In Silico Functional Meta-Analysis of 5,962 ABCA4 Variants in 3,928 Retinal Dystrophy Cases
In Silico Functional Meta-Analysis of 5,962 ABCA4 Variants in 3,928 Retinal Dystrophy Cases
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DOI：
10.1002/humu.23165
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发表时间：
2017-04-01
期刊：
影响因子：
3.9
通讯作者：
Cremers, Frans P. M.
中科院分区：
文献类型：
--
作者：
Cornelis, Stephanie S.;Bax, Nathalie M.;Cremers, Frans P. M.
ABCA4基因的变异与一系列遗传性视网膜疾病(IRD)有关，最突出的是常染色体隐性遗传(AR)Stargardt病(STGD1)和AR视锥-视杆营养不良。临床结果在很大程度上取决于变异的严重程度。为了提供准确的预后和选择新的治疗方法，对非截断ABCA4变异体的功能意义评估是重要的。我们从莱顿开放变异数据库中收集了3928例视网膜营养不良患者中所有已发表的ABCA4变异，并比较了它们在3270名高加索IRD病例和33370名非芬兰欧洲对照个体中的频率。除了270个蛋白质截断变异体外，191个非截断变异体在患者队列中显著丰富。此外，30个变种被认为是良性的。根据对照个体的等位基因频率对IRD病例中频繁变异的纯合子发生进行评估，证实了p.[Gly863Ala，Gly863del]变异的轻微性质，并发现了另外三个轻微变异(p.(Ala1038Val)，c.5714+5G>；A和p.(Arg2030Gln))。在大多数情况下，P.(Gly1961Glu)变异被预测为一种轻微的变异。基于这些数据，在计算机分析和美国医学遗传学和基因组学指南中，我们为ABCA4-LOVD数据库中的所有变异提供了从良性到致病性的五级病原性分类。(C)2017威利期刊公司。
Variants in the ABCA4 gene are associated with a spectrum of inherited retinal diseases (IRDs), most prominently with autosomal recessive (ar) Stargardt disease (STGD1) and ar cone-rod dystrophy. The clinical outcome to a large degree depends on the severity of the variants. To provide an accurate prognosis and to select patients for novel treatments, functional significance assessment of nontruncating ABCA4 variants is important. We collected all published ABCA4 variants from 3,928 retinal dystrophy cases in a Leiden Open Variation Database, and compared their frequency in 3,270 Caucasian IRD cases with 33,370 non-Finnish European control individuals. Next to the presence of 270 protein-truncating variants, 191 nontruncating variants were significantly enriched in the patient cohort. Furthermore, 30 variants were deemed benign. Assessing the homozygous occurrence of frequent variants in IRD cases based on the allele frequencies in control individuals confirmed the mild nature of the p.[Gly863Ala, Gly863del] variant and identified three additional mild variants (p.(Ala1038Val), c.5714+5G>A, and p.(Arg2030Gln)). The p.(Gly1961Glu) variant was predicted to act as a mild variant in most cases. Based on these data, in silico analyses, and American College of Medical Genetics and Genomics guidelines, we provide pathogenicity classifications on a five-tier scale from benign to pathogenic for all variants in the ABCA4-LOVD database. (C) 2017 Wiley Periodicals, Inc.