• Richard J. H. Smith
  • Guy Van Camp


Recent advances in the molecular biology of hearing and deafness are being transferred from the research laboratory to the clinical arena. This transfer of knowledge is enhancing patient care by facilitating the diagnosis of hereditary deafness. Traditionally, hereditary deafness has been distinguished from nongenetic causes of deafness by otologic, audiologic, and physical examinations, complemented by a family history and ancillary tests such as temporal bone computed tomography, urinalysis, thyroid function studies, ophthalmoscopy, and electrocardiography. Even using this test battery, an unequivocal distinction between genetic and nongenetic causes of deafness often is difficult. If comorbid conditions are identified, the deafness may fall into one of more than 400 recognized types of syndromic hearing loss, but if hearing loss segregates as the only abnormality, diagnosing the deafness as nonsyndromic and inherited is challenging.1


Hearing Loss Mutation Screening Denature High Performance Liquid Chromatography Nonsyndromic Hearing Loss Wolfram Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Smith RJH, Green GE, Van Camp G. Hereditary hearing loss and deafness [GeneClinics Web site]. 2003. Available at: Scholar
  2. 2.
    Green GE, Scott DA, McDonald JM, et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999;281:2211–2216.PubMedCrossRefGoogle Scholar
  3. 3.
    Van Camp G, Smith RJH. [Hereditary Hearing Loss home page]. 2003. Available at: Scholar
  4. 4.
    Guilford P, Ben Arab S, Blanchard S, et al. A non-syndromic form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat Genet. 1994;6:24–28.PubMedCrossRefGoogle Scholar
  5. 5.
    Kelsell DP, Dunlop J, Stevens HP, et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997;387:80–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Bruzzone R, White TW, Paul DL. Connections with connexins: the molecular basis of direct intercellular signaling. Eur J Biochem. 1996;238:1–27.PubMedCrossRefGoogle Scholar
  7. 7.
    Zelante L, Gasparini P, Estivill X, et al. Connexin 26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet. 1997;6:1605–1609.PubMedCrossRefGoogle Scholar
  8. 8.
    Denoyelle F, Weil D, Maw MA, et al. Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet. 1997;6:2173–2177.PubMedCrossRefGoogle Scholar
  9. 9.
    Estivill X, Fortina P, Surrey S, et al. Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 1998;351:394–398.PubMedCrossRefGoogle Scholar
  10. 10.
    Scott DA, Kraft ML, Carmi R, et al. Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss. Hum Mutat. 1998;11:387–394.PubMedCrossRefGoogle Scholar
  11. 11.
    Cohn ES, Kelley PM, Fowler TW, et al. Clinical studies of families with hearing loss attributable to mutations in the connexin 26 gene. Pediatrics. 1999:103;546–550.PubMedCrossRefGoogle Scholar
  12. 12.
    Kikuchi T, Adams JC, Paul DL, et al. Gap junction systems in the rat vestibular labyrinth: immunohistochemical and ultrastructural analysis. Acta Otolaryngol. 1994;114:520–528.PubMedGoogle Scholar
  13. 13.
    Kikuchi T, Kimura RS, Paul DL, et al. Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis. Anat Embryol (Berl). 1995;191:101–118.Google Scholar
  14. 14.
    Tekin M, Arnos KS, Pandya A. Advances in hereditary deafness. Lancet. 2001;358:1082–1090.PubMedCrossRefGoogle Scholar
  15. 15.
    Estivill X, Gasparini P [Connexin-deafness homepage]. 2003. Available at: http://davinci.crg.ies/deafness/.Google Scholar
  16. 16.
    Van Laer L, Coucke P, Mueller RF, et al. A common founder for the 35delG connexin 26 (GJB2) gene mutation in non-syndromic hearing impairment. J Med Genet. 2001;38:515–518.PubMedCrossRefGoogle Scholar
  17. 17.
    Kelley PM, Harris DJ, Comer BC, et al. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet. 1998;62:792–799.PubMedCrossRefGoogle Scholar
  18. 18.
