Novel compound heterozygous mutations in MYO7A Associated with Usher syndrome 1 in a Chinese family.

Xue Gao,Jiang Dong,Hui Zhao,Ming-Yu Han,Feng Xin,Jing-Qiao Lu,Yong-Yi Yuan,Guo-Jian Wang,Xi Lin,Fei Yu,Mei-Guang Zhang,Pu Dai,Jin-Cao Xu,Tiansen Li

doi:10.1371/journal.pone.0103415

Abstract

Usher syndrome is an autosomal recessive disease characterized by sensorineural hearing loss, age-dependent retinitis pigmentosa (RP), and occasionally vestibular dysfunction. The most severe form is Usher syndrome type 1 (USH1). Mutations in the MYO7A gene are responsible for USH1 and account for 29–55% of USH1 cases. Here, we characterized a Chinese family (no. 7162) with USH1. Combining the targeted capture of 131 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified two deleterious compound heterozygous mutations in the MYO7A gene: a reported missense mutation c.73G>A (p.G25R) and a novel nonsense mutation c.462C>A (p.C154X). The two compound variants are absent in 219 ethnicity-matched controls, co-segregates with the USH clinical phenotypes, including hearing loss, vestibular dysfunction, and age-dependent penetrance of progressive RP, in family 7162. Therefore, we concluded that the USH1 in this family was caused by compound heterozygous mutations in MYO7A.

Highlights

Usher syndrome is a clinically and genetically heterogeneous recessive disease with a worldwide prevalence of 1 in 16,000– 50,000 [1]
The most severe is Usher syndrome type 1 (USH1), which is characterized by severeto-profound congenital hearing loss, absence of vestibular function in most cases, and prepubertal-onset retinal degeneration, with impaired night vision and gradual restriction of the visual fields diagnosed as retinitis pigmentosa (RP)
Hundreds of different mutations of USH1 are listed in the Universal Mutation Database (UMD) USHbases, a comprehensive set of databases that records pathogenic mutations and unclassified variants in five genes causing USH1 [31]

Summary

Introduction

Usher syndrome is a clinically and genetically heterogeneous recessive disease with a worldwide prevalence of 1 in 16,000– 50,000 [1]. Based on the severity and progression of hearing loss, age at onset of retinitis pigmentosa (RP), and presence or absence of vestibular impairment, the majority of Usher syndrome cases can be classified into three clinical subtypes. The most severe is Usher syndrome type 1 (USH1), which is characterized by severeto-profound congenital hearing loss, absence of vestibular function in most cases, and prepubertal-onset retinal degeneration, with impaired night vision and gradual restriction of the visual fields diagnosed as RP. USH1 accounts for approximately one-third of Usher syndrome patients. Cohen et al has reported that among the deaf population, the proportion of patients with USH may be as high as 10%, making Usher syndrome an important diagnosis in clinical practices [2]. Molecular genetic testing can confirm or exclude Usher syndrome at an early age, even before the onset of visual problems [3]

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