全基因组测序揭示了连接蛋白 46（GJA3）基因中的一个反复出现的错义突变，导致常染色体显性板层白内障。
Whole-genome sequencing reveals a recurrent missense mutation in the Connexin 46 (GJA3) gene causing autosomal-dominant lamellar cataract.
机构信息
UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK.
Moorfields Eye Hospital, London, EC1V 2PD, UK.
出版信息
Eye (Lond). 2018 May 1;32(10):1661-1668. doi: 10.1038/s41433-018-0154-8.
PURPOSE
Congenital cataract, opacification of the ocular lens, is clinically and genetically a heterogeneous childhood disease. In this study we aimed to identify the underlying genetic cause of isolated autosomal-dominant lamellar cataract in a multi-generation English family.
METHODS
Whole-genome sequencing (WGS) was undertaken in two affected subjects and one unaffected individual. Segregation analysis was performed and a known cataract-causing mutation was identified. Segregation was further validated by sanger sequencing in the entire pedigree.
RESULTS
A heterozygous mutation c.7 G > T; p.D3Y was identified in an NH-terminal region of the gap junction protein GJA3 and found to co-segregate with disease.
CONCLUSION
We have identified a recurrent mutation in GJA3 in a large British pedigree causing the novel phenotype of autosomal-dominant congenital lamellar cataract. Previously, p.D3Y was found in a Hispanic family causing pulverulent cataract. WGS proved an efficient method to find the underlying molecular cause in this large family, which could not be mapped due to uninformative markers.
目的
先天性白内障是一种临床和遗传上异质性的儿童疾病，表现为眼球晶状体混浊。本研究旨在确定一个英国家系中常染色体显性板层白内障的潜在遗传病因。
方法
对 2 名受累者和 1 名无病个体进行全基因组测序（WGS）。进行分离分析，并确定已知的致白内障突变。对整个家系进行 Sanger 测序以进一步验证分离。
结果
在间隙连接蛋白 GJA3 的 NH2 末端区域发现了杂合突变 c.7G>T;p.D3Y，该突变与疾病共分离。
结论
我们在一个大型英国家系中发现了 GJA3 中的一个复发性突变，导致常染色体显性先天性板层白内障的新表型。此前，p.D3Y 曾在一个西班牙裔家庭中发现，导致白内障呈粉末状。WGS 证明了一种有效的方法，可以在这个由于无信息标记而无法定位的大家庭中找到潜在的分子病因。
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