    Morell RJ, Kim HJ, Hood LJ, et al. Mutations in the connexin 26 gene (GJB2) among Ashkenzi Jews with nonsyndromic recessive deafness. N Eng J Med. 1998;339:1500–1505.CrossRefGoogle Scholar
  19. 19.
    Kudo T, Ikeda K, Kure S, et al. Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population. Am J Med Genet. 2000;90:141–145.PubMedCrossRefGoogle Scholar
  20. 20.
    Denoyelle F, Marlin S, Weil D, et al. Clinical features of the prevalent form of childhood deafness, dFNB1, due to a connexin-26 gene defect: implications for genetic counseling. Lancet. 1999;353:1298–1303.PubMedCrossRefGoogle Scholar
  21. 21.
    Green GE, Mueller RF, Cohn ES, Avraham KB, Kanaan M, Smith RJH. Audiological manifestations and features of Connexin 26 deafness. Audiolog Med 2003;1:5–11.CrossRefGoogle Scholar
  22. 22.
    Kenna MA, Wu BL, Cotanche DA, et al. Connexin 26 studies in patients with sensorineural hearing loss. Arch Otolaryngol Head Neck Surg. 2001;127:1037–1042.PubMedGoogle Scholar
  23. 23.
    Hohl D. Towards a better classification of erythrokeratodermias. Br J Dermatol. 2000;143:1133–1137.PubMedCrossRefGoogle Scholar
  24. 24.
    Maestrini E, Korge BP, Ocana-Sierra J, et al. A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel’s syndrome) in three unrelated families. Hum Mol Genet. 1999;8:1237–1243.PubMedCrossRefGoogle Scholar
  25. 25.
    Fukushima K, Sugata K, Kasai N, et al. Better speech performance in cochlear implant patients with GJB2-related deafness. Int J Pediatr Otorhinolaryngol. 2002;62:151–157.PubMedCrossRefGoogle Scholar
  26. 26.
    Green GE, Scott DA, McDonald JM, et al. Performance of cochlear implant recipients with GJB2-related deafness. Am J Med Genet. 2002;109:167–170.PubMedCrossRefGoogle Scholar
  27. 27.
    Smith RJ. Mutation screening for deafness: more than simply another diagnostic test. Arch Otolaryngol Head Neck Surg. 2001;127:941–942.PubMedGoogle Scholar
  28. 28.
    Mueller RF, Nehammer A, Middleton A, et al. Congenital nonsyndromal sensorineural hearing impairment due to connexin 26 gene mutations—molecular and audiological findings. Int J Pediatr Otorhinolaryngol. 1999;50:3–13.PubMedCrossRefGoogle Scholar
  29. 29.
    Sobe T, Vreugde S, Shahin H, et al. The prevalence and expression of inherited connexin 26 mutations associated with nonsyndromic hearing loss in the Israeli population. Hum Genet. 2000;106:50–57.PubMedCrossRefGoogle Scholar
  30. 30.
    Ellis LA, Taylor CF, Taylor GR. A comparison of fluorescent SSCP and denaturing HPLC for high throughput mutations screening. Hum Mutat. 2000;15:556–564.PubMedCrossRefGoogle Scholar
  31. 31.
    Liu WG, Smith DI, Rechtzigel KJ, et al. Denaturing high performance liquid chromatography (DHPLC) used in the detection of germline and somatic mutations. Nucleic Acids Res. 1998;26:1396–1400.PubMedCrossRefGoogle Scholar
  32. 32.
    O’Donovan MC, Oefner PJ, Roberts SC, et al. Blind analysis of denaturing high-performance liquid chromatography as tool for mutation detection. Genomics. 1998;52:44–49.PubMedCrossRefGoogle Scholar
  33. 33.
    Taliani MR, Roberts SC, Dukek BA, et al. Sensitivity and specificity of denaturing high-pressure liquid chromatography for unknown protein C gene mutations. Genet Test. 2001;5:39–44.PubMedCrossRefGoogle Scholar
  34. 34.
    Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. 1997;17:411–422.PubMedCrossRefGoogle Scholar
  35. 35.
