Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy
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Published:2022-03-14
Issue:1
Volume:7
Page:
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ISSN:2056-7944
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Container-title:npj Genomic Medicine
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language:en
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Short-container-title:npj Genom. Med.
Author:
Lesurf RobertORCID, Said AbdelrahmanORCID, Akinrinade OyediranORCID, Breckpot JeroenORCID, Delfosse KathleenORCID, Liu TingORCID, Yao Roderick, Persad GabrielleORCID, McKenna Fintan, Noche Ramil R.ORCID, Oliveros WinonaORCID, Mattioli KaiaORCID, Shah Shreya, Miron Anastasia, Yang Qian, Meng Guoliang, Yue Michelle Chan Seng, Sung Wilson W. L.ORCID, Thiruvahindrapuram BhoomaORCID, Lougheed JaneORCID, Oechslin ErwinORCID, Mondal TapasORCID, Bergin LynnORCID, Smythe John, Jayappa ShashankORCID, Rao Vinay J.ORCID, Shenthar JayaprakashORCID, Dhandapany Perundurai S., Semsarian ChristopherORCID, Weintraub Robert G., Bagnall Richard D.ORCID, Ingles Jodie, 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 MartaORCID, Maass Philipp G.ORCID, Ellis JamesORCID, Scherer Stephen W.ORCID, Mital SeemaORCID,
Abstract
AbstractCardiomyopathy (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 × 10−7 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.
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology
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