Journal article
Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene
European journal of human genetics : EJHG, Vol.17(4), pp.517-524
04/2009
DOI: 10.1038/ejhg.2008.201
PMID: 18985073
Abstract
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 × 10
−3
and 1 × 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.
Details
- Title: Subtitle
- Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene
- Creators
- Nele Hilgert - , AntwerpMatthew J Huentelman - , Phoenix, AZAshley Q Thorburn - , Phoenix, AZErik Fransen - , AntwerpNele Dieltjens - , AntwerpMalgorzata Mueller-Malesinska - , WarsawAgnieszka Pollak - , WarsawAgata Skorka - , WarsawJaroslaw Waligora - , WarsawRafal Ploski - , WarsawPierangela Castorina - , MilanPaola Primignani - , MilanUmberto Ambrosetti - , MilanAlessandra Murgia - , PaduaEva Orzan - , PaduaArti Pandya - , Richmond, VAKathleen Arnos - , Washington, DCVirginia Norris - , Washington, DCPavel Seeman - , PraguePetr Janousek - , PragueDelphine Feldmann - , ParisSandrine Marlin - , ParisFrançoise Denoyelle - , ParisCarla J Nishimura - , Iowa city, IAAndreas Janecke - , InnsbruckDoris Nekahm-Heis - , InnsbruckAlessandro Martini - , FerraraElena Mennucci - , FerraraTimea Tóth - , DebrecenIstvan Sziklai - , DebrecenIgnacio del Castillo - , MadridFelipe Moreno - , MadridMichael B Petersen - , AthensVasiliki Iliadou - , ThessalonikiMustafa Tekin - , AnkaraArmagan Incesulu - , EskisehirEwa Nowakowska - , WarsawJerzy Bal - , WarsawPaul Van de Heyning - , AntwerpAnne-Françoise Roux - , MontpellierCatherine Blanchet - , MontpellierCyril Goizet - , BordeauxGuenaëlle Lancelot - , BordeauxGraça Fialho - , LisbonHelena Caria - , LisbonXue Zhong Liu - , Miami, FLOuyang Xiaomei - , Miami, FLPaul Govaerts - , AntwerpKaren Grønskov - , GlostrupKarianne Hostmark - , CopenhagenKlemens Frei - , ViennaIngeborg Dhooge - , GentStephen Vlaeminck - , GentErdmute Kunstmann - , WuerzburgLut Van Laer - , AntwerpRichard JH Smith - , Iowa city, IAGuy Van Camp - , Antwerp
- Resource Type
- Journal article
- Publication Details
- European journal of human genetics : EJHG, Vol.17(4), pp.517-524
- DOI
- 10.1038/ejhg.2008.201
- PMID
- 18985073
- NLM abbreviation
- Eur J Hum Genet
- ISSN
- 1018-4813
- eISSN
- 1476-5438
- Publisher
- Nature Publishing Group
- Alternative title
- Influence of modifiers on 35delG/35delG phenotype
- Language
- English
- Date published
- 04/2009
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984006324202771
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