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

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 genotypephenotype 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 Â 10 À3 and 1 Â 10 À4 . 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.

Prevalence of c.35delG and p.M34T mutations in the GJB2 gene in Estonia

“…The c.35delG mutation is the main cause of early childhood onset HL in Estonian children, and accounts for 75% of GJB2 alleles. This proportion is similar to that reported in studies of other Caucasian populations as ranging between 58 and 95% [12,14,[19][20][21][22][23][24][25].…”

High level of intrafamilial phenotypic variability of non-syndromic hearing loss in a Lur family due to delE120 mutation in GJB2 gene

“…Single nucleotide polymorphisms (SNPs) may have small modifying effects on the phenotype caused by GJB2 genotypes. Hilgert and colleagues using a wholegenome association (WGA) study have suggested that the variable phenotype in 35delG homozygous patients may not be explained by one major modifier gene [25]. However, further studies are needed to identify any possible modifiers.…”

GJB2 Gene Testing, Etiologic Diagnosis and Genetic Counseling in Romanian Persons With Prelingual Hearing Loss

“…This phenotypic variation was explained by the influence of modifier genes and/or environmental factors that lead to incomplete penetrance and variable expression [18,19]. Other studies consider that the phenotypic variation may be caused by a smaller effect of different interacting genes [20].…”