The application of next-generation sequencing to study congenital heart disease (CHD) is increasingly providing new insights into the causes and mechanisms of this prevalent birth anomaly. Whole-exome sequencing analysis identifies damaging gene variants altering single or contiguous nucleotides that are assigned pathogenicity based on statistical analyses of families and cohorts with CHD, high expression in the developing heart and depletion of damaging protein-coding variants in the general population. Gene classes fulfilling these criteria are enriched in patients with CHD and extracardiac abnormalities, evidencing shared pathways in organogenesis. Developmental single-cell transcriptomic data demonstrate the expression of CHD-associated genes in particular cell lineages, and emerging insights indicate that genetic variants perturb multicellular interactions that are crucial for cardiogenesis. Whole-genome sequencing analyses extend these observations, identifying non-coding variants that influence the expression of genes associated with CHD and contribute to the estimated ~55% of unexplained cases of CHD. These approaches combined with the assessment of common and mosaic genetic variants have provided a more complete knowledge of the causes and mechanisms of CHD. Such advances provide knowledge to inform the clinical care of patients with CHD or other birth defects and deepen our understanding of the complexity of human development. In this Review, we highlight known and candidate CHD-associated human genes and discuss how the integration of advances in developmental biology research can provide new insights into the genetic contributions to CHD.

下一代测序在先天性心脏病 (CHD) 研究中的应用越来越多地为这种普遍存在的出生异常的原因和机制提供了新的见解。全外显子组测序分析可识别改变单个或连续核苷酸的破坏性基因变异，这些变异根据对先天性心脏病家族和队列的统计分析、在发育中的心脏中的高表达和一般人群中破坏性蛋白质编码变异的耗竭，被指定为致病性。满足这些标准的基因类别在患有冠心病和心外异常的患者中得到丰富，证明了器官发生中的共享途径。发育单细胞转录组学数据证明了特定细胞谱系中 CHD 相关基因的表达，新的见解表明，遗传变异扰乱了对心脏发生至关重要的多细胞相互作用。全基因组测序分析扩展了这些观察结果，确定了影响与冠心病相关基因表达的非编码变异，并导致估计约 55% 的无法解释的冠心病病例。这些方法与常见和镶嵌遗传变异的评估相结合，提供了对冠心病病因和机制的更完整知识。这些进步为冠心病或其他先天缺陷患者的临床护理提供了知识，并加深了我们对人类发展复杂性的理解。在这篇评论中，