Variants of Anterior Segment Dysgenesis and Cerebral Involvement in a Large Family With a Novel COL4A1 Mutation
Variants of Anterior Segment Dysgenesis and Cerebral Involvement in a Large Family With a Novel COL4A1 Mutation
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DOI：
10.1016/j.ajo.2012.11.028
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发表时间：
2013-05-01
影响因子：
4.2
通讯作者：
Boman, Helge
中科院分区：
文献类型：
--
作者：
Rodahl, Eyvind;Knappskog, Per M.;Boman, Helge
目的：研究一个常染色体显性前段发育不良并伴有脑血管疾病的大家族的多种眼部表现，并确定其致病突变。设计：回顾性观察病例系列和实验室调查。方法：对家族4代45人进行眼科检查。分子遗传学研究包括单核苷酸多态性（SNP）标记分析和DNA测序。在1个个体中进行全外显子组测序。结果：观察到广泛的眼部表现。典型病例表现为角膜混浊、前粘连、虹膜发育不全。胚胎后毒瘤、矫正眼和早期白内障也可见。一个专性携带者和其他几个家庭成员有轻微的眼部异常，从而混淆了受影响和未受影响的个体的评分。4例发生脑出血，其中3例在出生时或出生后第一年发生。在关联研究中，7例角膜混浊患者被认为“肯定受到影响”。单倍型图谱显示，它们在染色体13q末端共享一个14cm的区域，该区域包含COL4A1的位点。受影响的家庭成员是一种新的COL4A1序列变异c.4881C > G （p.Asn1627Lys）的杂合，预计具有破坏性，在185名当地献血者中未发现。外显子组测序结果显示，该变异是候选区域中唯一未在dbSNP中发现的变异。结论：在携带COL4A1突变的家族成员中，前段发育不良的表现具有异质性。在临床表现难以分类的患者中，对家庭成员进行这种突变检测也使明确诊断成为可能。在前段发育不良合并脑出血的家庭中，应考虑COL4A1的遗传分析。[J]中华眼科杂志，2013;16(5):946-953。(C)爱思唯尔公司2013年版权所有。)
PURPOSE: To investigate the diverse ocular manifestations and identify the causative mutation in a large family with autosomal dominant anterior segment dysgenesis accompanied in some individuals by cerebral vascular disease.DESIGN: Retrospective observational case series and laboratory investigation.METHODS: Forty-five family members from 4 generations underwent ophthalmic examination. Molecular genetic investigation included analysis with single nucleotide polymorphism (SNP) markers and DNA sequencing. Whole exome sequencing was performed in 1 individual.RESULTS: A broad range of ocular manifestations was observed. Typical cases presented with corneal clouding, anterior synechiae, and iris hypoplasia. Posterior embryo-toxon, corectopia, and early cataract development were also seen. One obligate carrier and several other family members had minor ocular anomalies, thus confounding the scoring of affected and unaffected individuals. Cerebral hemorrhages had occurred in 4 individuals, in 3 at birth or during the first year of life. Seven patients with corneal clouding were considered "definitely affected" for linkage studies. Haplotype mapping revealed that they shared a 14 cM region in the terminal part of chromosome 13q that included the locus for COL4A1. The affected family members were heterozygous for a novel COL4A1 sequence variant c.4881C > G (p.Asn1627Lys) predicted to be damaging and not found among 185 local blood donors. Exome sequencing showed that this variant was the only one in the candidate region not found in dbSNP.CONCLUSION: Among the family members shown to carry the novel COL4A1 mutation, heterogenous presentations of anterior segment dysgenesis was seen. Testing family members for this mutation also made a definite diagnosis possible in patients with a clinical presentation difficult to classify. In families where anterior segment dysgenesis occurs together with cerebral hemorrhages, genetic analysis of COL4A1 should be considered. (Am J Ophthalmol 2013;155:946-953. (C) 2013 by Elsevier Inc. All rights reserved.)