    Phelps PD, Coffey RA, Trembath RC, et al. Radiological malformations of the ear in Pendred syndrome. Clin Radiol. 1998;53:268–273.PubMedCrossRefGoogle Scholar
  36. 36.
    Reardon W, Coffey R, Chowdhury T, et al. Prevalence, age of onset, and natural history of thyroid disease in Pendred syndrome. J Med Genet. 1999;36:595–598.PubMedGoogle Scholar
  37. 37.
    Morgans ME, Trotter WR. Association of congenital deafness with goitre: the nature of the thyroid defect. Lancet. 1958;1:607–609.PubMedCrossRefGoogle Scholar
  38. 38.
    Li XC, Everett LA, Lalwani AK, et al. A mutation in PDS causes nonsyndromic recessive deafness. Nat Genet. 1998;18:215–217.PubMedCrossRefGoogle Scholar
  39. 39.
    Scott DA, Wang R, Kreman TM, et al. Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and nonsyndromic hearing loss. Hum Mol Genet. 2000;9:1709–1715.PubMedCrossRefGoogle Scholar
  40. 40.
    Johnsen T, Sorensen MS, Feldt-Rasmussen U, et al. The variable intrafamiliar expressivity in Pendred’s syndrome. Clin Otolaryngol. 1989;14:395–399.PubMedCrossRefGoogle Scholar
  41. 41.
    Yong AML, Goh SS, Zhao Y, et al. Two Chinese families with Pendred’s syndrome—radiological imaging of the ear and molecular analysis of the pendrin gene. J Clin Endocrin Metab. 2001;86:3907–3911.CrossRefGoogle Scholar
  42. 42.
    Campbell C, Cucci RA, Green GE, et al. Pendred syndrome, DFNB4 and PDS—Identification of eight novel mutations and phenotypegenotype correlations. Hum Mut. 2001;17:403–411.PubMedCrossRefGoogle Scholar
  43. 43.
    Chang E, Kolln K, Smith RJH. [Pendred syndrome/BOR homepage]. 2003. Available at: Scholar
  44. 44.
    Masmoudi S, Charfedine I, Hmani M, et al. Pendred syndrome: phenotypic variability in two families carrying the same PDS missense mutation. Am J Med Genet. 2000;90:38–44.PubMedCrossRefGoogle Scholar
  45. 45.
    Prasad S, Kölln KA, Cucci RA, Trembath RC, Van Camp G, Smith RJH. Pendred syndrome and DFNB4—Mutation screening of SLC26A4 by denaturing high-performance liquid chromatography and the identification of seven novel mutations. Am J Med Genet 124A:1–9, 2004.CrossRefPubMedGoogle Scholar
  46. 46.
    Coyle B, Reardon W, Herbrick J, et al. Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre). Hum Mol Genet. 1998;7:1105–1112.PubMedCrossRefGoogle Scholar
  47. 47.
    Bespalova IN, Van Camp G, Bom SJ, et al. Mutations in the Wolfram syndrome 1 gene (WFS1) area a common cause of low frequency sensorineural hearing loss. Hum Mol Genet. 2001;10:2501–2508.PubMedCrossRefGoogle Scholar
  48. 48.
    Young TL, Ives E, Lynch E, et al. Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. Hum Mol Genet. 2001;10:2509–2514.PubMedCrossRefGoogle Scholar
  49. 49.
    Kunst HPM, Marres HAM, Huygen PLM, et al. Autosomal dominant non-syndromal low-frequency sensorineural hearing impairment linked to chromosome 4p16 (DFNA14): statistical analysis of hearing threshold in relation to age and evaluation of vestibuloocular functions. Audiology. 1999;38:165–173.PubMedCrossRefGoogle Scholar
  50. 50.
    Brodwolf S, Böddeker IR, Ziegler A, et al. Further evidence for linkage of low-mid frequency hearing impairment to the candidate region on chromosome 4p16.3. Clin Genet. 2001;60:155–160.PubMedCrossRefGoogle Scholar
  51. 51.
