SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15).

Andrew Dewan,Hee-Jin Kim,Hong-Hee Won,Sang Sun Cho,Jong-Won Kim,Hanka Venselaar,Chang-Seok Ki,Gert Vriend,Kyoung-Jin Park,Sung Hwa Hong

doi:10.1371/journal.pone.0079063

Abstract

Autosomal dominant non-syndromic hearing loss (AD-NSHL) is one of the most common genetic diseases in human and is well-known for the considerable genetic heterogeneity. In this study, we utilized whole exome sequencing (WES) and linkage analysis for direct genetic diagnosis in AD-NSHL. The Korean family had typical AD-NSHL running over 6 generations. Linkage analysis was performed by using genome-wide single nucleotide polymorphism (SNP) chip and pinpointed a genomic region on 5q31 with a significant linkage signal. Sequential filtering of variants obtained from WES, application of the linkage region, bioinformatic analyses, and Sanger sequencing validation identified a novel missense mutation Arg326Lys (c.977G>A) in the POU homeodomain of the POU4F3 gene as the candidate disease-causing mutation in the family. POU4F3 is a known disease gene causing AD-HSLH (DFNA15) described in 5 unrelated families until now each with a unique mutation. Arg326Lys was the first missense mutation affecting the 3rd alpha helix of the POU homeodomain harboring a bipartite nuclear localization signal sequence. The phenotype findings in our family further supported previously noted intrafamilial and interfamilial variability of DFNA15. This study demonstrated that WES in combination with linkage analysis utilizing bi-allelic SNP markers successfully identified the disease locus and causative mutation in AD-NSHL.

Highlights

Hearing loss is one of the most common hereditary diseases in human, and more than 70% of the cases are nonsyndromic (NSHL) [1,2]
We investigated on the deafness mutation in a large Korean family with Autosomal dominant non-syndromic hearing loss (AD-NSHL) by a combination approach of linkage analysis using single nucleotide polymorphism (SNP) chip and whole exome sequencing (WES)
Proband and Pedigree The detailed family history revealed a pedigree of a large Korean family (6 generations) with NSHL indicating the pattern of autosomal dominant inheritance (Figure 1A and Table S1)

Summary

Introduction

Hearing loss is one of the most common hereditary diseases in human, and more than 70% of the cases are nonsyndromic (NSHL) [1,2]. AD-NSHL represents one of the examples of extreme genetic heterogeneity in human with a growing list of causative genes by virtue of the recent advances in genomics technology [4,5]. Linkage analysis is one of the powerful approaches for the identification of disease-causing genes, and single nucleotide polymorphisms (SNPs), typically bi-allelic markers, have advantages in its abundance in the human genome and ease of typing with a high throughput. The abundance of variants across genome or exome makes the selection of ‘‘disease-causing’’ mutations still challenging. Narrowing down the genomic area in linkage with the disease significantly increases the power of WES in disease mutation identification

Methods

Results

Conclusion