Identification of genetic defects in 33 probands with Stargardt disease by WES-based bioinformatics gene panel analysis

Stargardt disease (STGD) is the most common hereditary macular degeneration in juveniles, with loss of central vision occurring in the first or second decade of life. The aim of this study is to identify the genetic defects in 33 probands with Stargardt disease. Clinical data and genomic DNA were collected from 33 probands from unrelated families with STGD. Variants in coding genes were initially screened by whole exome sequencing. Candidate variants were selected from all known genes associated with hereditary retinal dystrophy and then confirmed by Sanger sequencing. Putative pathogenic variants were further validated in available family members and controls. Potential pathogenic mutations were identified in 19 of the 33 probands (57.6%). These mutations were all present in ABCA4, but not in the other four STGD-associated genes or in genes responsible for other retinal dystrophies. Of the 19 probands, ABCA4 mutations were homozygous in one proband and compound heterozygous in 18 probands, involving 28 variants (13 novel and 15 known). Analysis of normal controls and available family members in 12 of the 19 families further support the pathogenicity of these variants. Clinical manifestation of all probands met the diagnostic criteria of STGD. This study provides an overview of a genetic basis for STGD in Chinese patients. Mutations in ABCA4 are the most common cause of STGD in this cohort. Genetic defects in approximately 42.4% of STGD patients await identification in future studies.

斯塔加德特病（Stargardt disease, STGD）是青少年群体中最常见的遗传性黄斑变性，患者通常于人生的第一个或第二个十年出现中心视力丧失。本研究旨在鉴定33例斯塔加德特病先证者的遗传缺陷。研究人员收集了33个无关斯塔加德特病家系先证者的临床资料与基因组DNA。首先通过全外显子测序（whole exome sequencing）筛选编码基因变异，从所有已知遗传性视网膜营养不良相关基因中筛选候选变异，随后通过桑格测序（Sanger sequencing）进行验证。对可获取的家系成员与对照样本中的疑似致病变异开展进一步验证。33例先证者中，19例（57.6%）检出潜在致病突变，此类突变均位于ABCA4基因，未在其余4个斯塔加德特病相关基因或其他视网膜营养不良致病基因中发现。在19例先证者中，1例为ABCA4纯合突变，18例为复合杂合突变，共涉及28个变异位点（13个为新发变异，15个为已知变异）。对19个家系中的12个家系的正常对照与可获取家系成员的分析，进一步支持了上述变异的致病性。所有先证者的临床表现均符合斯塔加德特病的诊断标准。本研究概述了中国人群斯塔加德特病的遗传基础，ABCA4基因突变是本队列中斯塔加德特病最常见的致病原因。约42.4%的斯塔加德特病患者的遗传缺陷有待后续研究进一步明确。