Cardiomyopathy (CMP) is a heritable genetic disorder. Protein-coding variants account for 20 to 30 percent of cases. The contribution of variants in noncoding DNA elements that regulate gene expression has not been explored. We performed whole genome sequencing (WGS) of 228 unrelated CMP families. Besides pathogenic protein coding variants in known CMP genes, 5% cases harbored rare loss of function variants in novel cardiac genes, with NRAP and FHOD3 being strong candidates. WGS also revealed a high burden of high risk variants in promoters and enhancers of CMP genes in an additional 20 percent cases (Odds ratio 2.14, 95 percent CI 1.60-2.86, p equals 5.26E-07 vs 1326 controls) with genes involved in alpha-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) specifically enriched for regulatory variants (False discovery rate less than 0.03). These findings were independently replicated in the Genomics England CMP cohort (n=1266). The functional effect of non-coding variants on transcription was functionally validated in patient myocardium and reporter assays in human cardiomyocytes, and that of novel gene variants in zebrafish knockouts. Our results show that functionally active variants in novel genes and in regulatory elements of CMP genes contribute strongly to the genomic etiology of childhood-onset CMP.

中文翻译：

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全基因组测序描述了儿童心肌病的调节基因和新型基因变异

心肌病（CMP）是一种遗传性遗传疾病。蛋白质编码变体占病例的20％到30％。尚未探讨变体在调节基因表达的非编码DNA元件中的作用。我们对228个不相关的CMP家族进行了全基因组测序（WGS）。除了已知的CMP基因中的致病蛋白编码变体外，还有5％的病例在新的心脏基因中具有罕见的功能变体丧失，其中NRAP和FHOD3是强候选者。WGS还显示，在另外20％的病例中，CMP基因的启动子和增强子中高风险变异的负担很重（赔率2.14，95％CI 1.60-2.86，p等于5.26E-07 vs 1326对照），而α基因参与其中-dystroglycan糖基化（FKTN，DTNA）和桥粒信号转导（DSC2，DSG2）专门用于调节变体（错误发现率小于0.03）。这些发现在Genomics England CMP队列（n = 1266）中被独立复制。非编码变体对转录的功能作用在人心肌细胞的患者心肌和报告基因检测中以及斑马鱼基因敲除中的新基因变体中得到了功能验证。我们的研究结果表明，新基因和CMP基因调控元件中的功能性活性变体对儿童期CMP的基因组病因学有很大贡献。以及斑马鱼基因敲除中的新基因变异。我们的结果表明，新基因和CMP基因调控元件中的功能性活性变体对儿童期CMP的基因组病因学有很大贡献。以及斑马鱼基因敲除中的新基因变异。我们的结果表明，新基因和CMP基因调控元件中的功能性活性变体对儿童期CMP的基因组病因学有很大贡献。