Abstract
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 × 10−7 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.
Highlights
Cardiomyopathy (CMP) is a primarily genetic disease with a prevalence of 1:500 to 1:2500 in the general population and an estimated 20 million people worldwide living with the disease[1]
T502fs variant observed in our patient with DCM was found in a 100,000 Genomes Project patient with DCM, and three different heterozygous splice variants in FHOD3 were observed at the same site in patients in the replication cohorts, all with HCM: c.1646 + 1G > C in an Australian patient[18], c.1646 + 1G > T in a 100,000 Genomes Project patient, and c.1646 + 1G > A in three 100,000 Genomes Project patients, suggesting a variant hotspot (Supplementary Fig. 1a; Supplementary Table 3)
A unique feature of our biobank is access to myocardial samples prioritization, we identified high-risk regulatory variants associated from patients undergoing cardiac surgery or transplantation
Summary
Cardiomyopathy (CMP) is a primarily genetic disease with a prevalence of 1:500 to 1:2500 in the general population and an estimated 20 million people worldwide living with the disease[1]. Several thousand new cases are diagnosed annually in North America[2]. A third are inherited, the remainder is sporadic, with most cases being autosomal dominant caused by rare variants in genes that impact muscle structure and function[3]. There are five phenotypes—hypertrophic (HCM), dilated (DCM), restrictive (RCM), left ventricular non-compaction (LVNC), and arrhythmogenic (ACM) cardiomyopathy. There is considerable genetic overlap between different CMP subtypes. Cardiomyopathy has a high penetrance and is the leading cause of heart failure and sudden cardiac death in childhood[4,5]. The genetic basis of early onset CMP has not been comprehensively evaluated
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