Key result
High-risk variants in promoters and enhancers of CMP genes were significantly enriched in childhood-onset cardiomyopathy cases compared to controls (OR 2.14; 95% CI 1.60-2.86; p=5.26x10^-7).
Why the study?
Protein-coding variants account for only 20-30% of cardiomyopathy cases, and the contribution of variants in non-coding regulatory DNA elements had not been explored.
Does whole-genome sequencing identify novel genic and regulatory variants that contribute to the etiology of childhood-onset cardiomyopathy?
Case-Control (n=1,554)
Does whole-genome sequencing identify novel genic and regulatory variants that contribute to the etiology of childhood-onset cardiomyopathy?
Odds Ratio: 2.14 (95% CI 1.6–2.86)
p-value: p=5.26x10^-7
Whole-genome sequencing identifies functionally active variants in novel genes and regulatory elements that significantly contribute to the genetic etiology of childhood-onset cardiomyopathy, expanding diagnostic yield beyond known protein-coding variants.
Should not yet alter clinical genetic testing in cardiomyopathy; leaves open non-coding and novel gene contributions for validation.
Cardiomyopathy (CMP) is a heritable genetic disorder. Protein-coding variants account for 20-30% of cases. The contribution of variants in non-coding 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% cases (Odds ratio 2.14, 95% CI 1.60-2.86, p=5.26×10 −7 vs 1326 controls) with genes involved in α-dystroglycan glycosylation ( FKTN, DTNA ) and desmosomal signaling ( DSC2, DSG2 ) specifically enriched for regulatory variants (False discovery rate <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.
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Lesurf et al. (2020) conducted a case-control in Childhood-onset cardiomyopathy (n=1,554). High-risk variants in promoters and enhancers of CMP genes vs. Controls was evaluated on Presence of high-risk variants in promoters and enhancers of CMP genes (OR 2.14, 95% CI 1.60-2.86, p=5.26x10^-7). High-risk variants in promoters and enhancers of CMP genes were significantly enriched in childhood-onset cardiomyopathy cases compared to controls (OR 2.14; 95% CI 1.60-2.86; p=5.26x10^-7).
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