Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy
Authors: Lesurf Robert , Said Abdelrahman , Akinrinade Oyediran , Breckpot Jeroen , Delfosse Kathleen , Liu Ting , Yao Roderick , Persad Gabrielle , McKenna Fintan , Noche Ramil R. , Oliveros Winona , Mattioli Kaia , Shah Shreya , Miron Anastasia , Yang Qian , Meng Guoliang , Yue Michelle Chan Seng , Sung Wilson W. L. , Thiruvahindrapuram Bhooma , Lougheed Jane , Oechslin Erwin , Mondal Tapas , Bergin Lynn , Smythe John , Jayappa Shashank , Rao Vinay J. , Shenthar Jayaprakash , Dhandapany Perundurai S. , Semsarian Christopher , Weintraub Robert G. , Bagnall Richard D. , Ingles Jodie ,   Genomics England Research Consortium, Ambrose J. C. , Arumugam P. , Baple E. L. , Bleda M. , Boardman-Pretty F. , Boissiere J. M. , Boustred C. R. , Brittain H. , Caulfield M. J. , Chan G. C. , Craig C. E. H. , Daugherty L. C. , de Burca A. , Devereau A. , Elgar G. , Foulger R. E. , Fowler T. , Furió-Tarí P. , Giess A. , Hackett J. M. , Halai D. , Hamblin A. , Henderson S. , Holman J. E. , Hubbard T. J. P. , Ibáñez K. , Jackson R. , Jones L. J. , Kasperaviciute D. , Kayikci M. , Kousathanas A. , Lahnstein L. , Lawson K. , Leigh S. E. A. , Leong I. U. S. , Lopez F. J. , Maleady-Crowe F. , Mason J. , McDonagh E. M. , Moutsianas L. , Mueller M. , Murugaesu N. , Need A. C. , Odhams C. A. , Orioli A. , Patch C. , Perez-Gil D. , Pereira M. B. , Polychronopoulos D. , Pullinger J. , Rahim T. , Rendon A. , Riesgo-Ferreiro P. , Rogers T. , Ryten M. , Savage K. , Sawant K. , Scott R. H. , Siddiq A. , Sieghart A. , Smedley D. , Smith K. R. , Smith S. C. , Sosinsky A. , Spooner W. , Stevens H. E. , Stuckey A. , Sultana R. , Tanguy M. , Thomas E. R. A. , Thompson S. R. , Tregidgo C. , Tucci A. , Walsh E. , Watters S. A. , Welland M. J. , Williams E. , Witkowska K. , Wood S. M. , Zarowiecki M. , Melé Marta , Maass Philipp G. , Ellis James , Scherer Stephen W. , Mital Seema 
Published: March 2022

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 × 10−7versus 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.