De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa.
De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa.
复制标题
从从头出现ARL3和色素性视网膜炎的明显常染色体显性传播。
DOI：
10.1371/journal.pone.0150944
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gorin MB
中科院分区：
文献类型：
--
作者：
Strom SP;Clark MJ;Martinez A;Garcia S;Abelazeem AA;Matynia A;Parikh S;Sullivan LS;Bowne SJ;Daiger SP;Gorin MB
视网膜色素变性是一种表型与不同的遗传原因。由于这种遗传异质性，通过外显子组测序对改变蛋白质的DNA变体进行全基因组鉴定和分析是发现新变体和疾病基因的有力工具。在这项研究中，外显子组测序分析被用来寻找潜在的因果DNA变异的两代家系与明显的显性视网膜色素变性。通过外显子组测序对三个受影响的成员（母亲和两个受影响的后代）进行变异鉴定和分析。索引病例的父母样本用于确定遗传。通过回顾性分析或桑格测序对另外94个视网膜色素变性家系进行随访检测。共鉴定出123个基因的136个高质量编码变异，这些变异与常染色体显性遗传病一致。其中，最强的遗传和功能候选者之一是ARL3中的c.269A>G（p.Tyr90Cys）变体。后续测试确定，该变体在指示病例中重新出现。在随访队列中未发现ARL3中其他假定的因果变异，这表明如果ARL3变异可导致adRP，则这是一种极其罕见的现象。
Retinitis pigmentosa is a phenotype with diverse genetic causes. Due to this genetic heterogeneity, genome-wide identification and analysis of protein-altering DNA variants by exome sequencing is a powerful tool for novel variant and disease gene discovery. In this study, exome sequencing analysis was used to search for potentially causal DNA variants in a two-generation pedigree with apparent dominant retinitis pigmentosa. Variant identification and analysis of three affected members (mother and two affected offspring) was performed via exome sequencing. Parental samples of the index case were used to establish inheritance. Follow-up testing of 94 additional retinitis pigmentosa pedigrees was performed via retrospective analysis or Sanger sequencing. A total of 136 high quality coding variants in 123 genes were identified which are consistent with autosomal dominant disease. Of these, one of the strongest genetic and functional candidates is a c.269A>G (p.Tyr90Cys) variant in ARL3. Follow-up testing established that this variant occurred de novo in the index case. No additional putative causal variants in ARL3 were identified in the follow-up cohort, suggesting that if ARL3 variants can cause adRP it is an extremely rare phenomenon.