Undescribed GJB2 c.35dupG homozygous prelingual distinguished from c.35delG homozygous/compound heterozygous deafs, dwelling a German ancestry Venezuelan isolate

Abstract

Abstract Background Among ten hearing-impaired (HI) families mostly of German descent dwelling the Venezuelan isolate Colonia Tovar, which were initially studied several decades ago to assess the etiology of their profound/prelingual nonsyndromic deafness phenotype, an undescribed genotype/phenotype was found. Forty-eight subjects, including 8 of the still living 143 originally searched with audiograms 4 decades ago, were retested and their DNA collected. A genomic search of 27 loci involved in HI was performed on a randomly chosen prelingual deaf patient. Subsequently, GJB2 sequencing was performed in all subjects from each pedigree. Haplotypes were constructed with five intragenic GJB2 SNPs (rs117685390, rs7994748, rs2274084, rs2274083, and rs3751385). Audiograms performed along 5 decades were compared to evaluate age-related hearing loss in the different genotypes found in the population. Results Three prelingual deaf siblings, having the highest recorded symmetrical hearing loss of all the known affected in the isolate, carried the very rare mutation c.35dupG (p.V13Cfs*35) at GJB2 in a homozygous condition. Two additional GJB2 mutations were identified (p.W77R and c.35delG) in the isolate. Allelic disequilibrium in both c.35dupG and p.W77R carriers (with in-phase haplotype T;T;G;A;C) were found, although not so in the 2 other found c.35delG independent haplotypes. A compound heterozygote in trans (c.35delG/c.35dupG) was audiometrically distinguishable from both the c.35dupG and c.35delG homozygotes. Conclusions A relatively higher frequency of mutation of c.35dupG found than elsewhere was retrospectively inferred for the ancient population of the Kaiserstuhl region in Germany, having an opposite epidemiological situation to the one found with the contiguous and very frequent c.35delG. Haplotype analysis suggests founder phenomena and independent occurrence, hundreds of generations back in Caucasoid populations for both mutations.