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Exome Sequencing Identifies Compound Heterozygous Mutations in CYP4V2 in a Pedigree with Retinitis Pigmentosa

Yun Wang , Liheng Guo , Su-Ping Cai , Meizhi Dai , Qiaona Yang, Wenhan Yu, Naihong Yan, Xiaomin Zhou, Jin Fu, Xinwu Guo, Pengfei Han, Jun Wang, Xuyang Liu | PLOS One | 31 May 2012 | doi.org/10.1371/journal.pone.0033673


Abstract

Retinitis pigmentosa (RP) is a heterogeneous group of progressive retinal degenerations characterized by pigmentation and atrophy in the mid-periphery of the retina. Twenty two subjects from a four-generation Chinese family with RP and thin cornea, congenital cataract and high myopia is reported in this study. All family members underwent complete ophthalmologic examinations. Patients of the family presented with bone spicule-shaped pigment deposits in retina, retinal vascular attenuation, retinal and choroidal dystrophy, as well as punctate opacity of the lens, reduced cornea thickness and high myopia. Peripheral venous blood was obtained from all patients and their family members for genetic analysis. After mutation analysis in a few known RP candidate genes, exome sequencing was used to analyze the exomes of 3 patients III2, III4, III6 and the unaffected mother II2. A total of 34,693 variations shared by 3 patients were subjected to several filtering steps against existing variation databases. Identified variations were verified in the rest family members by PCR and Sanger sequencing. Compound heterozygous c.802-8_810del17insGC and c.1091-2A>G mutations of the CYP4V2 gene, known as genetic defects for Bietti crystalline corneoretinal dystrophy, were identified as causative mutations for RP of this family.


Introduction

Retinitis pigmentosa (RP) is a heterogeneous group of progressive retinal degenerations characterized typically by pigmentation and atrophy in the mid-periphery of the retina. It was estimated to affect 1 in 3500 in the general population [1], [2]. Symptoms for RP include night blindness, tunnel vision and bone-spicule pigmentation in retina.


Considerable clinical and genetic heterogeneity was demonstrated in RP patients, with wide variations in age of onset, severity, clinical phenotype, rate of progression and pattern of inheritance. Genotype-phenotype correlations are not strong enough to predict for RP. About 20–30% of patients with RP also presented with non-ocular disorders such as hearing loss, obesity, and cognitive impairment. Such cases fall within more than 30 different syndromes [3].


Over 50 genes have been identified to cause RP, but still only explain no more than half of the clinical cases [3]. Therefore, there has been limited success with approaches of screening of known candidate genes for RP by conventional Sanger sequencing. Fortunately, exome sequencing technique has come to the aid by enabling the identification of disease-associated mutations by sequencing the whole exome of a small number of affected individuals [4]–[6].


In the present study, disease-associated mutations were identified in a large Chinese family with RP complicated with congenital cataract, corneal thinning and high myopia using the exome sequencing techniques.



 

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