Department of Genetics, Ucl Institute of Ophthalmology, University College London, London, UK.
Moorfields Eye Hospital NHS Foundation Trust, London, UK.
Ophthalmic Genet. 2022 Apr;43(2):218-223. doi: 10.1080/13816810.2021.1998556. Epub 2021 Nov 8.
Congenital cataracts are the most common cause of visual impairment worldwide. Inherited cataract is a clinically and genetically heterogeneous disease. Here we report disease-causing variants in a novel gene, , causing autosomal dominant posterior polar cataract. Variants in this gene are known to cause autosomal recessive congenital adrenal hyperplasia (CAH).
Using whole-exome sequencing (WES), we have identified disease-causing sequence variants in two families of British and Irish origin, and in two isolated cases of Asian-Indian and British origin. Bioinformatics analysis confirmed these variants as rare with damaging pathogenicity scores. Segregation was tested within the families using direct Sanger sequencing.
A nonsense variant NM_000500.9 c.955 C > T; p.Q319* was identified in in two families with posterior polar cataract and in an isolated case with unspecified congenital cataract phenotype. This is the same variant previously linked to CAH and identified as Q318* in the literature. We have also identified a rare missense variant NM_000500.9 c.770 T > C; p.M257T in an isolated case with unspecified congenital cataract phenotype.
This is the first report of separate sequence variants in associated with congenital cataract. Our findings extend the genetic basis for congenital cataract and add to the phenotypic spectrum of variants and particularly the CAH associated Q318* variant. CYP21A2 has a significant role in mineralo- and gluco-corticoid biosynthesis. These findings suggest that CYP21A2 may be important for extra-adrenal biosynthesis of aldosterone and cortisol in the eye lens.
先天性白内障是全球范围内导致视力损害的最常见原因。遗传性白内障是一种临床表现和遗传异质性疾病。本研究报告了一个新基因 中的致病变异，导致常染色体显性后极性白内障。该基因的变异已知可引起常染色体隐性先天性肾上腺增生症（CAH）。
使用全外显子组测序（WES），我们在两个具有英裔和爱尔兰血统的家族以及两个具有亚洲裔和英裔血统的孤立病例中发现了致病的序列变异。生物信息学分析证实这些变异是罕见的，具有破坏性的致病性评分。使用直接 Sanger 测序在家族内进行了遗传分离测试。
在两个具有后极性白内障的家族和一个具有未指定先天性白内障表型的孤立病例中，发现了一个无义变异 NM_000500.9 c.955 C>T;p.Q319*，该变异与先前与 CAH 相关的变异相同，并在文献中被鉴定为 Q318*。我们还在一个具有未指定先天性白内障表型的孤立病例中发现了一个罕见的错义变异 NM_000500.9 c.770 T>C;p.M257T。
这是第一个报道与先天性白内障相关的 基因中存在不同序列变异的研究。我们的研究结果扩展了先天性白内障的遗传基础，并增加了 变异的表型谱，特别是与 CAH 相关的 Q318*变异。CYP21A2 在矿皮质和糖皮质激素生物合成中具有重要作用。这些发现表明，CYP21A2 可能在眼睛晶状体中对醛固酮和皮质醇的肾上腺外生物合成很重要。
