Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Electrical Engineering and Computing Sciences, University of Cincinnati, Cincinnati, OH 45229, USA.
Am J Hum Genet. 2022 Feb 3;109(2):282-298. doi: 10.1016/j.ajhg.2021.12.006. Epub 2022 Jan 12.
To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.
为了了解原发性儿科心肌病的遗传贡献，我们对 528 名心肌病患儿进行了外显子组测序。使用临床解释指南和靶向心肌病相关基因，我们在 32%的受影响个体中确定了遗传原因。心肌病亚表型因种族、诊断时的年龄和家族史而异。<1 岁的婴儿分子诊断的可能性较小（p<0.001）。使用 1703 个候选基因和信息学工具的发现集，我们在 56%的受影响个体中发现了罕见的、有害的变异。与两个独立的对照集（1000 Genomes Project，p<0.001 和 SPARK 父母对照，p<1×10）相比，受影响个体中有害变异的负担过多。当按种族、变异类型和亚表型分层时，心肌病变异负担仍然丰富，强调了理解这些因素对遗传结构的贡献的重要性。在这个发现候选基因集中的富集表明，多基因机制是心肌病亚表型特异性病因和表现的基础。这些结果确定了儿科心肌病遗传结构的重要信息，并支持对儿童进行临床遗传测试的建议，同时说明了遗传结构在年龄、种族和亚表型方面的差异，并为更大规模的研究提供了依据，以调查多基因的贡献。
