Whole exome sequencing in a large pedigree with DCM identifies a novel mutation in RBM20.
Whole exome sequencing in a large pedigree with DCM identifies a novel mutation in RBM20.
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对 DCM 大谱系的全外显子组测序发现了 RBM20 的新突变。
DOI：
10.1080/00015385.2019.1674490
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发表时间：
2020
影响因子：
1.6
通讯作者：
Corveleyn,Anniek
中科院分区：
文献类型：
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作者：
Robyns,Tomas;Willems,Rik;VanCleemput,Johan;Jhangiani,Shalini;Muzny,Donna;Gibbs,Richard;Lupski,JamesR;Breckpot,Jeroen;Devriendt,Koenraad;Corveleyn,Anniek
背景：家族性扩张型心肌病（DCM）具有遗传异质性，至少与40个不同基因的突变有关。除了编码巨大蛋白Titin的TTN外，这些基因中没有一个具有超过5%的预期诊断率，使遗传诊断复杂化。全外显子组测序（WES）是鉴定致病基因的一种强有力的替代方法，但变异解释仍然具有挑战性。我们报告WES在一个大的家庭与常染色体显性DCM并发终末期心力衰竭和非持续性室性心律失常，其中没有致病突变被确定使用靶向基因面板，包括28 genes.Methods和results：WES应用于2受影响的堂兄弟。对鉴定的遗传变异进行严格过滤，包括群体变异频率、计算机模拟分析、直系同源和旁系同源保守。随后，对10种潜在致病变体进行桑格测序，以确认变体的存在并评价共分离。仅RBM20基因的外显子9中的一个变体（c.2714T > A，p.Met950Lys，NM_001334363）在7个受影响的家族成员中显示完全共分离，导致最大2点LOD得分为2.1，并表明这是导致表型的致病性突变。最近RBM20的突变已被链接到致炎性扩张型心肌病所造成的巨大的肌节蛋白titin和异常钙handling.Conclusions：我们报告了一个新的突变RBM20 WES在一个大的DCM家系鉴定。
Background:Familial dilated cardiomyopathy (DCM) is genetically heterogeneous and is associated with mutations in at least 40 different genes. Apart fromTTNencoding the giant protein Titin, none of these genes have an expected diagnostic yield of more than 5% complicating genetic diagnosis. Whole exome sequencing (WES) is a powerful alternative for the identification of the causal gene, however variant interpretation remains challenging. We report on WES in a large family with autosomal dominant DCM complicated by end stage heart failure and non-sustained ventricular arrhythmias in whom no causative mutation was identified using a targeted gene panel including 28 genes.Methods and results:WES was applied on 2 affected cousins. Stringent filtering of the identified genetic variants was performed including population variant frequencies, in silico analysis, orthologous and paralogous conservation. Subsequently Sanger sequencing was performed for 10 potential disease causing variants in order to confirm the presence of the variant and to evaluate co-segregation. Only one variant in exon 9 of the RBM20 gene (c.2714T > A, p.Met950Lys, NM_001334363) showed full co-segregation in the 7 affected family members resulting in a maximum 2-point LOD score of 2.1 and suggesting this as the pathogenic mutation responsible for the phenotype. Recently mutations in RBM20 have been linked to arrhythmogenic dilated cardiomyopathy caused by defective splicing of the giant sarcomere protein titin and abnormal calcium handling.Conclusions:We report the identification of a novel mutation in RBM20 by WES in a large pedigree with DCM.