genet 1997;34:656–665.

deafness students from Mongolia. Am J Hum Genet. 1999;65:1803-1806. Peters LM, Anderson DW, Griffith AJ, Grundfast KM, San Agustin TB, Madeo AC,

Hum Genet. 2002;10(1):72-6.

2002;11(23):2877-85.

2003;60(5-6):397-422.

ahead of print]

2006;79(6):1040-51.

1996;5(9):1339-43.

including most of *GJB6* in recessive non syndromic deafness: a digenic effect? Eur J

mitochondrial tRNASer(UCN) precursor coexisting with the A1555G mutation in

Friedman TB & Morell RJ. Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28. Hum Mol Genet.

Hermans-Borgmeyer I, Legius E, Matthijs G, Amiel J, Lyonnet S, Ceccherini I, Romeo G, Smith JC, Read AP, Wegner M & Goossens M. *SOX10* mutations in patients with Waardenburg-Hirschsprung disease. Nat Genet. 1998;18(2):171-3. Raphael Y & Altschuler RA. Structure and innervation of the cochlea. Brain Res Bull.

AU, Andrade PB, Khan SN, Khan S, Brewer CC, Ahmad W, Leal SM, Riazuddin S & Friedman TB. Mutations of *GIPC3* cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p. Hum Genet. 2011 Jun 10. [Epub

Riazuddin S, Khan SN, Riazuddin S & Friedman TB. Targeted capture and nextgeneration sequencing identifies C9orf75, encoding taperin, as the mutated gene in

P, Friedman PL, Anderson JM, Belyantseva IA, Forge A, Riazuddin S & Friedman TB. Tricellulin is a tight-junction protein necessary for hearing. Am J Hum Genet.

Husnain T, Belyantseva IA, Friedman PL, Riazuddin S, Friedman TB & Fahlke C. Molecular basis of DFNB73: mutations of *BSND* can cause nonsyndromic deafness

K, Naz S, Antonellis A, Pavan WJ, Green ED, Wilcox ER, Friedman PL, Morell RJ, Riazuddin S& Friedman TB. Mutations in *TRIOBP*, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive

Stickler syndrome type 2 has a mutation in the *COL11A1* gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen.Hum Mol Genet.

epidermal growth factor-mediated cell signaling, causes progressive hearing loss. Am J Hum Genet. 2007;80(6):1076-89.


Morell RJ, Kim HJ, Hood LJ, Goforth L, Friderici K, Fisher R, Van Camp G, Berlin CI,

Morle L, Bozon M, Alloisio N, Latour P, Vandenberghe A, Plauchu H, Collet L, Edery P,

Morton CC & Nance WE. Newborn hearing screening--a silent revolution. N Engl J Med.

Mount DB & Romero MF. The SLC26 gene family of multifunctional anion exchangers.

Mustapha M, Chouery E, Torchard-Pagnez D, Nouaille S, Khrais A, Sayegh FN, Mégarbané

I, USH1G, maps to chromosome 17q24-25. Hum Genet. 2002;110(4):348-50. Mustapha M, Weil D, Chardenoux S, Elias S, El-Zir E, Beckmann JS, Loiselet J & Petit C. An

Nal N, Ahmed ZM, Erkal E, Alper OM, Lüleci G, Dinç O, Waryah AM, Ain Q, Tasneem S,

Naz S, Giguere CM, Kohrman DC, Mitchem KL, Riazuddin S, Morell RJ, Ramesh A,

Naz S, Griffith AJ, Riazuddin S, Hampton LL, Battey JF Jr, Khan SN, Riazuddin S, Wilcox ER

Nelson WJ & Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science.

Newton V. Hearing loss and Waardenburg's syndrome: implications for genetic counselling.

Nie L. *KCNQ4* mutations associated with nonsyndromic progressive sensorineural hearing

Oliver TN, Berg JS & Cheney RE. Tails of unconventional myosins. Cell Mol Life Sci.

Ouyang XM, Xia XJ, Verpy E, Du LL, Pandya A, Petit C, Balkany T, Nance WE & Liu XZ.

