Whole exome sequencing identifies novel USH2A mutations and confirms Usher syndrome 2 diagnosis in Chinese retinitis pigmentosa patients

Tsz Kin Ng,Yingjie Cao,Shaowan Chen,Wenyu Tang,Haoyu Chen,Yuqian Zheng,Xiaoqiang Xiao

doi:10.1038/s41598-019-42105-0

Tsz Kin Ng, Yingjie Cao + Show 5 more

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https://doi.org/10.1038/s41598-019-42105-0

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Abstract

Retinitis pigmentosa (RP) is a common phenotype in multiple inherited retinal dystrophies (IRD). Disease gene identification can assist the clinical diagnosis of IRD patients for better clinical management, treatment and counseling. In this study, we aimed to delineate and characterize the disease-causing mutations in Chinese familial and sporadic patients with initial diagnosis of RP. Four unrelated Chinese families and 118 sporadic RP patients were recruited for whole exome sequencing analysis. A total of 5 reported and 3 novel USH2A mutations were identified in four Chinese probands. The probands and their family members showed typical RP features and mild to severe hearing impairment, confirming the diagnosis of Usher syndrome 2 (USH). Moreover, 11 sporadic RP patients were identified to carry the compound heterozygous mutations in the USH2A gene, confirming the diagnosis of USH2. The patients carried the truncating mutations had a younger age of first visit than the patients carried only the missense mutations (p = 0.017). In summary, this study revealed 8 novel USH2A variants in Chinese familial and sporadic RP patients, assuring that whole exome sequencing analysis is an adequate strategy to facilitate the clinical diagnosis of USH from the sporadic RP patients.

Highlights

Usher syndrome (USH) is an autosomal recessive disorder characterized by retinitis pigmentosa (RP) and bilateral sensorineural hearing loss, with vestibular dysfunction in certain patients[1]
Four unrelated Chinese families initially diagnosed with RP were recruited, following the recessive inheritance (Fig. 1)
We identified 10 sporadic RP patients, out of 118 recruited subjects, carrying at least 2 compound heterozygous USH2A mutations (Table 3), confirming the diagnosis of USH2

Summary

Introduction

Usher syndrome (USH) is an autosomal recessive disorder characterized by retinitis pigmentosa (RP) and bilateral sensorineural hearing loss, with vestibular dysfunction in certain patients[1]. On the basis of the severity, the progression of hearing impairment and RP as well as the presence of vestibular dysfunction, USH can be divided into three clinical subtypes[5]. USH1, the most severe subtype of USH, is featured by the congenital hearing loss and vestibular dysfunction as well as the pubertal onset of progressive RP6. USH2, the most common subtype of USH accounting for more than 50% of all USH patients, is classified by the moderate to severe deafness and the pubertal onset of progressive RP, but with normal vestibular functions. USH3 patients exhibits progressive hearing loss, but has variable onset of RP and vestibular dysfunction[7]. The USH2A gene is the major disease-causing gene for USH2; yet, it can be relevant to non-syndromic RP or atypical USH11,14. The clinical correlation of the identified mutations was analyzed

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