GJB2 mutations and degree of hearing loss: A multicenter study

Rikkert L. Snoeckx; Patrick L.M. Huygen; Delphine Feldmann; Sandrine Marlin; Françoise Denoyelle; Jaroslaw Waligora; Malgorzata Mueller-Malesinska; Agneszka Pollak; Rafal Ploski; Alessandra Murgia; Eva Orzan; Pierangela Castorina; Umberto Ambrosetti; Ewa Nowakowska-Szyrwinska; Jerzy Bal; Wojciech Wiszniewski; Andreas R. Janecke; Doris Nekahm-Heis; Pavel Seeman; Olga Bendova; Margaret A. Kenna; Anna Frangulov; Heidi L. Rehm; Mustafa Tekin; Armagan Incesulu; Hans Henrik M. Dahl; Desirée Du Sart; Lucy Jenkins; Deirdre Lucas; Maria Bitner-Glindzicz; Karen B. Avraham; Zippora Brownstein; Ignacio Del Castillo; Felipe Moreno; Nikolaus Blin; Markus Pfister; Istvan Sziklai; Timea Toth; Philip M. Kelley; Edward S. Cohn; Lionel Van Maldergem; Pascale Hilbert; Anne Françoise Roux; Michel Mondain; Lies H. Hoefsloot; Cor W.R.J. Cremers; Tuija Löppönen; Heikki Löppönen; Agnete Parving; Karen Gronskov; Iris Schrijver; Joseph Roberson; Francesca Gualandi; Alessandro Martini; Geneviève Lina-Granade; Nathalie Pallares-Ruiz; Céu Correia; Graça Fialho; Kim Cryns; Nele Hilgert; Paul Van De Heyning; Carla J. Nishimura; Richard J.H. Smith; Guy Van Camp

doi:10.1086/497996

GJB2 mutations and degree of hearing loss: A multicenter study

Rikkert L. Snoeckx, Patrick L.M. Huygen, Delphine Feldmann, Sandrine Marlin, Françoise Denoyelle, Jaroslaw Waligora, Malgorzata Mueller-Malesinska, Agneszka Pollak, Rafal Ploski, Alessandra Murgia, Eva Orzan, Pierangela Castorina, Umberto Ambrosetti, Ewa Nowakowska-Szyrwinska, Jerzy Bal, Wojciech Wiszniewski, Andreas R. Janecke, Doris Nekahm-Heis, Pavel Seeman, Olga BendovaMargaret A. Kenna, Anna Frangulov, Heidi L. Rehm, Mustafa Tekin, Armagan Incesulu, Hans Henrik M. Dahl, Desirée Du Sart, Lucy Jenkins, Deirdre Lucas, Maria Bitner-Glindzicz, Karen B. Avraham, Zippora Brownstein, Ignacio Del Castillo, Felipe Moreno, Nikolaus Blin, Markus Pfister, Istvan Sziklai, Timea Toth, Philip M. Kelley, Edward S. Cohn, Lionel Van Maldergem, Pascale Hilbert, Anne Françoise Roux, Michel Mondain, Lies H. Hoefsloot, Cor W.R.J. Cremers, Tuija Löppönen, Heikki Löppönen, Agnete Parving, Karen Gronskov, Iris Schrijver, Joseph Roberson, Francesca Gualandi, Alessandro Martini, Geneviève Lina-Granade, Nathalie Pallares-Ruiz, Céu Correia, Graça Fialho, Kim Cryns, Nele Hilgert, Paul Van De Heyning, Carla J. Nishimura, Richard J.H. Smith, Guy Van Camp

Research output: Contribution to journal › Article › peer-review

439 Scopus citations

Abstract

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P < .0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes-35delG/R143W (median 105 dB) and 35delG/dela(G/B6-D13S1830) (median 108 dB)-had significantly more-severe HI than that of 35delG homozygotes.

Original language	English (US)
Pages (from-to)	945-957
Number of pages	13
Journal	American Journal of Human Genetics
Volume	77
Issue number	6
DOIs	https://doi.org/10.1086/497996
State	Published - Dec 2005
Externally published	Yes

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Snoeckx, R. L., Huygen, P. L. M., Feldmann, D., Marlin, S., Denoyelle, F., Waligora, J., Mueller-Malesinska, M., Pollak, A., Ploski, R., Murgia, A., Orzan, E., Castorina, P., Ambrosetti, U., Nowakowska-Szyrwinska, E., Bal, J., Wiszniewski, W., Janecke, A. R., Nekahm-Heis, D., Seeman, P., ... Van Camp, G. (2005). GJB2 mutations and degree of hearing loss: A multicenter study. American Journal of Human Genetics, 77(6), 945-957. https://doi.org/10.1086/497996

