Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene

Nele Hilgert, Matthew J Huentelman, Ashley Q Thorburn, Erik Fransen, Nele Dieltjens, Malgorzata Mueller-Malesinska, Agnieszka Pollak, Agata Skorka, Jaroslaw Waligora, Rafal Ploski, Pierangela Castorina, Paola Primignani, Umberto Ambrosetti, Alessandra Murgia, Eva Orzan, Arti Pandya, Kathleen Arnos, Virginia Norris, Pavel Seeman, Petr Janousek, Delphine Feldmann, Sandrine Marlin, Françoise Denoyelle, Carla J Nishimura, Andreas Janecke, Doris Nekahm-Heis, Alessandro Martini, Elena Mennucci, Timea Tóth, Istvan Sziklai, Ignacio del Castillo, Felipe Moreno, Michael B Petersen, Vasiliki Iliadou, Mustafa Tekin, Armagan Incesulu, Ewa Nowakowska, Jerzy Bal, Paul Van de Heyning, Anne-Françoise Roux, Catherine Blanchet, Cyril Goizet, Guenaëlle Lancelot, Graça Fialho, Helena Caria, Xue Zhong Liu, Ouyang Xiaomei, Paul Govaerts, Karen Grønskov, Karianne Hostmark, Klemens Frei, Ingeborg Dhooge, Stephen Vlaeminck, Erdmute Kunstmann, Lut Van Laer, Richard JH Smith, Guy Van Camp
Eur J Hum Genet. 2008-11-05; 17(4): 517-524
DOI: 10.1038/EJHG.2008.201


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1. Eur J Hum Genet. 2009 Apr;17(4):517-24. doi: 10.1038/ejhg.2008.201. Epub 2008 Nov
5.

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

Hilgert N(1), Huentelman MJ, Thorburn AQ, Fransen E, Dieltjens N,
Mueller-Malesinska M, Pollak A, Skorka A, Waligora J, Ploski R, Castorina P,
Primignani P, Ambrosetti U, Murgia A, Orzan E, Pandya A, Arnos K, Norris V,
Seeman P, Janousek P, Feldmann D, Marlin S, Denoyelle F, Nishimura CJ, Janecke A,
Nekahm-Heis D, Martini A, Mennucci E, Tóth T, Sziklai I, Del Castillo I, Moreno
F, Petersen MB, Iliadou V, Tekin M, Incesulu A, Nowakowska E, Bal J, Van de
Heyning P, Roux AF, Blanchet C, Goizet C, Lancelot G, Fialho G, Caria H, Liu XZ,
Xiaomei O, Govaerts P, Grønskov K, Hostmark K, Frei K, Dhooge I, Vlaeminck S,
Kunstmann E, Van Laer L, Smith RJ, Van Camp G.

Author information:
(1)Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene
identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all
cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with
35delG being the most frequent mutation in Caucasians. Although a
genotype-phenotype correlation has been established for most GJB2 genotypes, the
HL of 35delG homozygous patients is mild to profound. We hypothesise that this
phenotypic variability is at least partly caused by the influence of modifier
genes. By performing a whole-genome association (WGA) study on 35delG
homozygotes, we sought to identify modifier genes. The association study was
performed by comparing the genotypes of mild/moderate cases and profound cases.
The first analysis included a pooling-based WGA study of a first set of 255
samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis
resulted in a ranking of all analysed single-nucleotide polymorphisms (SNPs)
according to their P-values. The top 250 most significantly associated SNPs were
genotyped individually in the same sample set. All 192 SNPs that still had
significant P-values were genotyped in a second independent set of 297 samples
for replication. The significant P-values were replicated in nine SNPs, with
combined P-values between 3 x 10(-3) and 1 x 10(-4). This study suggests that the
phenotypic variability in 35delG homozygous patients cannot be explained by the
effect of one major modifier gene. Significantly associated SNPs may reflect a
small modifying effect on the phenotype. Increasing the power of the study will
be of greatest importance to confirm these results.

DOI: 10.1038/ejhg.2008.201
PMCID: PMC2883287
PMID: 18985073 [Indexed for MEDLINE]

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