Exome Sequencing Analysis Identifies Compound Heterozygous Mutation in ABCA4 in a Chinese Family with Stargardt Disease

Yu Zhou,Zhenglin Yang,Xianjun Zhu,Xiong Zhu,Fang Hao,Zhili Wang,He Lin,Liya Wang,Hui Chen,Lulin Huang,Siyu Tao,Youping Li

doi:10.1371/journal.pone.0091962

Abstract

Stargardt disease is the most common cause of juvenile macular dystrophy. Five subjects from a two-generation Chinese family with Stargardt disease are reported in this study. All family members underwent complete ophthalmologic examinations. Patients of the family initiated the disease during childhood, developing progressively impaired central vision and bilateral atrophic macular lesions in the retinal pigmental epithelium (RPE) that resembled a “beaten-bronze” appearance. Peripheral venous blood was obtained from all patients and their family members for genetic analysis. Exome sequencing was used to analyze the exome of two patients II1, II2. A total of 50709 variations shared by the two patients were subjected to several filtering steps against existing variation databases. Identified variations were verified in all family members by PCR and Sanger sequencing. Compound heterozygous variants p.Y808X and p.G607R of the ATP-binding cassette, sub-family A (ABC1), member 4 (ABCA4) gene, which encodes the ABCA4 protein, a member of the ATP-binding cassette (ABC) transport superfamily, were identified as causative mutations for Stargardt disease of this family. Our findings provide one novel ABCA4 mutation in Chinese patients with Stargardt disease.

Highlights

Stargardt disease (STGD), which is known as juvenile macular degeneration, was first reported by Karl Stargardt in 1909
Stargardt disease is associated with significant loss in photoreceptor cells and a massive deposition of lipofuscin-like material in the retinal pigment epithelium, which has been observed in aging human eyes [6,7]
We focused only on the functional SNP/Indel, including non-synonymous variants (NS), splice acceptor and donor site mutations (SS), and frameshift coding-region insertions or deletions (Indels), which were more likely to be pathogenic than others, especially those in homozygous or multiple heterozygous status

Summary

Introduction

Stargardt disease (STGD), which is known as juvenile macular degeneration, was first reported by Karl Stargardt in 1909. It is one of the most common hereditary retinal dystrophies with an estimated prevalence of at least 1:10,000 [1,2,3]. Fundus examination is frequently normal early in the course of disease, even when patients already complain of vision loss. At this stage, the clinical diagnosis of Stargardt disease may be missed. Stargardt disease is associated with significant loss in photoreceptor cells and a massive deposition of lipofuscin-like material in the retinal pigment epithelium, which has been observed in aging human eyes [6,7]

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Results

Conclusion