A multitiered analysis platform for genome sequencing: Design and initial findings of the Australian Genomics Cardiovascular Disorders Flagship.

Autor:	Austin R; Australian Genomics, Parkville, VIC, Australia.; Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, QLD, Australia., Brown JS; Australian Genomics, Parkville, VIC, Australia.; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia.; Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., Casauria S; Australian Genomics, Parkville, VIC, Australia.; Murdoch Children's Research Institute, Parkville, VIC, Australia., Madelli EO; Australian Genomics, Parkville, VIC, Australia.; Murdoch Children's Research Institute, Parkville, VIC, Australia., Mattiske T; Australian Genomics, Parkville, VIC, Australia., Boughtwood T; Australian Genomics, Parkville, VIC, Australia.; Murdoch Children's Research Institute, Parkville, VIC, Australia., Metke A; The Australian e-Health Research Centre, CSIRO, Herston, QLD, Australia., Davis A; Murdoch Children's Research Institute, Parkville, VIC, Australia.; Royal Children's Hospital, Parkville, VIC, Australia.; The University of Melbourne, Parkville, VIC, Australia., Horton AE; Monash Children's Hospital and Monash Heart, Monash Health, Clayton, VIC, Australia.; Department of Genomic Medicine, The Royal Melbourne Hospital Parkville, VIC, Australia.; Victorian Heart Institute, Monash University, Clayton, VIC, Australia., Winlaw D; Sydney Children's Hospital Network, Westmead, NSW, Australia., Das D; Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia., Soka M; Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia., Giannoulatou E; Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia., Rath EM; Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia., Haan E; SA clinical Genetics Service, Women's and Children's Hospital, North Adelaide, SA, Australia., Blue GM; Heart Centre for Children, Sydney Children's Hospital Network, Sydney, NSW, Australia.; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia., Vohra J; The University of Melbourne, Parkville, VIC, Australia.; Department of Genomic Medicine, The Royal Melbourne Hospital Parkville, VIC, Australia., Atherton JJ; School of Medicine, The University of Queensland, St Lucia, QLD, Australia.; Cardiology Department, Royal Brisbane and Women's Hospital, Herston, QLD, Australia., van Spaendonck-Zwarts K; Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, QLD, Australia., Cox K; SA Pathology, Adelaide, SA, Australia., Burnett L; Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.; School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Healthcare Clinical Campus, UNSW Sydney, Darlinghurst, NSW, Australia.; Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia., Wallis M; Tasmanian Clinical Genetics Service, Tasmanian Health Service, Hobart, TAS, Australia.; School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia., Haas M; Australian Genomics, Parkville, VIC, Australia.; Murdoch Children's Research Institute, Parkville, VIC, Australia., Quinn MCJ; Australian Genomics, Parkville, VIC, Australia.; Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, QLD, Australia., Pachter N; King Edward Memorial Hospital, Subiaco, WA, Australia.; Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia., Poplawski NK; Discipline of Paediatrics, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.; Adult Genetic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia., Stark Z; Australian Genomics, Parkville, VIC, Australia.; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia., Bagnall RD; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia., Weintraub RG; Murdoch Children's Research Institute, Parkville, VIC, Australia.; Royal Children's Hospital, Parkville, VIC, Australia.; The University of Melbourne, Parkville, VIC, Australia., Pantaleo SJ; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia., Lunke S; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia., De Fazio P; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia., Thompson T; The University of Melbourne, Parkville, VIC, Australia.; Department of Genomic Medicine, The Royal Melbourne Hospital Parkville, VIC, Australia., James P; Department of Genomic Medicine, The Royal Melbourne Hospital Parkville, VIC, Australia., Chang Y; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia., Fatkin D; Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia.; Cardiology Department, St Vincent's Hospital, Darlinghurst, NSW, Australia., Macciocca I; Royal Children's Hospital, Parkville, VIC, Australia.; The University of Melbourne, Parkville, VIC, Australia.; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia., Ingles J; Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia., Dunwoodie SL; Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia., Semsarian C; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia., McGaughran J; Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, QLD, Australia.; School of Medicine, The University of Queensland, St Lucia, QLD, Australia.
Jazyk:	angličtina
Zdroj:	Genetics in medicine open [Genet Med Open] 2024 Mar 25; Vol. 2, pp. 101842. Date of Electronic Publication: 2024 Mar 25 (Print Publication: 2024).
DOI:	10.1016/j.gimo.2024.101842
Abstrakt:	Purpose: The Australian Genomics Cardiovascular Disorders Flagship was a national multidisciplinary collaboration. It aimed to investigate the feasibility of genome sequencing (GS) and functional genomics to resolve variants of uncertain significance (VUS) in the clinical management of patients and families with cardiomyopathies, primary arrhythmias, and congenital heart disease (CHD). Methods: Between April 2019 and December 2021, 600 probands meeting cardiovascular disorder criteria from 17 cardiology and genetics clinics across Australia were enrolled in the Flagship and underwent GS. The Flagship adopted a tiered approach to GS analysis. Tier 1 analysis assessed genes with established clinical validity for each cardiovascular condition. Tier 2 analysis assessed lesser-evidenced research-based genes. Tier 3 analysis assessed the functional impact of VUS that remained after tier 1 and tier 2 analysis. Results: Overall, a pathogenic or likely pathogenic variant was identified in 41% of participants with a cardiomyopathy, 40% with an arrhythmia syndrome, and 15% with a familial CHD/CHD+Extra Cardiac Anomalies. A VUS outcome ranged from 13% for arrhythmias to 34% for CHD/CHD+Extra Cardiac Anomalies participants. Tier 2 research analysis identified a likely pathogenic/pathogenic variant for a further 15 participants and a VUS for an additional 15 participants. Conclusion: The Flagship successfully facilitated a model of care that harnesses clinical GS and functional genomics for the resolution of VUS in the clinical setting. This valuable data set can be used to inform clinical practice and facilitate research into the future. Competing Interests: The authors declare no conflicts of interest. (Crown Copyright 2024 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.)
Databáze:	MEDLINE
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