Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene

Abstract

Objective: To identify the genetic etiology in a family with autosomal dominant progressive sensorineural hearing loss.

Design: Prospective molecular genetic research study.

Setting: Academic genetic research laboratory.

Participants: Seventeen members of a family with dominant progressive nonsyndromic sensorineural hearing loss: 9 affected, 6 unaffected, and 2 spouses.

Interventions: Clinical data from questionnaires, interviews, serial audiograms, and medical records; genetic data from genome-wide linkage analysis and candidate gene mutation analysis.

Main outcome measures: Symptoms, age at onset, serial audiometric data, and the presence or absence of a deafness-associated mutation.

Results: Affected individuals in this family presented with autosomal dominant nonsyndromic high-frequency progressive sensorineural hearing loss, with age at onset ranging from 1 to 21 years. Genome-wide linkage analysis of single-nucleotide polymorphisms yielded evidence of linkage to an 18.9-Mb region on chromosome 1p34-p36, with a multipoint logarithm of odds score of 3.6. This interval contains a known deafness gene, KCNQ4, which underlies DNFA2 deafness. Sequencing of the 14 coding exons and intron-exon junctions of KCNQ4 revealed a novel heterozygous missense mutation, c.859G>C, p.Gly287Arg. The mutation disrupts the highly conserved GYG motif (glycine-tyrosine-glycine) of the phosphate-binding loop, hypothesized to be critical in maintaining pore structure and function. All 274 controls were negative for the mutation.

Conclusions: Autosomal dominant high-frequency hearing loss is genetically heterogeneous, and linkage analysis is an efficient means of identifying the etiology in larger families. Deafness in this family is caused by a novel mutation in KCNQ4.

Figure 1

Pedigree of family 63 segregating progressive high-frequency sensorineural hearing loss. Single-nucleotide polymorphisms are listed to the left of the individual’s genotype. The haplotype segregating with deafness is highlighted with a gray box. The interval is defined by recombination events at rs1886651 (centromeric) and rs926979 (telomeric). KCNQ4 maps between rs209598 and rs883062.

Figure 2

Sequencing chromatogram of KCNQ4 exon 6 in a representative affected individual demonstrating the heterozygous c.859G>C base substitution (arrow) that results in a p.Gly287Arg amino acid substitution.