Mutations in the alternatively spliced exons of *USH1C* cause non-syndromic

linked to the DFNB6 locus. Am J Hum Genet. 2002;71(3):632-6.

loss. Curr Opin Otolaryngol Head Neck Surg. 2008;16(5):441-4.

vestibular dysfunction. J Med Genet. 2004;41(8):591-5.

recessive deafness. Hum Genet. 2002 Jul;111(1):26-30.

Am J Hum Genet. 2007;80(6):1076-89.

Med. 1998 Nov 19;339(21):1500-5.

Pflugers Archiv 2004;447:710-721.

Clin North Am. 1975;8(1):19-48.

2004;303(5663):1483-7.

1999;56:243-257.

J Laryngol Otol. 1990;104(2):97-103.

368-370.

2006;354(20):2151-64.

1999;8(3):409-12.

epidermal growth factor-mediated cell signaling, causes progressive hearing loss.

Oddoux C, Ostrer H, Keats B & Friedman TB. Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J

Godet J & Lina-Granade G. A novel C202F mutation in the connexin26 gene (*GJB2*) associated with autosomal dominant isolated hearing loss. J Med Genet. 2000; 37:

A, Loiselet J, Lathrop M, Petit C & Weil D. A novel locus for Usher syndrome type

alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21. Hum Mol Genet.

Husnain T, Chattaraj P, Riazuddin S, Boger E, Ghosh M, Kabra M, Riazuddin S, Morell RJ & Friedman TB. Mutational spectrum of *MYO15A*: the large N-terminal extension of myosin XVA is required for hearing. Hum Mutat. 2007;28(10):1014-9. Nance WE & Sweeney A. Symposium on sensorineural hearing loss in children: early

detection and intervention. Genetic factors in deafness of early life. Otolaryngol

Srisailpathy S, Deshmukh D, Riazuddin S, Griffith AJ, Friedman TB, Smith RJ & Wilcox ER. Mutations in a novel gene, *TMIE*, are associated with hearing loss

& Friedman TB. Mutations of *ESPN* cause autosomal recessive deafness and


Genetics of Hearing Loss 243

Shin JJ, Keamy DG Jr & Steinberg EA. Medical and surgical interventions for hearing loss

Siemens J, Lillo C, Dumont RA, Reynolds A, Williams DS, Gillespie PG & Müller U.

Sirmaci A, Erbek S, Price J, Huang M, Duman D, Cengiz FB, Bademci G, Tokgöz-Yilmaz S,

Smith RJ & Hone S. Genetic screening for deafness. Pediatr Clin North Am. 2003;50(2):315-

Smith RJ, Berlin CI, Hejtmancik JF, Keats BJ, Kimberling WJ, Lewis RA, Möller CG, Pelias

Smith RJ, Lee EC, Kimberling WJ, Daiger SP, Pelias MZ, Keats BJ, Jay M, Bird A, Reardon W,

Stevenson VA, Ito M & Milunsky JM. Connexin-30 deletion analysis in connexin-26

Szabo R, Wu Q, Dickson RB, Netzel-Arnett S, Antalis TM & Bugge TH. Type II transmembrane serine proteases. Thromb Haemost. 2003; 90(2):185-93. Tassabehji M, Newton VE & Read AP. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat Genet. 1994;8(3):251-5. Tekin M, Arnos KS & Pandya A. Advances in hereditary deafness. Lancet

Unal M, Tamer L, Doğruer ZN, Yildirim H, Vayisoğlu Y & Camdeviren H. N-

Vahava O, Morell R, Lynch ED, Weiss S, Kagan ME, Ahituv N, Morrow JE, Lee MK,

Van Camp G, Snoeckx RL, Hilgert N, van den Ende J, Fukuoka H, Wagatsuma M, Suzuki H,

van der Loop FT, Heidet L, Timmer ED, van den Bosch BJ, Leinonen A, Antignac C,

Van Eyken E, Van Camp G & Van Laer L. The complexity of age-related hearing

progressive hearing loss in humans. Science. 1998;279(5358):1950-4.