Snoeckx, RL, Huygen, PLM, Feldmann, D, Marlin, S, Denoyelle, F, Waligora, J, Mueller-Malesinska, M, Pollak, A, Ploski, R, Murgia, A, Orzan, E, Castorina, P, Ambrosetti, U, Nowakowska-Szyrwinska, E, Bal, J, Wiszniewski, W, Janecke, AR, Nekahm-Heis, D, Seeman, P, Bendova, O, Kenna, MA, Frangulov, A, Rehm, HL, Tekin, M, Incesulu, A, Dahl, HHM, Du Sart, D, Jenkins, L, Lucas, D, Bitner-Glindzicz, M, Avraham, KB, Brownstein, Z, Del Castillo, I, Moreno, F, Blin, N, Pfister, M, Sziklai, I, Toth, T, Kelley, PM, Cohn, ES, Van Maldergem, L, Hilbert, P, Roux, AF, Mondain, M, Hoefsloot, LH, Cremers, CWRJ, Löppönen, T, Löppönen, H, Parving, A, Gronskov, K, Schrijver, I, Roberson, J, Gualandi, F, Martini, A, Lina-Granade, G, Pallares-Ruiz, N, Correia, C, Fialho, G, Cryns, K, Hilgert, N, Van De Heyning, P, Nishimura, CJ, Smith, RJH & Van Camp, G 2005, 'GJB2 mutations and degree of hearing loss: A multicenter study', American Journal of Human Genetics, vol. 77, no. 6, pp. 945-957. https://doi.org/10.1086/497996

@article{5a924f1450954b0b9e8da657ec3c9350,

title = "GJB2 mutations and degree of hearing loss: A multicenter study",

abstract = "Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P < .0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes-35delG/R143W (median 105 dB) and 35delG/dela(G/B6-D13S1830) (median 108 dB)-had significantly more-severe HI than that of 35delG homozygotes.",

author = "Snoeckx, {Rikkert L.} and Huygen, {Patrick L.M.} and Delphine Feldmann and Sandrine Marlin and Fran{\c c}oise Denoyelle and Jaroslaw Waligora and Malgorzata Mueller-Malesinska and Agneszka Pollak and Rafal Ploski and Alessandra Murgia and Eva Orzan and Pierangela Castorina and Umberto Ambrosetti and Ewa Nowakowska-Szyrwinska and Jerzy Bal and Wojciech Wiszniewski and Janecke, {Andreas R.} and Doris Nekahm-Heis and Pavel Seeman and Olga Bendova and Kenna, {Margaret A.} and Anna Frangulov and Rehm, {Heidi L.} and Mustafa Tekin and Armagan Incesulu and Dahl, {Hans Henrik M.} and {Du Sart}, Desir{\'e}e and Lucy Jenkins and Deirdre Lucas and Maria Bitner-Glindzicz and Avraham, {Karen B.} and Zippora Brownstein and {Del Castillo}, Ignacio and Felipe Moreno and Nikolaus Blin and Markus Pfister and Istvan Sziklai and Timea Toth and Kelley, {Philip M.} and Cohn, {Edward S.} and {Van Maldergem}, Lionel and Pascale Hilbert and Roux, {Anne Fran{\c c}oise} and Michel Mondain and Hoefsloot, {Lies H.} and Cremers, {Cor W.R.J.} and Tuija L{\"o}pp{\"o}nen and Heikki L{\"o}pp{\"o}nen and Agnete Parving and Karen Gronskov and Iris Schrijver and Joseph Roberson and Francesca Gualandi and Alessandro Martini and Genevi{\`e}ve Lina-Granade and Nathalie Pallares-Ruiz and C{\'e}u Correia and Gra{\c c}a Fialho and Kim Cryns and Nele Hilgert and {Van De Heyning}, Paul and Nishimura, {Carla J.} and Smith, {Richard J.H.} and {Van Camp}, Guy",

note = "Funding Information: This study was supported by grants from the University of Antwerp, the Vlaams Fonds voor Wetenschappelijk Onderzoek and the Interuniversity Attraction Poles program P5/19 of the Belgian Federal Science Policy (to G.V.C.), and the National Institutes of Health (National Institute on Deafness and Other Communication Disorders [NIDOCD] R01-DC02842) (to R.J.H.S.). Additional grants are from the Internal Grant Agency of the Ministry of Health of the Czech Republic (IGA MH CR NM 7417-3), the Israel ministry of science and technology (to K.B.A.), the Turkish Academy of Sciences in the framework of the young scientist award program (MT/TUBA-GEBIP/2001-2-19), the Polish State Committee for Scientific Research (3P05A15024), the Programa Ram{\'o}n y Cajal of Ministerio de Ciencia y Tecnolog{\'i}a (to I.d.C.), the Spanish Fondo de Investigaciones Sanitarias (FIS G03/203 and FIS PI020807), the G. Passe & R. Williams Foundation (to H.H.M.D), and NIDOCD grant DC005248 (to M.A.K.). This study was initiated through the European Union GENDEAF study group. ",

year = "2005",

month = dec,

doi = "10.1086/497996",

language = "English (US)",

volume = "77",

pages = "945--957",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - GJB2 mutations and degree of hearing loss

T2 - A multicenter study

AU - Snoeckx, Rikkert L.

