Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy.
Full text not available from this repository.Item Type: | Article |
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Official URL: | https://doi.org/10.1038/s41525-022-00288-y |
Journal or Publication Title: | npj Genomic Medicine |
Volume: | 7 |
Number: | 1 |
Date: | 14 March 2022 |
Divisions: | Bioinformatics and Molecular Genetics Molecular Cardiology |
Depositing User: | General Admin |
Identification Number: | 10.1038/s41525-022-00288-y |
ISSN: | 2056-7944 |
Date Deposited: | 08 Jan 2023 23:08 |
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 × 10-7 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. |
Creators: | Creators Email Lesurf, Robert UNSPECIFIED Said, Abdelrahman UNSPECIFIED Akinrinade, Oyediran UNSPECIFIED Breckpot, Jeroen UNSPECIFIED Delfosse, Kathleen UNSPECIFIED Liu, Ting UNSPECIFIED Yao, Roderick UNSPECIFIED Persad, Gabrielle UNSPECIFIED McKenna, Fintan UNSPECIFIED Noche, Ramil R. UNSPECIFIED Oliveros, Winona UNSPECIFIED Mattioli, Kaia UNSPECIFIED Shah, Shreya UNSPECIFIED Miron, Anastasia UNSPECIFIED Yang, Qian UNSPECIFIED Meng, Guoliang UNSPECIFIED Yue, Michelle Chan Seng UNSPECIFIED Sung, Wilson W. L. UNSPECIFIED Thiruvahindrapuram, Bhooma UNSPECIFIED Lougheed, Jane UNSPECIFIED Oechslin, Erwin UNSPECIFIED Mondal, Tapas UNSPECIFIED Bergin, Lynn UNSPECIFIED Smythe, John UNSPECIFIED Jayappa, Shashank UNSPECIFIED Rao, Vinay J. UNSPECIFIED Shenthar, Jayaprakash UNSPECIFIED Dhandapany, Perundurai S. UNSPECIFIED Semsarian, Christopher UNSPECIFIED Weintraub, Robert G. UNSPECIFIED Bagnall, Richard D. UNSPECIFIED Ingles, Jodie UNSPECIFIED Ambrose, J. C. UNSPECIFIED Arumugam, P. UNSPECIFIED Baple, E. L. UNSPECIFIED Bleda, M. UNSPECIFIED Boardman-Pretty, F. UNSPECIFIED Boissiere, J. M. UNSPECIFIED Boustred, C. R. UNSPECIFIED Brittain, H. UNSPECIFIED Caulfield, M. J. UNSPECIFIED Chan, G. C. UNSPECIFIED Craig, C. E. H. UNSPECIFIED Daugherty, L. C. UNSPECIFIED de Burca, A. UNSPECIFIED Devereau, A. UNSPECIFIED Elgar, G. UNSPECIFIED Foulger, R. E. UNSPECIFIED Fowler, T. UNSPECIFIED Furió-Tarí, P. UNSPECIFIED Giess, A. UNSPECIFIED Hackett, J. M. UNSPECIFIED Halai, D. UNSPECIFIED Hamblin, A. UNSPECIFIED Henderson, S. UNSPECIFIED Holman, J. E. UNSPECIFIED Hubbard, T. J. P. UNSPECIFIED Ibáñez, K. UNSPECIFIED Jackson, R. UNSPECIFIED Jones, L. J. UNSPECIFIED Kasperaviciute, D. UNSPECIFIED Kayikci, M. UNSPECIFIED Kousathanas, A. UNSPECIFIED Lahnstein, L. UNSPECIFIED Lawson, K. UNSPECIFIED Leigh, S. E. A. UNSPECIFIED Leong, I. U. S. UNSPECIFIED Lopez, F. J. UNSPECIFIED Maleady-Crowe, F. UNSPECIFIED Mason, J. UNSPECIFIED McDonagh, E. M. UNSPECIFIED Moutsianas, L. UNSPECIFIED Mueller, M. UNSPECIFIED Murugaesu, N. UNSPECIFIED Need, A. C. UNSPECIFIED Odhams, C. A. UNSPECIFIED Orioli, A. UNSPECIFIED Patch, C. UNSPECIFIED Perez-Gil, D. UNSPECIFIED Pereira, M. B. UNSPECIFIED Polychronopoulos, D. UNSPECIFIED Pullinger, J. UNSPECIFIED Rahim, T. UNSPECIFIED Rendon, A. UNSPECIFIED Riesgo-Ferreiro, P. UNSPECIFIED Rogers, T. UNSPECIFIED Ryten, M. UNSPECIFIED Savage, K. UNSPECIFIED Sawant, K. UNSPECIFIED Scott, R. H. UNSPECIFIED Siddiq, A. UNSPECIFIED Sieghart, A. UNSPECIFIED Smedley, D. UNSPECIFIED Smith, K. R. UNSPECIFIED Smith, S. C. UNSPECIFIED Sosinsky, A. UNSPECIFIED Spooner, W. UNSPECIFIED Stevens, H. E. UNSPECIFIED Stuckey, A. UNSPECIFIED Sultana, R. UNSPECIFIED Tanguy, M. UNSPECIFIED Thomas, E. R. A. UNSPECIFIED Thompson, S. R. UNSPECIFIED Tregidgo, C. UNSPECIFIED Tucci, A. UNSPECIFIED Walsh, E. UNSPECIFIED Watters, S. A. UNSPECIFIED Welland, M. J. UNSPECIFIED Williams, E. UNSPECIFIED Witkowska, K. UNSPECIFIED Wood, S. M. UNSPECIFIED Zarowiecki, M. UNSPECIFIED Melé, Marta UNSPECIFIED Maass, Philipp G. UNSPECIFIED Ellis, James UNSPECIFIED Scherer, Stephen W. UNSPECIFIED Mital, Seema UNSPECIFIED |
Last Modified: | 08 Jan 2023 23:08 |
URI: | https://eprints.centenary.org.au/id/eprint/1325 |
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