Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing
Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing
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DOI：
10.1371/journal.pone.0168966
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发表时间：
2016-12-22
期刊：
影响因子：
3.7
通讯作者：
Gonzalez-Duarte, Roser
中科院分区：
文献类型：
--
作者：
de Castro-Miro, Marta;Tonda, Raul;Gonzalez-Duarte, Roser
研究背景基于NGS的基因诊断彻底改变了人类遗传学领域。在这项研究中，我们的目的是确定新的基因和突变的全外显子组测序（WES）负责遗传性视网膜营养不良（IRD）。MethodsA队列的33个家系影响的各种视网膜疾病进行了分析WES。最初的优先级分析包括大约300个IRD相关基因。在非诊断的家庭进行了搜索的致病性突变的新genes.ResultsGenetic诊断达到18个家庭。此外，还为另外10种情况提出了一个合理的候选人。三分之二的突变是新的，包括4个染色体重排，这扩大了IRD等位基因异质性，并突出了私人突变的贡献。我们的研究结果促使临床重新评估一些患者，导致分配到综合征，而不是非综合征IRD。值得注意的是，WES公布了非综合征型IRD的四个新候选者：SEMA 6 B，CEP 78，CEP 250，SCLT 1，后两个先前与综合征型疾病相关。我们提供的功能数据支持CEP 250中的错义突变改变cilia formation.ConclusionThe诊断效率的WES，并严格按照ACMG/AMP标准是55%，在报告的致病基因或功能支持的新的候选人，加上30%的家庭，其中可能的致病性或VGUS/VUS变异体被确定在合理的候选人。我们的研究结果突出了WES用于IRD分子诊断的临床实用性，提供了更广泛的突变和伴随的遗传变异，并挑战了我们对综合征与非综合征，致病基因与修饰基因的观点。
BackgroundNGS-based genetic diagnosis has completely revolutionized the human genetics field. In this study, we have aimed to identify new genes and mutations by Whole Exome Sequencing (WES) responsible for inherited retinal dystrophies (IRD).MethodsA cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. Initial prioritization analysis included around 300 IRD-associated genes. In non-diagnosed families a search for pathogenic mutations in novel genes was undertaken.ResultsGenetic diagnosis was attained in 18 families. Moreover, a plausible candidate is proposed for 10 more cases. Two thirds of the mutations were novel, including 4 chromosomal rearrangements, which expand the IRD allelic heterogeneity and highlight the contribution of private mutations. Our results prompted clinical re-evaluation of some patients resulting in assignment to a syndromic instead of non-syndromic IRD. Notably, WES unveiled four new candidates for non-syndromic IRD: SEMA6B, CEP78, CEP250, SCLT1, the two latter previously associated to syndromic disorders. We provide functional data supporting that missense mutations in CEP250 alter cilia formation.ConclusionThe diagnostic efficiency of WES, and strictly following the ACMG/AMP criteria is 55% in reported causative genes or functionally supported new candidates, plus 30% families in which likely pathogenic or VGUS/VUS variants were identified in plausible candidates. Our results highlight the clinical utility of WES for molecular diagnosis of IRD, provide a wider spectrum of mutations and concomitant genetic variants, and challenge our view on syndromic vs non-syndromic, and causative vs modifier genes.