Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy

Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy.

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Item Type: Article
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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