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 journalArticle

324 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)945-957
Number of pages13
JournalAmerican Journal of Human Genetics
Volume77
Issue number6
DOIs
StatePublished - Dec 2005

Fingerprint

Hearing Loss
Multicenter Studies
Mutation
Genotype
Homozygote
Persons With Hearing Impairments
Genetic Heterogeneity
Inner Ear
Mutation Rate
Routine Diagnostic Tests
Genes
Homeostasis
Cross-Sectional Studies
Newborn Infant
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Snoeckx, R. L., Huygen, P. L. M., Feldmann, D., Marlin, S., Denoyelle, F., Waligora, J., ... 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

GJB2 mutations and degree of hearing loss : A multicenter study. / Snoeckx, Rikkert L.; Huygen, Patrick L.M.; Feldmann, Delphine; Marlin, Sandrine; Denoyelle, Françoise; Waligora, Jaroslaw; Mueller-Malesinska, Malgorzata; Pollak, Agneszka; Ploski, Rafal; Murgia, Alessandra; Orzan, Eva; Castorina, Pierangela; Ambrosetti, Umberto; Nowakowska-Szyrwinska, Ewa; Bal, Jerzy; Wiszniewski, Wojciech; Janecke, Andreas R.; Nekahm-Heis, Doris; Seeman, Pavel; Bendova, Olga; Kenna, Margaret A.; Frangulov, Anna; Rehm, Heidi L.; Tekin, Mustafa; Incesulu, Armagan; Dahl, Hans Henrik M.; Du Sart, Desirée; Jenkins, Lucy; Lucas, Deirdre; Bitner-Glindzicz, Maria; Avraham, Karen B.; Brownstein, Zippora; Del Castillo, Ignacio; Moreno, Felipe; Blin, Nikolaus; Pfister, Markus; Sziklai, Istvan; Toth, Timea; Kelley, Philip M.; Cohn, Edward S.; Van Maldergem, Lionel; Hilbert, Pascale; Roux, Anne Françoise; Mondain, Michel; Hoefsloot, Lies H.; Cremers, Cor W.R.J.; Löppönen, Tuija; Löppönen, Heikki; Parving, Agnete; Gronskov, Karen; Schrijver, Iris; Roberson, Joseph; Gualandi, Francesca; Martini, Alessandro; Lina-Granade, Geneviève; Pallares-Ruiz, Nathalie; Correia, Céu; Fialho, Graça; Cryns, Kim; Hilgert, Nele; Van De Heyning, Paul; Nishimura, Carla J.; Smith, Richard J.H.; Van Camp, Guy.

In: American Journal of Human Genetics, Vol. 77, No. 6, 12.2005, p. 945-957.

Research output: Contribution to journalArticle

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
Snoeckx RL, Huygen PLM, Feldmann D, Marlin S, Denoyelle F, Waligora J et al. GJB2 mutations and degree of hearing loss: A multicenter study. American Journal of Human Genetics. 2005 Dec;77(6):945-957. https://doi.org/10.1086/497996
Snoeckx, Rikkert L. ; Huygen, Patrick L.M. ; Feldmann, Delphine ; Marlin, Sandrine ; Denoyelle, Françoise ; Waligora, Jaroslaw ; Mueller-Malesinska, Malgorzata ; Pollak, Agneszka ; Ploski, Rafal ; Murgia, Alessandra ; Orzan, Eva ; Castorina, Pierangela ; Ambrosetti, Umberto ; Nowakowska-Szyrwinska, Ewa ; Bal, Jerzy ; Wiszniewski, Wojciech ; Janecke, Andreas R. ; Nekahm-Heis, Doris ; Seeman, Pavel ; Bendova, Olga ; Kenna, Margaret A. ; Frangulov, Anna ; Rehm, Heidi L. ; Tekin, Mustafa ; Incesulu, Armagan ; Dahl, Hans Henrik M. ; Du Sart, Desirée ; Jenkins, Lucy ; Lucas, Deirdre ; Bitner-Glindzicz, Maria ; Avraham, Karen B. ; Brownstein, Zippora ; Del Castillo, Ignacio ; Moreno, Felipe ; Blin, Nikolaus ; Pfister, Markus ; Sziklai, Istvan ; Toth, Timea ; Kelley, Philip M. ; Cohn, Edward S. ; Van Maldergem, Lionel ; Hilbert, Pascale ; Roux, Anne Françoise ; Mondain, Michel ; Hoefsloot, Lies H. ; Cremers, Cor W.R.J. ; Löppönen, Tuija ; Löppönen, Heikki ; Parving, Agnete ; Gronskov, Karen ; Schrijver, Iris ; Roberson, Joseph ; Gualandi, Francesca ; Martini, Alessandro ; Lina-Granade, Geneviève ; Pallares-Ruiz, Nathalie ; Correia, Céu ; Fialho, Graça ; Cryns, Kim ; Hilgert, Nele ; Van De Heyning, Paul ; Nishimura, Carla J. ; Smith, Richard J.H. ; Van Camp, Guy. / GJB2 mutations and degree of hearing loss : A multicenter study. In: American Journal of Human Genetics. 2005 ; Vol. 77, No. 6. pp. 945-957.
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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.",
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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

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.

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