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Abstract：
Pediatric cataract is clinically and genetically heterogeneous and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome sequencing. We identified four different heterozygous variants, three in the large families and one in the isolated case. Family A, with a novel missense variant (c.178G>C, p.Gly60Arg) in GJA8 with lamellar cataract; family B, with a recurrent variant in GJA8 (c.262C>T, p.Pro88Ser) associated with nuclear cataract; and family C, with a novel variant in GJA3 (c.771dupC, p.Ser258GlnfsTer68) causing a lamellar phenotype. Individual D had a novel variant in GJA3 (c.82G>T, p.Val28Leu) associated with congenital cataract. Each sequence variant was found to co-segregate with disease. Here, we report three novel and one recurrent disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract. Our study further extends the mutation spectrum of these genes and further facilitates clinical diagnosis. A recurrent p.P88S variant in GJA8 causing isolated nuclear cataract provides evidence of further phenotypic heterogeneity associated with this variant.
摘要：
小儿白内障在临床上和遗传上是异质性的，是全世界儿童失明的最常见原因。在这项研究中,我们的目的是在三个英国大家族和一个孤立的常染色体显性先天性白内障病例中确定致病变异，使用全外显子组测序。我们鉴定了四种不同的杂合变体，三个在大家庭中，一个在孤立的情况下。家庭A,具有新颖的错义变体(c.178G>C，p.Gly60Arg）在GJA8伴层状白内障中；家族B，在GJA8中具有复发性变体(c.262C>T，p.Pro88Ser)与核性白内障相关；和C族，在GJA3中有一个新的变体(c.771dupC，p.Ser258GlnfsTer68）引起层状表型。个体D在GJA3中有一个新的变体(c.82G>T，p.Val28Leu）与先天性白内障相关。发现每个序列变体与疾病共分离。这里,我们报道了导致常染色体显性遗传先天性白内障的间隙连接蛋白编码基因中3个新的和1个复发性致病序列变异。我们的研究进一步扩展了这些基因的突变谱，进一步促进了临床诊断。GJA8中复发的p.P88S变体导致孤立的核性白内障提供了与该变体相关的进一步表型异质性的证据。
