Evidence for a founder mutation causing DFNA5 hearing loss in East Asians

Abstract

Mutations in the DFNA5 gene are known to cause autosomal dominant non-syndromic hearing loss (ADNSHL). To date, five DFNA5 mutations have been reported, all of which were different in the genomic level. In this study, we ascertained a Korean family with autosomal dominant, progressive and sensorineural hearing loss and performed linkage analysis that revealed linkage to the DFNA5 locus on chromosome 7. Sequence analysis of DFNA5 identified a 3-bp deletion in intron 7 (c.991-15_991-13del) as the cause of hearing loss in this family. As the same mutation had been reported in a large Chinese family segregating DFNA5 hearing loss, we compared their DFNA5 mutation-linked haplotype with that of the Korean family. We found a conserved haplotype, suggesting that the 3-bp deletion is derived from a single origin in these families. Our observation raises the possibility that this mutation may be a common cause of autosomal dominant progressive hearing loss in East Asians.

Molecular analysis of TMC1 gene in the Korean patients with nonsyndromic hearing loss

“…In contrast, the prevalence of the TMC1 mutation in autosomal recessive nonsyndromic hearing loss was found in ~5% of the Tunisian, 4.8% of the Pakistani, and 2.25% of the Sudanese populations, indicating a remarkable contribution of hearing loss in these countries (Meyer et al, 2005;Santos et al, 2005;Tlili et al, 2008). In Korea, three different genes, COCH, DFNA5, and POU4F3, have been reported in one autosomal dominant nonsyndromic hearing loss families Lee et al, 2010;Park et al, 2010). In addition, the GJB2 and SLC26A4 genes are considered major causative genes for autosomal recessive nonsyndromic hearing loss although their contribution to hearing loss have not extensively examined in the Korean population (Park et al, 2003;Lee et al, 2008).…”

Histopathology of the Human Inner Ear in a Patient With Sensorineural Hearing Loss Caused by a Variant in DFNA5

“…2). This variant has been previously reported in several East Asian families affected with dominant nonsyndromic hearing loss (4)(5)(6) and is shown to result in aberrant mRNA splicing causing skipping of exon 8 (4,5), which is predicted to lead to a frameshift starting at amino acid position 330 and a premature stop codon at position 372.…”

“…In this report, we present the histopathology of the inner ears of a patient with hearing loss and a genetically confirmed mutation in DFNA5 (heterozygous c.991-21TTC [2]) located on intron 7, identical to that described in an East Asian population (4)(5)(6). This patient suffered from a late onset progressive bilateral sensorineural hearing loss starting in the high frequencies and subsequently underwent cochlear implantation in one ear with initial successful results.…”

“…Although other DFNA5 variants have been reported in population databases (Exome Aggregation Consortium [ExAC], Cambridge, MA; http://exac.broadinstitute.org) (accessed on January 2015), only those causing exon 8 skipping have been associated with hearing loss. Vestibular symptomatology and test abnormalities are rarely described in patients with DFNA5 mutations (2,5).…”

“…Several pathogenic allelic variants of the gene have been described, including in Dutch (1,2) and Asian families (3)(4)(5)(6), all of which result in skipping of exon 8 (7). The phenotypic pattern of hearing loss includes late onset, bilateral, symmetrical, high-frequency sensorineural loss with progression to involve all frequencies (8).…”