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Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy.
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; Melé, Marta; Maass, Philipp G; Ellis, James; Scherer, Stephen W; Mital, Seema.
Afiliación
  • Lesurf R; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Said A; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Akinrinade O; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Breckpot J; St. George's University School of Medicine, Grenada, Grenada.
  • Delfosse K; Department of Human Genetics, UZ Leuven, Leuven, Belgium.
  • Liu T; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Yao R; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Persad G; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • McKenna F; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Noche RR; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • Oliveros W; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Mattioli K; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Shah S; Zebrafish Genetics and Disease Models Core, The Hospital for Sick Children, Toronto, ON, Canada.
  • Miron A; Life Sciences Department, Barcelona Supercomputing Center, Barcelona, Catalonia, Spain.
  • Yang Q; Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Meng G; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Yue MCS; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Sung WWL; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Thiruvahindrapuram B; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • Lougheed J; Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
  • Oechslin E; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
  • Mondal T; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
  • Bergin L; Division of Cardiology, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
  • Smythe J; Peter Munk Cardiac Centre, Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada.
  • Jayappa S; Department of Pediatrics, Hamilton Health Sciences Centre, Hamilton, ON, Canada.
  • Rao VJ; Division of Cardiology, London Health Sciences Centre, London, ON, Canada.
  • Shenthar J; Department of Pediatrics, Kingston General Hospital, Kingston, ON, Canada.
  • Dhandapany PS; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore (inStem), Bangalore, India.
  • Semsarian C; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore (inStem), Bangalore, India.
  • Weintraub RG; Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India.
  • Bagnall RD; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore (inStem), Bangalore, India.
  • Ingles J; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia.
  • Melé M; Cardiology Department, Royal Children's Hospital, Melbourne, Australia.
  • Maass PG; Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia.
  • Ellis J; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
  • Scherer SW; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia.
  • Mital S; Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia.
NPJ Genom Med ; 7(1): 18, 2022 Mar 14.
Article en En | MEDLINE | ID: mdl-35288587
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: NPJ Genom Med Año: 2022 Tipo del documento: Article País de afiliación: Canadá
Texto completo
Añadir a Mi BVS
Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: NPJ Genom Med Año: 2022 Tipo del documento: Article País de afiliación: Canadá