*COL9A1* gene. Am J Hum Genet. 2006;79(3):449-57.

acetyltransferase 2 gene polymorphism and presbycusis. Laryngoscope.

Skvorak AB, Morton CC, Blumenfeld A, Frydman M, Friedman TB, King MC & Avraham KB. Mutation in transcription factor *POU4F3* associated with inherited

Smets RM, Vanhoenacker F, Declau F, Van de Heyning P & Usami S. A new autosomal recessive form of Stickler syndrome is caused by a mutation in the

Jefferson JA, Maxwell AP, Monnens LA, Schröder CH & Smeets HJ. Autosomal dominant Alport syndrome caused by a *COL4A3* splice site mutation. Kidney Int.

impairment: contributing environmental and genetic factors. Audiol Neurootol.

Head Neck Surg. 2011;144(5):662-75.

Consortium. Am J Med Genet. 1994;50(1):32-8.

11. Genomics. 1992;14(4):995-1002.

2001;358(9287):1082-90.

2005;115(12):2238-41.

2000;58(5):1870-5.

2007b;12(6):345-58.

heterozygotes. Genet Test. 2003;7:151-4.

2004;428(6986):950-5.

Genet. 2010;86(5):797-804.

29.

associated with congenital cytomegalovirus: a systematic review. Otolaryngol

Cadherin 23 is a component of the tip link in hair-cell stereocilia. Nature.

Hişmi B, Ozdağ H, Oztürk B, Kulaksizoğlu 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. A truncating mutation in *SERPINB6* is associated with autosomal-recessive nonsyndromic sensorineural hearing loss. Am J Hum

MZ & Tranebjaerg L. Clinical diagnosis of the Usher syndromes. Usher Syndrome

Guest M, et al. Localization of two genes for Usher syndrome type I to chromosome


Rigoli L, Prisco F, Caruso RA, Iafusco D, Ursomanno G, Zuccarello D, Ingenito N, Rigoli M

Robertson NG, Lu L, Heller S, Merchant SN, Eavey RD, McKenna M, Nadol JB Jr, Miyamoto

Ruf RG, Xu PX, Silvius D, Otto EA, Beekmann F, Muerb UT, Kumar S, Neuhaus TJ, Kemper

Sahin-Calapoglu N, Calapoglu M & Karaguzel A. Non-syndromic recessive hearing loss

Schraders M, Lee K, Oostrik J, Huygen PL, Ali G, Hoefsloot LH, Veltman JA, Cremers FP,

Schraders M, Oostrik J, Huygen PL, Strom TM, van Wijk E, Kunst HP, Hoefsloot LH,

Schultz JM, Khan SN, Ahmed ZM, Riazuddin S, Waryah AM, Chhatre D, Starost MF, Ploplis

Scott HS, Kudoh J, Wattenhofer M, Shibuya K, Berry A, Chrast R, Guipponi M, Wang J,

Shabbir MI, Ahmed ZM, Khan SY, Riazuddin S, Waryah AM, Khan SN, Camps RD, Ghosh

Shah KN, Dalal SJ, Desai MP, Sheth PN, Joshi NC & Ambani LM. White forelock,

Sheffield VC, Kraiem Z, Beck JC, Nishimura D, Stone EM, Salameh M, Sadeh O & Glaser B.

variant of Waardenburg syndrome. J Pediatr. 1981;99(3):432-5.

defect in thyroid iodine organification. Nat Genet. 1996;12:424-426.

with vestibular dysfunction. Am J Hum Genet. 2010;86(4):604-10.

DFNB39. Am J Hum Genet. 2009;85(1):25-39.

recessive deafness. Nat Genet. 2001;27(1):59-63.

DNA complexes. Proc Natl Acad Sci U S A. 2004;101(21):8090-5.

Med. 2001;18(4):334-6.

2005;12(3):31-35.

2010;86(2):138-47.

2006;43(8):634-40.