    Huygen PLM, Bom SJ, Van Camp G, et al. The clinical presentation of the DFNA loci where causative genes have not yet been cloned: DFNA4, DFNA6/14, DFNA7, DFNA16, DFNA20 and DFNA21. In: Cremers CWRJ, Smith RJH, eds. Advances in Otorhinolaryngology. Basel: Karger; 2002;98–106.Google Scholar
  52. 52.
    Bom SJH, Van Camp G, Cryns K, et al. Autosomal dominant lowfrequency hearing impairment (DFNA6/14): a clinical and genetic family study. Otol Neurotol. 2002:23:876–884.PubMedCrossRefGoogle Scholar
  53. 53.
    Lynch ED, Lee MK, morrow JE, et al. Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science. 1997;278:1223–1224.CrossRefGoogle Scholar
  54. 54.
    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.PubMedCrossRefGoogle Scholar
  55. 55.
    Strom TM, Hörtnagel 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.PubMedCrossRefGoogle Scholar
  56. 56.
    Cremers CWRJ, Wijdeveld PG, Pinckers AJ. Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atonia of the urinary tract and bladder, and other abnormalities (Wolfram syndrome): a review of 88 cases from the literature with personal observations on 3 new patients. Acta Paediatr Scand Suppl. 1977;264:1–16.PubMedGoogle Scholar
  57. 57.
    Higashi K. Otologic findings of DIDMOAD syndrome. Am J Otol. 1991;12:57–60.PubMedGoogle Scholar
  58. 58.
    Cryns K, Pfister M, Pennings RJE, et al. Mutations in the WFS1 gene that cause low frequency sensorineural hearing loss are small noninactivating mutations. Hum Genet. 2002;110:389–394.PubMedCrossRefGoogle Scholar
  59. 59.
    Prasad S, Kölln KA, Cucci RA, Trembath RC, Van Camp G, Smith RJH. Pendred syndrome and DFNB4-Mutation screening of SLC26A4 by denaturing high-performance liquid chromatography and the identification of seven novel mutations. Am J Med Genet. 2004;124A:1–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Takeda K, Inoue H, Tanizawa Y, et al. WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet. 2001;10:477–484.PubMedCrossRefGoogle Scholar
  61. 61.
    Sivakumaran TA, Lesperance MM. WFS1 Gene Mutation and Polymorphism Database [database online]. 2003. Available at: Scholar
  62. 62.
    Awata T, Inoue K, Kurihara S, et al. Missense variations of the gene responsible for Wolfram syndrome (WFS1/wolframin) in Japanese: possible contribution of the Arg456His mutation to type 1 diabetes as a nonautoimmune genetic basis. Biochem Biophys Res Commun. 2000;268:612–616.PubMedCrossRefGoogle Scholar
  63. 63.
    Minton JAL, Hattersley AT, Owen K, et al. Association studies of genetic variation in the WFS1 gene and type 2 diabetes in U. K. populations. Diabetes. 2002;51:1287–1290.PubMedCrossRefGoogle Scholar
  64. 64.
    Domenech E, Gomez-Zaera M, Nunes V. WFS1 mutations in Spanish patients with diabetes mellitus and deafness. Eur J Hum Genet. 2002;10:421–426.PubMedCrossRefGoogle Scholar
  65. 65.
    Abdelhak S, Kalatzis V, Heilig R, et al. Protein, nucleotide, a human homologue of the Drosophila eyes absent gene underlies branchiooto-renal (BOR) syndrome and identifies a novel gene family. Nat Genet. 1997;15:157–164.PubMedCrossRefGoogle Scholar
  66. 66.
    Abdelhak S, Kalatzis V, Heilig R, et al. Protein, nucleotide, clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1. Hum Mol Genet. 1997;6:2247–2255.PubMedCrossRefGoogle Scholar
  67. 67.
    Kumar S, Kimberling WJ, Weston MD, et al. Identification of three novel mutations in human EYA1 protein associated with branchiooto-renal syndrome. Hum Mutat. 1998;11:443–449.PubMedCrossRefGoogle Scholar
  68. 68.
