Costain Gregory, Silversides Candice K, Bassett Anne S
Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Medical Genetics Residency Training Program, University of Toronto and Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
NPJ Genom Med. 2016 Sep 14;1:16031. doi: 10.1038/npjgenmed.2016.31.
Congenital heart disease (CHD) is the most common class of major malformations in humans. The historical association with large chromosomal abnormalities foreshadowed the role of submicroscopic rare copy number variations (CNVs) as important genetic causes of CHD. Recent studies have provided robust evidence for these structural variants as genome-wide contributors to all forms of CHD, including CHD that appears isolated without extra-cardiac features. Overall, a CNV-related molecular diagnosis can be made in up to one in eight patients with CHD. These include and inherited variants at established (chromosome 22q11.2), emerging (chromosome 1q21.1), and novel loci across the genome. Variable expression of rare CNVs provides support for the notion of a genetic spectrum of CHD that crosses traditional anatomic classification boundaries. Clinical genetic testing using genome-wide technologies (e.g., chromosomal microarray analysis) is increasingly employed in prenatal, paediatric and adult settings. CNV discoveries in CHD have translated to changes to clinical management, prognostication and genetic counselling. The convergence of findings at individual gene and at pathway levels is shedding light on the mechanisms that govern human cardiac morphogenesis. These clinical and research advances are helping to inform whole-genome sequencing, the next logical step in delineating the genetic architecture of CHD.
先天性心脏病（CHD）是人类最常见的一类主要畸形。其与大型染色体异常的历史关联预示着亚微观罕见拷贝数变异（CNV）作为CHD重要遗传病因的作用。最近的研究为这些结构变异作为全基因组范围内导致各种形式CHD的因素提供了有力证据，包括那些看似孤立且无心脏外特征的CHD。总体而言，高达八分之一的CHD患者可做出与CNV相关的分子诊断。这些包括已确定位点（22号染色体q11.2区域）、新兴位点（1号染色体q21.1区域）以及全基因组范围内新位点的致病性和遗传性变异。罕见CNV的可变表达为跨越传统解剖学分类界限的CHD遗传谱系概念提供了支持。在产前、儿科和成人环境中，越来越多地采用全基因组技术（如染色体微阵列分析）进行临床基因检测。CHD中CNV的发现已转化为临床管理、预后评估和遗传咨询方面的变化。在单个基因和通路水平上的研究结果趋同，正在揭示控制人类心脏形态发生的机制。这些临床和研究进展有助于为全基因组测序提供信息，这是描绘CHD遗传结构的下一个合理步骤。