& Barberi I. Association of the T14709C mutation of mitochondrial DNA with maternally inherited diabetes mellitus and/or deafness in an Italian family. Diabet

RT, Linthicum FH Jr, Lubianca Neto JF, Hudspeth AJ, Seidman CE, Morton CC & Seidman JG. Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Nat Genet. 1998;20(3):299-303.

MJ, Raymond RM Jr, Brophy PD, Berkman J, Gattas M, Hyland V, Ruf EM, Schwartz C, Chang EH, Smith RJ, Stratakis CA, Weil D, Petit C & Hildebrandt F. SIX1 mutations cause branchio-oto-renal syndrome by disruption of *EYA1*-SIX1-

linkaged *TMPRSS3* gene in the Turkish population. SDÜ Týp Fak Derg.

Basit S, Ansar M, Cremers CW, Kunst HP, Ahmad W, Admiraal RJ, Leal SM & Kremer H. Homozygosity mapping reveals mutations of *GRXCR1* as a cause of autosomal-recessive nonsyndromic hearing impairment. Am J Hum Genet.

Cremers CW, Admiraal RJ & Kremer H. Mutations in *PTPRQ* are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated

B, Buckley S, Velásquez D, Kabra M, Lee K, Hassan MJ, Ali G, Ansar M, Ghosh M, Wilcox ER, Ahmad W, Merlino G, Leal SM, Riazuddin S, Friedman TB & Morell RJ. Noncoding mutations of *HGF* are associated with nonsyndromic hearing loss,

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. Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal

M, Kabra M, Belyantseva IA, Friedman TB & Riazuddin S. Mutations of human *TMHS* cause recessively inherited non-syndromic hearing loss. J Med Genet.

pigmentary disorder of irides, and long segment Hirschsprung disease: possible

Pendred syndrome maps to chromosome 7q21-34 and is caused by an intrinsic


Genetics of Hearing Loss 245

Wagatsuma M, Kitoh R, Suzuki H, Fukuoka H, Takumi Y, Usami S. Distribution and

Wallis C, Ballo R, Wallis G, Beighton P & Goldblatt J. X-linked mixed deafness with stapes

Walsh T, Pierce SB, Lenz DR, Brownstein Z, Dagan-Rosenfeld O, Shahin H, Roeb W,

nonsyndromic hearing loss DFNA51. Am J Hum Genet. 2010;87(1):101-9. Walsh T, Walsh V, Vreugde S, Hertzano R, Shahin H, Haika S, Lee MK, Kanaan M, King MC

Wang A, Liang Y, Fridell RA, Probst FJ, Wilcox ER, Touchman JW, Morton CC, Morell RJ,

Wang QJ, Lu CY, Li N, Rao SQ, Shi YB, Han DY, Li X, Cao JY, Yu LM, Li QZ, Guan MX,

Wattenhofer M, Sahin-Calapoglu N, Andreasen D, Kalay E, Caylan R, Braillard B, Fowler-

Wayne S, Robertson NG, DeClau F, Chen N, Verhoeven K, Prasad S, Tranebjärg L, Morton

Weil D, Blanchard S, Kaplan J, Guilford P, Gibson F, Walsh J, Mburu P, Varela A, Levilliers

Weston MD, Luijendijk MW, Humphrey KD, Möller C, Kimberling WJ. Mutations in the

Wilch E, Azaiez H, Fisher RA, Elfenbein J, Murgia A, Birkenhäger R, Bolz H, Da Silva-Costa

responsible for Usher syndrome type 1B. Nature. 1995;374(6517):60-1. Wester DC, Atkin CL, Gregory MC. Alport syndrome: clinical update. J Am Acad Audiol.

a large Chinese family. J Med Genet. 2004;41(6):e80.

of the protein. Hum Genet. 2005;117(6):528-35.

type II. Am J Hum Genet. 2004;74(2):357-66.

loss. Clin Genet. 2007;72(4):339-44.

1988;3(4):299-301.

2002;99(11):7518-23.

1998; 280 (5368):1447-51.

2001;10(3):195-200.

1995;6(1):73-9.

2010;78(3):267-74.

frequencies of *CDH23* mutations in Japanese patients with non-syndromic hearing

fixation in a Mauritian kindred: linkage to Xq probe pDP34. Genomics.

