Epidemiology of Genetic Hearing Loss

ABSTRACT

Epidemiological studies more than a century ago demonstrated that genetic factors are major contributors to hearing loss. Many genes associated with hearing loss have now been identified, although mutations in one of them, GJB2, explain a high proportion of genetic deafness in several populations. Environmental factors such as viruses (in particular, cytomegalovirus), ototoxic drugs, and noise also are associated with hearing loss, as is the aging process. Genetic hearing loss may be either syndromic (other organs and tissues are abnormal) or nonsyndromic. The majority show an autosomal recessive pattern of inheritance, but autosomal dominant, X-linked, and mitochondrial forms of hearing loss are found. In this article, four hearing loss syndromes, Jervell and Lange-Nielsen, Wolfram, branchio-otorenal, and Alport, are described; respectively, they are caused by mutations in genes encoding a potassium channel complex (KCNQ1, KCNE1), extracellular matrix proteins (COL4A3, COL4A4, COL4A5), transcription factors (EYA1, SIX1), and a protein that may be a novel endoplasmic reticulum calcium channel or a regulator of channel activity (WFS1). The contribution of mitochondrial DNA (mtDNA) mutations to hearing loss also is discussed.

Jervell and Lange-Nielsen - Wolfram - Alport - BOR - mtDNA - CMV

REFERENCES

• 1 Martini A, Trevisi P. Classification and epidemiology. In: Willems P Genetic Hearing Loss. New York, NY; Marcel Dekker 2004: 49-63
• 2 Vohr B, Widen J, Cone-Wesson B et al.. Identification of neonatal hearing impairment: characteristics of infants in the neonatal intensive care unit and well-baby nursery.  Ear Hear. 2000;  21 373-382
• 3 Hotchkiss D. Demographic aspects of hearing impairment: questions and answers. 2nd ed. Washington, DC; Center for Assessment and Demographic Studies, Gallaudet University
• 4 Nance W, Pandya A. Genetic epidemiology of deafness. In: Keats B, Popper A, Fay R Genetics and Auditory Disorders. New York, NY; Springer 2002: 67-91
• 5 Bell A G. Memoir upon the formation of a deaf variety of the human race. Washington, DC; National Academy of Sciences 1884
• 6 Fay E A. Marriages of the Deaf in America. Washington, DC; Volta Bureau 1898: 1-527
• 7 Marazita M L, Ploughman L M, Rawlings B, Remington E, Arnos K S, Nance W E. Genetic epidemiological studies of early-onset deafness in the U.S. school-age population.  Am J Med Genet. 1993;  46 486-491
• 8 Morton N E. Genetic epidemiology of hearing loss.  Ann NY Acad Sci. 1991;  630 16-31
• 9 Liu X, Xu L, Zhang S, Xu Y. Epidemiological and genetic studies of congenital profound deafness in the general population of Sichuan, China.  Am J Med Genet. 1994;  53 192-195
• 10 Smith R, Bale J, White K. Sensorineural hearing loss in children.  Lancet. 2005;  365 879-890
• 11 Keats B, Berlin C. Introduction and overview: genetics in auditory science and clinical audiology. In: Keats B, Popper A, Fay R Genetics and Auditory Disorders. New York, NY; Springer 2002: 1-22
• 12 Cheng X, Li L, Brashears S et al.. Connexin 26 variants and auditory neuropathy/dys-synchrony among children in schools for the deaf.  Am J Med Genet. 2005;  139A 13-18
• 13 Rea P, Gibson W. Evidence for surviving outer hair cell function in congenitally deaf ears.  Laryngoscope. 2003;  113 2030-2040
• 14 Berlin C, Hood L, Morlet T et al.. Absent or elevated middle ear muscle reflexes in the presence of normal otoacoustic emissions: a universal finding in 136 cases of auditory neuropathy/dys-synchrony.  J Am Acad Audiol. 2005;  16 546-553
• 15 Berlin C, Bordelon J, St John P et al.. Reversing click polarity may uncover auditory neuropathy in infants.  Ear Hear. 1998;  19 37-47
• 16 Kim T, Isaacson B, Sivakumaran T, Starr A, Keats B, Lesperance M. A gene responsible for autosomal dominant auditory neuropathy (AUNA1) maps to 13q14-21.  J Med Genet. 2004;  41 872-876
• 17 Sugiura S, Yoshikawa T, Nishiyama Y et al.. Detection of herpes virus DNAs in perilymph obtained from patients with sensorineural hearing loss by real-time polymerase chain reaction.  Laryngoscope. 2004;  114 2235-2238
• 18 Barbi M, Binda S, Caroppo S, Ambrosetti U, Corbetta C, Sergi P. A wider role for congenital cytomegalovirus infection in sensorineural hearing loss.  Pediatr Infect Dis J. 2003;  22 39-42