    Kumar S, Deffenbacher K, Cremers CW, et al. Branchio-oto-renal syndrome: identification of novel mutations, molecular characterization, mutation distribution, and prospects for genetic testing. Genet Test. 1998;1:243–251.CrossRefGoogle Scholar
  69. 69.
    Usami S, Abe S, Shinkawa H, et al. EYA1 nonsense mutation in a Japanese branchio-oto-renal syndrome family. J Hum Genet. 1999;44:261–265.PubMedCrossRefGoogle Scholar
  70. 70.
    Fraser FC, Sproule JR, Halal F. Frequency of the branchio-oto-renal (BOR) syndrome in children with profound hearing loss. Am J Med Genet. 1980;7:341–349.PubMedCrossRefGoogle Scholar
  71. 71.
    Chen A, Francis M, Ni L, et al. Phenotypic manifestations of branchio-oto-renal syndrome. Am J Med Genet. 1995;58:365–370.PubMedCrossRefGoogle Scholar
  72. 72.
    Carmi R, Binshtock M, abeliovich D. The branchio-oto-renal (BOR) syndrome: report of bilateral renal agenesis in three sibs. Am J Med Genet. 1983;14:625–627.PubMedCrossRefGoogle Scholar
  73. 73.
    Cremers CWRJ, Fikkers-Van Noord M. The earpits-deafness syndrome: clinical and genetic aspects. Int J Pediatr Otorhinolaryngol. 1980;2:309–322.PubMedCrossRefGoogle Scholar
  74. 74.
    Greenberg CR, Trevenen CL, Evans JA. The BOR syndrome and renal agenesis. Prenatal Diagn. 1988;8:103–108.CrossRefGoogle Scholar
  75. 75.
    Van Widdershoven J, Monnens L, Assmann K, et al. Renal disorders in the branchio-oto-renal syndrome. Helv Paediatr Acta. 1983;38:513–522.PubMedGoogle Scholar
  76. 76.
    Chitayat D, hodgkinson KA, Chen MF, et al. Branchio-oto-renal syndrome: further delineation of an underdiagnosed syndrome. Am J Med Genet. 1992;43:970–975.PubMedCrossRefGoogle Scholar
  77. 77.
    Fitch N, Sorolovitz H. Severe renal dysgenesis produced by a dominant gene. Am J Dis Child. 1976;130:1356–1357.PubMedGoogle Scholar
  78. 78.
    Gu JZ, wagner MJ, Haan EA, et al. Detection of a megabase deletion in a patient with branchio-oto-renal syndrome (BOR) and trichorhino-phalangeal syndrome (TRPS): implications for mapping and cloning of the BOR gene. Genomics. 1996;31:201–206.PubMedCrossRefGoogle Scholar
  79. 79.
    Haan EA, Hull YJ, White S, et al. Tricho-rhino-phalangeal and branchio-oto syndromes in a family with an inherited rearrangement of chromosome 8q. Am J Med Genet. 1989;32:490–494.PubMedCrossRefGoogle Scholar
  80. 80.
    Vincent C, Kalatzis V, Compain S, et al. A proposed new contiguous gene syndrome on 8q consists of branchio-oto-renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia: implications for the mapping of the BOR gene. Hum Mol Genet. 1994;3:1859–1866.PubMedCrossRefGoogle Scholar
  81. 81.
    Vervoort V, Smith RJH, O’Brien J, et al. Genomic rearrangements of EYA1 account for a large fraction of families with BOR syndrome. Eur J Hum Genet. 2002;10:757–766.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Richard J. H. Smith
    • 1
    • 2
    • 3
  • Guy Van Camp
    • 4
  1. 1.Department of OtolaryngologyUniversity of IowaIowa CityUSA
  2. 2.Molecular Otolaryngology Research LaboratoriesUniversity of IowaIowa CityUSA
  3. 3.Department of Internal Medicine, Division of NephrologyUniversity of IowaIowa CityUSA
  4. 4.Department of Medical GeneticsUniversity of AntwerpAntwerpBelgium

Personalised recommendations