Contribution of single-gene defects to congenital cardiac left-sided lesions in the prenatal setting
Contribution of single-gene defects to congenital cardiac left-sided lesions in the prenatal setting
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DOI：
10.1002/uog.21883
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发表时间：
2020-08-01
影响因子：
7.1
通讯作者：
He, Y.
中科院分区：
文献类型：
--
作者：
Sun, H.;Yi, T.;He, Y.
目的探讨单基因缺陷在心脏左侧病变(LSL)遗传病因中的作用，评价全外显子组测序(WES)对无非整倍体或致病拷贝数变异(PCNV)的LSLS胎儿单基因缺陷的增量诊断率。符合条件的LSL为主动脉瓣闭锁或狭窄、左心发育不良综合征(HLHS)。对这些胎儿及其父母的标本依次进行CNV测序(CNV-seq)和WES。CNV-seq用于鉴定非整倍体和pCNV，而Wes用于鉴定非整倍体或pCNV的诊断遗传变异。结果在本研究的80例孕妇中，27例(33.8%)有基因诊断。CNV-seq分析发现6例(7.5%)胎儿为非整倍体，8例(10.0%)为pCNV。对其余66例进行WES分析，发现13例(19.7%)存在诊断基因变异，表明WES对整个队列的诊断率为16.3%(13/80)。KMT2D是LSL中最常见的突变基因(7/66(10.6%))，其次是NOTCH1(4/66(6.1%))。在该队列中KMT2D突变的病例中，HLHS是最常见的心脏表型(4/7)。另有6例(9.1%)的候选基因存在潜在的有害变异。结论单基因缺陷与胎儿LSLS的遗传有关。在我们的胎儿队列中，KMT2D突变约占LSL的10%。WES有可能为无非整倍体或pCNV的LSL胎儿提供基因诊断。版权所有(C)2019 ISUOG。由John Wiley&Sons Ltd.出版。
Objectives To explore the contribution of single-gene defects to the genetic cause of cardiac left-sided lesions (LSLs), and to evaluate the incremental diagnostic yield of whole-exome sequencing (WES) for single-gene defects in fetuses with LSLs without aneuploidy or a pathogenic copy-number variant (pCNV).Methods Between 10 April 2015 and 30 October 2018, we recruited 80 pregnant women diagnosed with a LSL who had termination of pregnancy and genetic testing. Eligible LSLs were aortic valve atresia or stenosis, hypoplastic left heart syndrome (HLHS). CNVsequencing (CNV-seq) and WES were performed sequentially on specimens from these fetuses and their parents. CNV-seq was used to identify aneuploidies and pCNVs, while WES was used to identify diagnostic genetic variants in cases without aneuploidy or pCNV.Results Of 80 pregnancies included in the study, 27 (33.8%) had a genetic diagnosis. CNV-seq analysis identified six (7.5%) fetuses with aneuploidy and eight (10.0%) with pCNVs. WES analysis of the remaining 66 cases revealed diagnostic genetic variants in 13 (19.7%) cases, indicating that the diagnostic yield of WES for the entire cohort was 16.3% (13/80). KMT2D was the most frequently mutated gene (7/66 (10.6%)) in fetuses with LSL without aneuploidy or pCNVs, followed by NOTCH1 (4/66 (6.1%)). HLHS was the most prevalent cardiac phenotype (4/7) in cases with a KMT2D mutation in this cohort. An additional six (9.1%) cases were found to have potentially deleterious variants in candidate genes.Conclusions Single-gene defects contribute substantially to the genetic etiology of fetal LSLs. KMT2D mutations accounted for approximately 10% of LSLs in our fetal cohort. WEShas the potential to provide genetic diagnoses in fetuses with LSLs without aneuploidy or pCNVs. Copyright (C) 2019 ISUOG. Published by John Wiley & Sons Ltd.