Whole exome sequencing identified novel CRB1 mutations in Chinese and Indian populations with autosomal recessive retinitis pigmentosa.

Yin Yang,Bo Gong,Xianjun Zhu,Zhenglin Yang,Jie Li,Periasamy Sundaresan,Yaru Zhai,Lulin Huang,Hao Fang,Zhilin Jiang,Ramasamy Kim,Yeming Yang,Yu Zhou

doi:10.1038/srep33681

Abstract

Retinitis pigmentosa (RP) is a leading cause of inherited blindness characterized by progressive degeneration of the retinal photoreceptor cells. This study aims to identify genetic mutations in a Chinese family RP-2236, an Indian family RP-IC-90 and 100 sporadic Indian individuals with autosomal recessive RP (arRP). Whole exome sequencing was performed on the index patients of RP-2236, RP-IC-90 and all of the 100 sporadic Indian patients. Direct Sanger sequencing was used to validate the mutations identified. Four novel mutations and one reported mutation in the crumbs homolog 1 (CRB1) gene, which has been known to cause severe retinal dystrophies, were identified. A novel homozygous splicing mutation c.2129-1G>C was found in the three patients In family RP-2236. A homozygous point mutation p.R664C was found in RP-IC-90. A novel homozygous mutation p.G1310C was identified in patient I-44, while novel compound heterozygous mutations p.N629D and p.A593T were found in patient I-7. All mutations described above were not present in the 1000 normal controls. In conclusion, we identified four novel mutations in CRB1 in a cohort of RP patients from the Chinese and Indian populations. Our data enlarges the CRB1 mutation spectrums and may provide new target loci for RP diagnose and treatment.

Highlights

Central vision and legal blindness[1]
A Chinese family with three patients affected with retinitis pigmentosa, an Indian family with one patient affected with retinitis pigmentosa, 100 sporadic Indian Retinitis pigmentosa (RP) patients and 1000 normal control were recruited in the study (Fig. 1)
Representative clinical features of patient IV:[2] in the Chinese family RP-2236. (A) Fundus photographs showed the loss of pigment epithelial with narrowed arterioles, pale optic disk and irregular pigment clumps with both peripheral retina and macula involved in both eyes. (B) fundus fluorescein angiography (FFA) images showed extensive transmitted and blocked fluorescence due to loss of pigment epithelium with scattered pigment clumps. (C) multifocal electroretinography (mfERG) records showed weak response under neither scotopic nor photopic condition, especially at the peripheral retina

Summary

Introduction

Due to its high heterogeneity and diversity of inheritance patterns, the clinical presentation of RP is much variable and the molecular diagnosis of syndromic and non-syndromic RP is very challenging. Autosomal recessive RP (arRP) is the most common form of RP worldwide and 36 genes/loci have been associated with autosomal recessive RP (RetNet) to date. These mutations can only explain about 50–60% of RP cases and the heritability of 40% of the total RP cases worldwide remains unknown[4]. The new next-generation sequencing (NGS) technology has been successfully used for the molecular diagnosis and gene identification of disease genes[5,6]. With the aim of investigating novel mutations in the RP disease, we performed whole exome sequencing in a Chinese family RP-2236, an Indian family RP-IC-90 and 100 sporadic Indian individuals with autosomal recessive RP (arRP)

Objectives

Methods

Results

Conclusion