npj Genomic Medicine (Mar 2022)
Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy
- Robert Lesurf,
- Abdelrahman Said,
- Oyediran Akinrinade,
- Jeroen Breckpot,
- Kathleen Delfosse,
- Ting Liu,
- Roderick Yao,
- Gabrielle Persad,
- Fintan McKenna,
- Ramil R. Noche,
- Winona Oliveros,
- Kaia Mattioli,
- Shreya Shah,
- Anastasia Miron,
- Qian Yang,
- Guoliang Meng,
- Michelle Chan Seng Yue,
- Wilson W. L. Sung,
- Bhooma Thiruvahindrapuram,
- Jane Lougheed,
- Erwin Oechslin,
- Tapas Mondal,
- Lynn Bergin,
- John Smythe,
- Shashank Jayappa,
- Vinay J. Rao,
- Jayaprakash Shenthar,
- Perundurai S. Dhandapany,
- Christopher Semsarian,
- Robert G. Weintraub,
- Richard D. Bagnall,
- Jodie Ingles,
- Genomics England Research Consortium,
- Marta Melé,
- Philipp G. Maass,
- James Ellis,
- Stephen W. Scherer,
- Seema Mital
Affiliations
- Robert Lesurf
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Abdelrahman Said
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Oyediran Akinrinade
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Jeroen Breckpot
- Department of Human Genetics
- Kathleen Delfosse
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Ting Liu
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Roderick Yao
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Gabrielle Persad
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Fintan McKenna
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Ramil R. Noche
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Winona Oliveros
- Life Sciences Department, Barcelona Supercomputing Center
- Kaia Mattioli
- Division of Genetics, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School
- Shreya Shah
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Anastasia Miron
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Qian Yang
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Guoliang Meng
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children
- Michelle Chan Seng Yue
- Princess Margaret Cancer Center, University Health Network
- Wilson W. L. Sung
- The Centre for Applied Genomics, The Hospital for Sick Children
- Bhooma Thiruvahindrapuram
- The Centre for Applied Genomics, The Hospital for Sick Children
- Jane Lougheed
- Division of Cardiology, Children’s Hospital of Eastern Ontario
- Erwin Oechslin
- Peter Munk Cardiac Centre, Division of Cardiology, Toronto General Hospital, University of Toronto
- Tapas Mondal
- Department of Pediatrics, Hamilton Health Sciences Centre
- Lynn Bergin
- Division of Cardiology, London Health Sciences Centre
- John Smythe
- Department of Pediatrics, Kingston General Hospital
- Shashank Jayappa
- Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore (inStem)
- Vinay J. Rao
- Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore (inStem)
- Jayaprakash Shenthar
- Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research
- Perundurai S. Dhandapany
- Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore (inStem)
- Christopher Semsarian
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney
- Robert G. Weintraub
- Cardiology Department, Royal Children’s Hospital
- Richard D. Bagnall
- Department of Cardiology, Royal Prince Alfred Hospital
- Jodie Ingles
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney
- Genomics England Research Consortium
- Marta Melé
- Life Sciences Department, Barcelona Supercomputing Center
- Philipp G. Maass
- Genetics and Genome Biology Program, The Hospital for Sick Children
- James Ellis
- Department of Molecular Genetics, University of Toronto
- Stephen W. Scherer
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Seema Mital
- Genetics and Genome Biology Program, The Hospital for Sick Children
- DOI
- https://doi.org/10.1038/s41525-022-00288-y
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 1 – 17
Abstract
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.