McCarthy S, Nord AS, Gordon CR, Ben-Neriah Z, Sebat J, Kanaan M, Lee MK, Frydman M, King MC & Avraham KB. Genomic duplication and overexpression of *TJP2*/ZO-2 leads to altered expression of apoptosis genes in progressive

& Avraham KB. From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc Natl Acad Sci U S A.

Noben-Trauth K, Camper SA & Friedman TB. Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science.

Yang WY & Shen Y. Y-linked inheritance of non-syndromic hearing impairment in

Jaeger N, Reymond A, Rossier BC, Karaguzel A & Antonarakis SE. A novel *TMPRSS3* missense mutation in a DFNB8/10 family prevents proteolytic activation

CC, Ryan AF, Van Camp G & Smith RJ. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet.

J, Weston MD, Kelley PM, Kimberling WJ, Wagenaar M, Levi-Acobas F, Larget-Piet D, Munnich A, Steel KP, Brown SM & Petit C. Defective myosin VIIA gene

*VLGR1* gene implicate G-protein signaling in the pathogenesis of Usher syndrome

SM, Del Castillo I, Haaf T, Hoefsloot L, Kremer H, Kubisch C, Le Marechal C, Pandya A, Sartorato EL, Schneider E, Van Camp G, Wuyts W, Smith RJ, Friderici KH. A novel DFNB1 deletion allele supports the existence of a distant cisregulatory region that controls *GJB2* and *GJB6* expression. Clin Genet.


Van Eyken E, Van Camp G, Fransen E, Topsakal V, Hendrickx JJ, Demeester K, Van de

Van Eyken E, Van Laer L, Fransen E, Topsakal V, Lemkens N, Laureys W, Nelissen N,

Van Laer L, Huizing EH, Verstreken M, van Zuijlen D, Wauters JG, Bossuyt PJ, Van de

Van Laer L, Huyghe JR, Hannula S, Van Eyken E, Stephan DA, Mäki-Torkko E, Aikio P,

Van Laer L, Van Eyken E, Fransen E, Huyghe JR, Topsakal V, Hendrickx JJ, Hannula S,

with age-related hearing impairment. Hum Mol Genet. 2008;17(2):159-69. Varga R, Avenarius MR, Kelley PM, Keats BJ, Berlin CI, Hood LJ, Morlet TG, et al. *OTOF*

dominant non-syndromic hearing impairment. Nat Genet. 1998;19(1):60-2. Verpy E, Masmoudi S, Zwaenepoel I, Leibovici M, Hutchin TP, Del Castillo I, Nouaille S,

Veske A, Oehlmann R, Younus F, Mohyuddin A, Müller-Myhsok B, Mehdi SQ & Gal A.

Vikkula M, Mariman EC, Lui VC, Zhidkova NI, Tiller GE, Goldring MB, van Beersum SE, de

age-related hearing impairment? Hum Mutat. 2006;27(10):1007-16

hearing impairment. J Med Genet. 2007a;44(9):570-8.

DFNA5. Nat Genet. 1998;20(2):194-7.

Eur J Hum Genet. 2010;18(6):685-93.

DFNB16 locus. Nat Genet. 2001;29(3):345-9.

1996;5(1):165-8.

Heyning P, Mäki-Torkko E, Hannula S, Sorri M, Jensen M, Parving A, Bille M, Baur M, Pfister M, Bonaconsa A, Mazzoli M, Orzan E, Espeso A, Stephens D, Verbruggen K, Huyghe J, Dhooge I, Huygen P, Kremer H, Cremers CW, Kunst S, Manninen M, Pyykkö I, Lacava A, Steffens M, Wienker TF & Van Laer L. Contribution of the N-acetyltransferase 2 polymorphism NAT2\*6A to age-related

Vandevelde A, Wienker T, Van De Heyning P & Van Camp G. *KCNQ4*: a gene for

Heyning P, McGuirt WT, Smith RJ, Willems PJ, Legan PK, Richardson GP & Van Camp G. Nonsyndromic hearing impairment is associated with a mutation in

Fransen E, Lysholm-Bernacchi A, Sorri M, Huentelman MJ & Van Camp G. A genome-wide association study for age-related hearing impairment in the Saami.

