PDF(Pubmed)
Abstract：
Atrioventricular septal defect (AVSD) is a deleterious subtype of congenital heart diseases (CHD) characterized by atrioventricular canal defect. The pathogenic genetic changes of AVSD remain elusive, particularly for copy number variation (CNV), a large segment variation of the genome, which is one of the major forms of genetic variants resulting in congenital heart diseases. In the present study, we recruited 150 AVSD cases and 100 healthy subjects as controls for whole exome sequencing (WES). We identified total 4255 rare CNVs using exon Hidden Markov model (XHMM) and screened rare CNVs by eliminating common CNVs based on controls and Database of Genomic Variants (DGV). Each patient contained at least 9 CNVs, and the CNV burden was prominently presented in chromosomes 19,22,21&16. Small CNVs (<500 kb) were frequently observed. By leveraging gene-based burden test, we further identified 20 candidate AVSD-risk genes. Among them, DYRK1A, OBSCN and TTN were presented in the core disease network of CHD and highly and dynamically expressed in the heart during the development, which indicated they possessed the high potency to be AVSD-susceptible genes. These findings not only provided a roadmap for finally unveiling the genetic cause of AVSD, but also provided more resources and proofs for clinical genetics.
摘要：
房室间隔缺损（AVSD）是先天性心脏病（CHD）的一种有害亚型，其特征是房室道缺损。AVSD的致病基因变化仍然难以捉摸，特别是对于拷贝数变异(CNV)，基因组的大部分变异，这是导致先天性心脏病的主要遗传变异形式之一。在本研究中,我们招募了150例AVSD病例和100例健康受试者作为全外显子组测序(WES)的对照.我们使用外显子隐马尔可夫模型（XHMM）鉴定了总共4255个稀有CNV，并通过基于对照和基因组变异数据库（DGV）消除常见CNV来筛选稀有CNV。每位患者至少含有9个CNVs,CNV负担主要存在于19,22,21和16号染色体中。经常观察到小CNV(<500kb)。通过利用基于基因的负担测试，我们进一步确定了20个候选AVSD风险基因.其中,DYRK1A,OBSCN和TTN存在于CHD的核心疾病网络中，并在发育过程中在心脏中高度动态地表达，这表明它们具有AVSD易感基因的高效力。这些发现不仅为最终揭示AVSD的遗传原因提供了路线图，也为临床遗传学提供了更多的资源和证据。
