TitleWhole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy.
Publication TypeJournal Article
Year of Publication2022
AuthorsLesurf R, Said A, Akinrinade O, Breckpot J, Delfosse K, Liu T, Yao R, Persad G, McKenna F, Noche RR, Oliveros W, Mattioli K, Shah S, Miron A, Yang Q, Meng G, Yue MChan Seng, Sung WWL, Thiruvahindrapuram B, Lougheed J, Oechslin E, Mondal T, Bergin L, Smythe J, Jayappa S, Rao VJ, Shenthar J, Dhandapany PS, Semsarian C, Weintraub RG, Bagnall RD, Ingles J, Melé M, Maass PG, Ellis J, Scherer SW, Mital S
Corporate AuthorsGenomics England Research Consortium
JournalNPJ Genom Med
Volume7
Issue1
Pagination18
Date Published2022 Mar 14
ISSN2056-7944
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 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.

DOI10.1038/s41525-022-00288-y
Alternate JournalNPJ Genom Med
PubMed ID35288587
Grant ListPJT 175034 / / Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) /
ENP 161429 / / Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) /
PJT 175034 / / Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) /
DGE1144152 / / National Science Foundation (NSF) /
1154992 / / Department of Health | National Health and Medical Research Council (NHMRC) /
1162929 / / Department of Health | National Health and Medical Research Council (NHMRC) /

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