Exome Sequencing Identifies a Founder Frameshift Mutation in an Alternative Exon of USH1C as the Cause of Autosomal Recessive Retinitis Pigmentosa with Late-Onset Hearing Loss

Samer Khateb,Dror Sharon,Menachem Gross,Tamar Ben-Yosef,Ornit Crystal-Shalit,Eyal Banin,Saul Merin,Lina Zelinger,Anneke I Den Hollander

doi:10.1371/journal.pone.0051566

Abstract

We used a combined approach of homozygosity mapping and whole exome sequencing (WES) to search for the genetic cause of autosomal recessive retinitis pigmentosa (arRP) in families of Yemenite Jewish origin. Homozygosity mapping of two arRP Yemenite Jewish families revealed a few homozygous regions. A subsequent WES analysis of the two index cases revealed a shared homozygous novel nucleotide deletion (c.1220delG) leading to a frameshift (p.Gly407Glufs*56) in an alternative exon (#15) of USH1C. Screening of additional Yemenite Jewish patients revealed a total of 16 homozygous RP patients (with a carrier frequency of 0.008 in controls). Funduscopic and electroretinography findings were within the spectrum of typical RP. While other USH1C mutations usually cause Usher type I (including RP, vestibular dysfunction and congenital deafness), audiometric screening of 10 patients who are homozygous for c.1220delG revealed that patients under 40 years of age had normal hearing while older patients showed mild to severe high tone sensorineural hearing loss. This is the first report of a mutation in a known USH1 gene that causes late onset rather than congenital sensorineural hearing loss. The c.1220delG mutation of USH1C accounts for 23% of RP among Yemenite Jewish patients in our cohort.

Highlights

Retinitis pigmentosa (RP) [MIM #268000] is the most common inherited retinal degeneration with an estimated worldwide prevalence of about 1:4000 [1,2]
We report here of the identification of a novel USH1C founder mutation in Yemenite Jewish (YJ) patients with autosomal recessive retinitis pigmentosa (arRP)
Nonsyndromic deafness was reported in only two families so far: patients from the original DFNB18 family were homozygous for a ‘‘leaky’’ splice-site mutation (IVS12+5G.C) that might affect the splicing of exons 11 and 12 [9], and patients from a Chinese family were homozygous for a missense change (p.Pro608Arg) but no functional assay was performed to prove the pathogenicity of this change [21]

Summary

Introduction

Retinitis pigmentosa (RP) [MIM #268000] is the most common inherited retinal degeneration with an estimated worldwide prevalence of about 1:4000 [1,2]. An interesting group of retinal disease genes can cause both syndromic and nonsyndromic phenotypes, not always with a clear disease mechanism: for example, USH2A mutations can cause the USH phenotype and RP alone [4,5,6,7,8]; USH1C and MYO7A mutations have been associated with the USH phenotype and hearing impairment alone [9,10]. The Yemenite Jewish (YJ) population is ancient (over 2,000 years) and comprised of several small communities. A single founder mutation in the CERKL gene (c.238+1G.A) has been reported by us as the cause of inherited widespread retinal degeneration with early macular involvement in about 30% of cases of YJ origin [11]

Methods

Results

Conclusion