Novel WFS1 mutations in patients with low-to-middle frequency hearing loss.

Abstract

Hearing loss (HL) is the most common sensorineural disorder in human. It is estimated that genetic factors contribute to over 50% of prelingual hearing loss. Most of dominant HHL patients manifest postlingual progressive hearing loss that mainly affect high frequencies. However, mutations in a few dominant HL genes, such as WFS1, TECTA and DIAPH1, cause distinct audiogram that primarily affects the low and middle frequencies. We recruited twelve independent HL families with worse low or middle frequency audiograms. Each proband of these families was excluded for pathogenic mutations in GJB2, SLC26A4, and MT-RNR1 genes. Mutation screening was performed by whole exome sequencing. Next, candidate variants were validated in each family by sanger sequencing. Six heterozygous WFS1 variants were identified in six families, including three novel mutations (c.2519T>G, p.F840C; c.2048T>G, p.M683R and c.2419A>C, p.S807R) and three previously reported variants (c.2005T>C, p.Y669H; c.2590G>A, p.E864K and c.G2389A, p.D797N). All the novel mutations were absent in 100 ethnically matched controls and were predicted to be deleterious by multiple algorithms. We identified three novel and three previously reported WFS1 mutations in six unrelated Chinese families. Our findings enriched the genotype-phenotype spectrum of WFS1 related NSHL. Additional genotype-phenotype correlation study will clarify the detailed phenotypic range caused by WFS1 mutations.