The burden of splice-disrupting variants in inherited heart disease and unexplained sudden cardiac death.

Autor: Singer ES; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Crowe J; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Holliday M; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Isbister JC; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia., Lal S; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Nowak N; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia., Yeates L; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.; Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW, Sydney, NSW, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia., Burns C; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia., Rajagopalan S; Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia., Macciocca I; Murdoch Children's Research Institute, University of Melbourne, Melbourne, VIC, Australia.; Victorian Clinical Genetics Services, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia., King I; Murdoch Children's Research Institute, University of Melbourne, Melbourne, VIC, Australia., Wacker J; Department of Cardiology, Royal Children's Hospital, Melbourne, VIC, Australia., Ingles J; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.; Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW, Sydney, NSW, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia., Weintraub RG; Murdoch Children's Research Institute, University of Melbourne, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia.; Department of Cardiology, Royal Children's Hospital, Melbourne, VIC, Australia., Semsarian C; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia., Bagnall RD; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia. r.bagnall@centenary.org.au.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. r.bagnall@centenary.org.au.
Jazyk: angličtina
Zdroj: NPJ genomic medicine [NPJ Genom Med] 2023 Oct 11; Vol. 8 (1), pp. 29. Date of Electronic Publication: 2023 Oct 11.
DOI: 10.1038/s41525-023-00373-w
Abstrakt: There is an incomplete understanding of the burden of splice-disrupting variants in definitively associated inherited heart disease genes and whether these genes can amplify from blood RNA to support functional confirmation of splicing outcomes. We performed burden testing of rare splice-disrupting variants in people with inherited heart disease and sudden unexplained death compared to 125,748 population controls. ClinGen definitively disease-associated inherited heart disease genes were amplified using RNA extracted from fresh blood, derived cardiomyocytes, and myectomy tissue. Variants were functionally assessed and classified for pathogenicity. We found 88 in silico-predicted splice-disrupting variants in 128 out of 1242 (10.3%) unrelated participants. There was an excess burden of splice-disrupting variants in PKP2 (5.9%), FLNC (2.7%), TTN (2.8%), MYBPC3 (8.2%) and MYH7 (1.3%), in distinct cardiomyopathy subtypes, and KCNQ1 (3.6%) in long QT syndrome. Blood RNA supported the amplification of 21 out of 31 definitive disease-associated inherited heart disease genes. Our functional studies confirmed altered splicing in six variants. Eleven variants of uncertain significance were reclassified as likely pathogenic based on functional studies and six were used for cascade genetic testing in 12 family members. Our study highlights that splice-disrupting variants are a significant cause of inherited heart disease, and that analysis of blood RNA confirms splicing outcomes and supports variant pathogenicity classification.
(© 2023. Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.)
Databáze: MEDLINE
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