AU - Huygen, Patrick L.M.

AU - Feldmann, Delphine

AU - Marlin, Sandrine

AU - Denoyelle, Françoise

AU - Waligora, Jaroslaw

AU - Mueller-Malesinska, Malgorzata

AU - Pollak, Agneszka

AU - Ploski, Rafal

AU - Murgia, Alessandra

AU - Orzan, Eva

AU - Castorina, Pierangela

AU - Ambrosetti, Umberto

AU - Nowakowska-Szyrwinska, Ewa

AU - Bal, Jerzy

AU - Wiszniewski, Wojciech

AU - Janecke, Andreas R.

AU - Nekahm-Heis, Doris

AU - Seeman, Pavel

AU - Bendova, Olga

AU - Kenna, Margaret A.

AU - Frangulov, Anna

AU - Rehm, Heidi L.

AU - Tekin, Mustafa

AU - Incesulu, Armagan

AU - Dahl, Hans Henrik M.

AU - Du Sart, Desirée

AU - Jenkins, Lucy

AU - Lucas, Deirdre

AU - Bitner-Glindzicz, Maria

AU - Avraham, Karen B.

AU - Brownstein, Zippora

AU - Del Castillo, Ignacio

AU - Moreno, Felipe

AU - Blin, Nikolaus

AU - Pfister, Markus

AU - Sziklai, Istvan

AU - Toth, Timea

AU - Kelley, Philip M.

AU - Cohn, Edward S.

AU - Van Maldergem, Lionel

AU - Hilbert, Pascale

AU - Roux, Anne Françoise

AU - Mondain, Michel

AU - Hoefsloot, Lies H.

AU - Cremers, Cor W.R.J.

AU - Löppönen, Tuija

AU - Löppönen, Heikki

AU - Parving, Agnete

AU - Gronskov, Karen

AU - Schrijver, Iris

AU - Roberson, Joseph

AU - Gualandi, Francesca

AU - Martini, Alessandro

AU - Lina-Granade, Geneviève

AU - Pallares-Ruiz, Nathalie

AU - Correia, Céu

AU - Fialho, Graça

AU - Cryns, Kim

AU - Hilgert, Nele

AU - Van De Heyning, Paul

AU - Nishimura, Carla J.

AU - Smith, Richard J.H.

AU - Van Camp, Guy

N1 - Funding Information: This study was supported by grants from the University of Antwerp, the Vlaams Fonds voor Wetenschappelijk Onderzoek and the Interuniversity Attraction Poles program P5/19 of the Belgian Federal Science Policy (to G.V.C.), and the National Institutes of Health (National Institute on Deafness and Other Communication Disorders [NIDOCD] R01-DC02842) (to R.J.H.S.). Additional grants are from the Internal Grant Agency of the Ministry of Health of the Czech Republic (IGA MH CR NM 7417-3), the Israel ministry of science and technology (to K.B.A.), the Turkish Academy of Sciences in the framework of the young scientist award program (MT/TUBA-GEBIP/2001-2-19), the Polish State Committee for Scientific Research (3P05A15024), the Programa Ramón y Cajal of Ministerio de Ciencia y Tecnología (to I.d.C.), the Spanish Fondo de Investigaciones Sanitarias (FIS G03/203 and FIS PI020807), the G. Passe & R. Williams Foundation (to H.H.M.D), and NIDOCD grant DC005248 (to M.A.K.). This study was initiated through the European Union GENDEAF study group.

PY - 2005/12

Y1 - 2005/12

N2 - Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P < .0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes-35delG/R143W (median 105 dB) and 35delG/dela(G/B6-D13S1830) (median 108 dB)-had significantly more-severe HI than that of 35delG homozygotes.

AB - Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P < .0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes-35delG/R143W (median 105 dB) and 35delG/dela(G/B6-D13S1830) (median 108 dB)-had significantly more-severe HI than that of 35delG homozygotes.

UR - http://www.scopus.com/inward/record.url?scp=28144444402&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=28144444402&partnerID=8YFLogxK

U2 - 10.1086/497996

DO - 10.1086/497996

M3 - Article

C2 - 16380907

AN - SCOPUS:28144444402

SN - 0002-9297

VL - 77

SP - 945

EP - 957

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

GJB2 mutations and degree of hearing loss: A multicenter study

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