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Whole genome sequencing delineates regulatory, structural, and cryptic splice variants in early onset cardiomyopathy

Cardiomyopathy (CMP) is a heritable disorder. Over 50% 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 1,953 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 % 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 % 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.

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Dataset ID Description Technology Samples
EGAD00001008477 HiSeq X Ten 114
Publications Citations
Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy.
NPJ Genom Med 7: 2022 18
Age and Sex Differences in the Genetics of Cardiomyopathy.
J Cardiovasc Transl Res 16: 2023 1287-1302
Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants.
J Cardiovasc Transl Res 16: 2023 1303-1309
Genome-wide enhancer-associated tandem repeats are expanded in cardiomyopathy.
EBioMedicine 101: 2024 105027