Abstract：
Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent-offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with \'damaging\' in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases.
摘要：
先天性心脏病（CHD）是活出生儿童中最常见的先天性异常。与综合征性CHD(SCHD)相比，孤立性CHD（ICHD）的遗传基础复杂，潜在的致病机制似乎错综复杂，还没有完全理解。除了罕见的孟德尔病，大多数ICHD都假定体细胞镶嵌或复杂的多因素遗传结构。我们使用从心脏组织中提取的先证者DNA对73个亲代ICHD三重奏进行了外显子组测序（ES）。我们在发育中的人类心脏中表达的心脏相关基因的计算机预测中，鉴定了六个种系从头变异和625种系罕见遗传变异，具有“破坏性”。没有CHD相关的体细胞变异。传输不平衡测试（TDT）和关联测试（AT）没有统计学上的显着结果，除了纤毛基因中的错义变异的AT。体细胞突变不是ICHD的常见原因。罕见的从头和遗传性蛋白质损伤变异可能有助于ICHD，可能是寡基因或多基因疾病模型的一部分。TDT和AT未能提供信息结果，可能是由于缺乏力量,但为未来更大的队列研究提供了框架.总的来说,在个别ICHD病例中,ES对心脏组织的诊断价值有限.
