Lesurf Robert, Said Abdelrahman, Akinrinade Oyediran, Breckpot Jeroen, Delfosse Kathleen, Liu Ting, Yao Roderick, Persad Gabrielle, McKenna Fintan, Noche Ramil R, Oliveros Winona, Mattioli Kaia, Shah Shreya, Miron Anastasia, Yang Qian, Meng Guoliang, Yue Michelle Chan Seng, Sung Wilson W L, Thiruvahindrapuram Bhooma, Lougheed Jane, Oechslin Erwin, Mondal Tapas, Bergin Lynn, Smythe John, Jayappa Shashank, Rao Vinay J, Shenthar Jayaprakash, Dhandapany Perundurai S, Semsarian Christopher, Weintraub Robert G, Bagnall Richard D, Ingles Jodie, Melé Marta, Maass Philipp G, Ellis James, Scherer Stephen W, Mital Seema
Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
St. George's University School of Medicine, Grenada, Grenada.
NPJ Genom Med. 2022 Mar 14;7(1):18. doi: 10.1038/s41525-022-00288-y.
Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.
心肌病（CMP）是一种遗传性疾病。超过50%的病例在临床基因检测板检测中无法确定相关基因。非编码DNA元件中导致隐匿性剪接并调节基因表达的变异的作用尚未得到探索。我们分析了209名儿科CMP患者的发现队列以及1953个独立的复制基因组和外显子组的全基因组测序（WGS）数据。我们搜索了蛋白质编码变异以及预测会影响基因功能或表达的非编码变异。39%的病例在已知的CMP基因中存在致病性编码变异，5%在其他候选CMP基因中存在高风险功能丧失（LoF）变异。15%在CMP基因的启动子和增强子中存在高风险调控变异（与对照组相比，优势比为2.25，p = 6.70×10）。参与α- dystroglycan糖基化（FKTN、DTNA）和桥粒信号传导（DSC2、DSG2）的基因在调控变异中富集程度最高（优势比为6.7 - 58.1）。在患者心肌以及人类心肌细胞的报告基因检测和斑马鱼CRISPR基因敲除实验中证实了功能效应。我们为新基因以及已知CMP基因调控元件中功能活跃变异对早发性CMP的基因组贡献提供了有力证据。
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