Mäki-Torkko E, Jensen M, Demeester K, Baur M, Bonaconsa A, Mazzoli M, Espeso A, Verbruggen K, Huyghe J, Huygen P, Kunst S, Manninen M, Konings A, Diaz-Lacava AN, Steffens M, Wienker TF, Pyykkö I, Cremers CW, Kremer H, Dhooge I, Stephens D, Orzan E, Pfister M, Bille M, Parving A, Sorri M, Van de Heyning PH & Van Camp G. The grainyhead like 2 gene (*GRHL2*), alias TFCP2L3, is associated

mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele. J Med Genet. 2006; 43(7):576-81. Verhoeven K, Van Laer L, Kirschhofer K, Legan PK, Hughes DC, Schatteman I, Verstreken

M, Van Hauwe P, Coucke P, Chen A, Smith RJ, Somers T, Offeciers FE, Van de Heyning P, Richardson GP, Wachtler F, Kimberling WJ, Willems PJ, Govaerts PJ & Van Camp G. Mutations in the human alpha-tectorin gene cause autosomal

Blanchard S, Lainé S, Popot JL, Moreno F, Mueller RF & Petit C. Mutations in a new gene encoding a protein of the hair bundle cause non-syndromic deafness at the

Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from Pakistan. Hum Mol Genet.

Waal Malefijt MC, van den Hoogen FH, Ropers HH, Mayne R, Cheah KE, Olsen BR, Warman ML & Brunner HG. Autosomal dominant and recessive osteochondrodysplasias associated with the *COL11A2* locus. Cell 1995;80(3):431-7.


**12** 

Sadaf Naz

*Pakistan* 

*School of Biological Sciences, University of the Punjab, Lahore* 

**Genetics of Nonsyndromic Recessively** 

**and Progressive Deafness in Humans** 

Nonsyndromic deafness in humans involves hearing loss as the only presenting feature in contrast to syndromes in which hearing loss is accompanied by other abnormalities. The majority of nonsyndromic deafness is recessively inherited which involves mutations of

Deafness is a sensory impairment which results in a partial or total loss in reception of sound. The intensity of sound can be measured in decibels (dB). It is usual to assess hearing thresholds at frequencies of 0.25, 0.5, 1, 2, 4 and 8 KHz. Sounds of each frequency are presented at different intensities to a subject and the response is recorded graphically as an audiogram. A loss in hearing is indicated if the threshold for perception of sound for any frequency is elevated by 10 dB or greater as compared to the defined standard value for each frequency. Like visual foveae, organisms also have acoustic foveae, in which a certain frequency occupies greater space and is resolved more than other frequencies. In humans, the frequencies of 2 to 4 KHz are finely resolved. The frequencies of 0.5-2 KHz are the most important for hearing conversations. Therefore, individuals can have usable hearing if deafness does not impair these frequencies to a profound degree. A hearing loss of >91 dB constitutes profound deafness while those between 41 to 90 dB are defined as moderate (41-55 dB), moderate to severe (56-70 dB) or severe hearing loss (71-90 dB), respectively. Progressive deafness involves a gradual loss in the ability to hear over

The genetics and biology of moderate to severe and progressive hearing loss in humans has been understudied. More than 65 loci have been mapped for nonsyndromic recessively inherited deafness. Notably, mutations of only some of these genes are associated with stable moderate to severe hearing loss (Chishti et al., 2009; Naz et al., 2003; Villamar et al., 1999; Zwaenepoel et al., 2002). The past few years have revealed mutations in more than 10 genes and loci which can cause variable degrees of hearing loss or progressive deafness in humans. Additionally, the observation of intra- and inter- familial variability in the degree of deafness associated with identical mutations in a few genes has also implicated

**1. Introduction** 

both alleles of a gene.

time.

**Inherited Moderate to Severe** 