• 19 Johnson S, Hosford-Dunn H, Paryani S, Yeager A, Malachowski N. Prevalence of sensorineural hearing loss in premature and sick term infants with perinatally acquired cytomegalovirus infection.  Ear Hear. 1986;  7 325-327
• 20 Fowler K, McCollister R, Dahle A, Boppana S, Britt W, Pass R. Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection.  J Pediatr. 1997;  130 624-630
• 21 Madden C, Wiley S, Schleiss M et al.. Audiometric, clinical and educational outcomes in a pediatric symptomatic congenital cytomegalovirus (CMV) population with sensorineural hearing loss.  Int J Pediatr Otorhinolaryngol. 2005;  69 1191-1198
• 22 Griffith A, Friedman T. Autosomal and X-linked auditory disorders. In: Keats B, Popper A, Fay R Genetics and Auditory Disorders. New York, NY; Springer 2002: 121-227
• 23 Van Laer L, Cryns K, Smith R, Van Camp G. Nonsyndromic hearing loss.  Ear Hear. 2003;  24 275-288
• 24 Varga R, Avenarius M, Kelley P et al.. OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature-sensitive auditory neuropathy allele.  J Med Genet. 2006;  43 576-581
• 25 Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the QT interval and sudden death.  Am Heart J. 1957;  54 58-59
• 26 Chorbachi R, Graham J M, Ford J, Raine C. Cochlear implantation in Jervell and Lange-Nielsen syndrome.  Int J Pediatr Otorhinolaryngol. 2002;  66 213-221
• 27 Chiang C, Roden D. The long QT syndromes: genetic basis and clinical implications.  J Am Coll Cardiol. 2000;  36 1-12
• 28 Neyroud N, Tesson F, Denjoy I et al.. A novel mutation in the potassium channel gene KVLQT causes the Jervell and Lange-Nielsen cardioauditory syndrome.  Nat Genet. 1997;  15 186-189
• 29 Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y. KCNE1 mutations cause Jervell and Lange-Nielsen syndrome.  Nat Genet. 1997;  17 267-268
• 30 Vetter D E, Mann J R, Wangemann P et al.. Inner ear defects induced by null mutation of the isk gene.  Neuron. 1996;  17 1251-1264
• 31 Tranebjaerg L. Jervell and Lange-Nielsen syndrome. In: Willems P Genetic Hearing Loss. New York, NY; Marcel Dekker 2004: 117-132
• 32 Splawski I, Shen J, Timothy K et al.. Spectrum of mutations in long-QT syndrome genes KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.  Circulation. 2000;  102 1178-1185
• 33 Lee M, Ravenel J, Hu R et al.. Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice.  J Clin Invest. 2000;  106 1447-1455
• 34 Casimiro M, Knollmann B, Ebert S et al.. Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen syndrome.  Proc Natl Acad Sci USA. 2001;  98 2526-2531
• 35 Rivas A, Francis H. Inner ear abnormalities in a Kcnq1 (Kvlqt1) knockout mouse: a model of Jervell and Lange-Nielsen syndrome.  Otol Neurotol. 2005;  26 415-424
• 36 Wolfram D, Wagener H. Diabetes mellitus and simple optic atrophy among siblings: report of four cases.  Mayo Clin Proc. 1938;  13 715-718
• 37 Swift R, Polymeropoulos M, Torres R, Swift M. Predisposition of Wolfram syndrome heterozygotes to psychiatric illness.  Mol Psychiatry. 1998;  3 86-91
• 38 Inoue H, Tanizawa Y, Wasson J et al.. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).  Nat Genet. 1998;  20 143-148
• 39 Strom T M, Hortnagel K, Hofmann S et al.. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein.  Hum Mol Genet. 1998;  7 2021-2028
• 40 Cryns K, Sivakumarraan T, Van den Ouweland J et al.. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus and psychiatric genetics.  Hum Mutat. 2003;  22 275-287
• 41 El-Shanti H, Lidral A, Jarrah N, Druhan L, Ajlouni K. Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q.  Am J Hum Genet. 2000;  66 1229-1236
• 42 Riggs A, Bernal-Mizrachi E, Ohsugi M et al.. Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis.  Diabetologia. 2005;  48 2313-2321
• 43 Melnick M, Bixler D, Nance W E, Silk K, Yune H. Familial branchio-oto-renal dysplasia: a new addition to the branchial arch syndromes.  Clin Genet. 1976;  9 25-34
• 44 Kumar S. Branchio-oto-renal syndrome. In: Willems P Genetic Hearing Loss. New York, NY; Marcel Dekker 2004: 139-151
• 45 Chang E H, Menezes M, Meyer N C et al.. Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences.  Hum Mutat. 2004;  23 582-589
• 46 Ruf R, Xu P, Silvius D et al.. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.  Proc Natl Acad Sci USA. 2004;  101 8090-8095
