Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia.
Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia.
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DOI：
10.1111/cge.12379
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发表时间：
2014-11
影响因子：
3.5
通讯作者：
Semina EV
中科院分区：
文献类型：
--
作者：
Deml B;Reis LM;Maheshwari M;Griffis C;Bick D;Semina EV
无眼球/小眼球(A/M)是一种发育性眼畸形，定义为完全不存在或眼睛大小变小。A/M是一种异质性疾病，有许多致病基因被发现；然而，大约一半的病例缺乏分子诊断。我们在一个A/M家系中进行了完整的外显子组测序，其中有两个患病的兄弟姐妹，两个未患病的兄弟姐妹，以及未受影响的父母；眼部表型被分离，仅有轻度发育迟缓/学习困难的报道，先证者在16个月时脑部MRI正常。71个已知的A/M基因未发现致病突变。进一步分析发现COL4A1，c.2317G>；A，p.(Gly773Arg)有一个共同的杂合子突变，在未患病的父母和兄弟姐妹中没有发现。对24个不相关的A/M外显子的分析发现，在另一例单侧小眼炎、双侧小角膜、青光眼和Peter畸形的患者中，发现了一种新的c.2122G>；A，p.(Gly708Arg)突变；该突变在未受影响的母亲中缺失，未受影响的父亲不存在。COL4A1的突变与一系列人类疾病有关；最一致的特征是脑血管疾病，伴有各种眼畸形、肾脏和肌肉缺陷。这项研究扩大了COL4A1表型的范围，并建议对A/M患者进行筛查，而不考虑MRI表现或推测的遗传模式。
Anophthalmia/microphthalmia (A/M) is a developmental ocular malformation defined as complete absence or reduction in size of the eye. A/M is a heterogeneous disorder with numerous causative genes identified; however, about half the cases lack a molecular diagnosis. We undertook whole exome sequencing in an A/M family with two affected siblings, two unaffected siblings, and unaffected parents; the ocular phenotype was isolated with only mild developmental delay/learning difficulties reported and a normal brain MRI in the proband at 16 months. No pathogenic mutations were identified in 71 known A/M genes. Further analysis identified a shared heterozygous mutation in COL4A1, c.2317G>A, p.(Gly773Arg) that was not seen in the unaffected parents and siblings. Analysis of twenty-four unrelated A/M exomes identified a novel c.2122G>A, p.(Gly708Arg) mutation in an additional patient with unilateral microphthalmia, bilateral microcornea, glaucoma and Peters anomaly; the mutation was absent in the unaffected mother and the unaffected father was not available. Mutations in COL4A1 have been linked to a spectrum of human disorders; the most consistent feature is cerebrovascular disease with variable ocular anomalies, kidney and muscle defects. This study expands the spectrum of COL4A1 phenotypes and indicates screening in patients with A/M regardless of MRI findings or presumed inheritance pattern.
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