TY - JOUR T1 - Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy. JF - NPJ Genom Med Y1 - 2022 A1 - Lesurf, Robert A1 - Said, Abdelrahman A1 - Akinrinade, Oyediran A1 - Breckpot, Jeroen A1 - Delfosse, Kathleen A1 - Liu, Ting A1 - Yao, Roderick A1 - Persad, Gabrielle A1 - McKenna, Fintan A1 - Noche, Ramil R A1 - Oliveros, Winona A1 - Mattioli, Kaia A1 - Shah, Shreya A1 - Miron, Anastasia A1 - Yang, Qian A1 - Meng, Guoliang A1 - Yue, Michelle Chan Seng A1 - Sung, Wilson W L A1 - Thiruvahindrapuram, Bhooma A1 - Lougheed, Jane A1 - Oechslin, Erwin A1 - Mondal, Tapas A1 - Bergin, Lynn A1 - Smythe, John A1 - Jayappa, Shashank A1 - Rao, Vinay J A1 - Shenthar, Jayaprakash A1 - Dhandapany, Perundurai S A1 - Semsarian, Christopher A1 - Weintraub, Robert G A1 - Bagnall, Richard D A1 - Ingles, Jodie A1 - Melé, Marta A1 - Maass, Philipp G A1 - Ellis, James A1 - Scherer, Stephen W A1 - Mital, Seema AB -

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.

VL - 7 IS - 1 ER -