• 47 Kumar S, Deffenbacher K, Marres H, Cremers C, Kimberling W. Genome-wide search and genetic localization of a second gene associated with autosomal dominant branchio-oto-renal syndrome: clinical and genetic implications.  Am J Hum Genet. 2000;  66 1715-1720
• 48 Rickard S, Boxer M, Trompeter R, Bitner-Glindzicz M. Importance of clinical evaluation and molecular testing in the branchio-oto-renal (BOR) syndrome and overlapping phenotypes.  J Med Genet. 2000;  37 623-627
• 49 Xu P, Adams J, Peters H, Brown M, Heaney S, Maas R. Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordial.  Nat Genet. 1999;  23 113-117
• 50 Johnson K, Cook S, Erway L et al.. Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome.  Hum Mol Genet. 1999;  8 645-653
• 51 Zheng W, Huang L, Wei Z, Silvius D, Tang B, Xu P. The role of Six1 in mammalian auditory system development.  Development. 2003;  130 3989-4000
• 52 Alport A. Hereditary familial congenital haemorrhagic nephritis.  BMJ. 1927;  1 504-506
• 53 Kashtan C. Alport syndrome: an inherited disorder of renal, ocular, and cochlear basement membranes.  Medicine. 1999;  78 338-360
• 54 Barker D F, Hostikka S L, Zhou J et al.. Identification of mutations in the COL4A5 collagen gene in Alport syndrome.  Science. 1990;  248 1224-1227
• 55 Gross O, Netzer K, Lambrecht R, Seibold S, Wever M. Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counseling.  Nephrol Dial Transplant. 2002;  17 1218-1227
• 56 Lemmink H, Mochizuki T, van den Heuvel L et al.. Mutations in the type IV collagen alpha 3 (COL4A3) gene in autosomal recessive Alport syndrome.  Hum Mol Genet. 1994;  3 1269-1273
• 57 Mochizuki T, Lemmink H, Mariyama M et al.. Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome.  Nat Genet. 1994;  8 77-81
• 58 Boye E, Mollet G, Forestier L et al.. Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome.  Am J Hum Genet. 1998;  63 1329-1340
• 59 Heidet L, Arrondel C, Forestier L et al.. Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome.  J Am Soc Nephrol. 2001;  12 97-106
• 60 Pescucci C, Mari F, Longo I et al.. Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene.  Kidney Int. 2004;  65 1598-1603
• 61 Slajpah M, Meglic A, Furlan P, Glavac D. The importance of non-invasive genetic analysis in the initial diagnostics of Alport syndrome in young patients.  Pediatr Nephrol. 2005;  20 1260-1264
• 62 Rheault M N, Kren S M, Thielen B K et al.. Mouse model of X-linked Alport syndrome.  J Am Soc Nephrol. 2004;  15 1466-1474
• 63 Cox M L, Lees G E, Kashtan C E, Murphy K E. Genetic cause of X-linked Alport syndrome in a family of domestic dogs.  Mamm Genome. 2003;  14 396-403
• 64 Zheng K, Thorner P S, Marrano P, Baumal R, McInnes R. Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the alpha 5 chain of collagen type IV.  Proc Natl Acad Sci USA. 1994;  91 3989-3993
• 65 Lees G E, Helman R G, Kashtan C E et al.. New form of X-linked dominant hereditary nephritis in dogs.  Am J Vet Res. 1999;  60 373-383
• 66 Cosgrove D, Meehan D T, Grunkemeyer J A et al.. Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome.  Genes Dev. 1996;  10 2981-2992
• 67 Miner J H, Sanes J R. Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome.  J Cell Biol. 1996;  135 1403-1413
• 68 Lu W, Phillips C L, Killen P D et al.. Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome.  Genomics. 1999;  61 113-124
• 69 Andrews K L, Mudd J L, Li C, Miner J H. Quantitative trait loci influence renal disease progression in a mouse model of Alport syndrome.  Am J Pathol. 2002;  160 721-730
• 70 Fischel-Ghodsian N. Mitochondrial deafness.  Ear Hear. 2003;  24 303-313
• 71 Jaber L, Shohat M, Bu X et al.. Sensorineural deafness inherited as a tissue specific mitochondrial disorder.  J Med Genet. 1992;  29 86-90
• 72 Prezant T, Agapian J, Bohlman M et al.. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness.  Nat Genet. 1993;  4 289-294
• 73 Estivill X, Govea N, Barcelo A et al.. Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment with aminoglycosides.  Am J Hum Genet. 1998;  62 27-35
• 74 Fischel-Ghodsian N, Bykhovskaya Y, Taylor K et al.. Temporal bone analysis of patients with presbycusis reveals high frequency of mitochondrial mutations.  Hear Res. 1997;  110 147-154
• 75 Johnson K, Zheng Q, Bykhovskaya Y, Spirina O, Fischel-Ghodsian N. A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice.  Nat Genet. 2001;  27 191-194