The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic.

Autor: Stafford F; Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia., Krishnan N; Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia., Richardson E; Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia., Butters A; Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia., Hespe S; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia., Burns C; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia., Gray B; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia., Medi C; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia., Nowak N; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia., Isbister JC; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia., Raju H; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.; Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia., Richmond D; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia., Ryan MP; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia., Singer ES; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia., Sy RW; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia., Yeates L; Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia., Bagnall RD; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia., Semsarian C; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia., Ingles J; Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia. jodie.ingles@populationgenomics.org.au.; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia. jodie.ingles@populationgenomics.org.au.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia. jodie.ingles@populationgenomics.org.au.; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia. jodie.ingles@populationgenomics.org.au.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia. jodie.ingles@populationgenomics.org.au.
Jazyk: angličtina
Zdroj: Genome medicine [Genome Med] 2022 Dec 28; Vol. 14 (1), pp. 145. Date of Electronic Publication: 2022 Dec 28.
DOI: 10.1186/s13073-022-01149-0
Abstrakt: Background: The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and is primarily indicated for screening of at-risk relatives. Here, we evaluate the role of genomics in diagnosis and management among consecutive individuals attending a specialised clinic and identify those with the highest likelihood of having a monogenic disease.
Methods: A retrospective audit of 1697 consecutive, unrelated probands referred to a specialised, multidisciplinary clinic between 2002 and 2020 was performed. A concordant clinical and genetic diagnosis was considered solved. Cases were classified as likely monogenic based on a score comprising a positive family history, young age at onset, and severe phenotype, whereas low-scoring cases were considered to have a likely complex aetiology. The impact of a genetic diagnosis was evaluated.
Results: A total of 888 probands fulfilled the inclusion criteria, and genetic testing identified likely pathogenic or pathogenic (LP/P) variants in 330 individuals (37%) and suspicious variants of uncertain significance (VUS) in 73 (8%). Research-focused efforts identified 46 (5%) variants, missed by conventional genetic testing. Where a variant was identified, this changed or clarified the final diagnosis in a clinically useful way for 51 (13%). The yield of suspicious VUS across ancestry groups ranged from 15 to 20%, compared to only 10% among Europeans. Even when the clinical diagnosis was uncertain, those with the most monogenic disease features had the greatest diagnostic yield from genetic testing.
Conclusions: Research-focused efforts can increase the diagnostic yield by up to 5%. Where a variant is identified, this will have clinical utility beyond family screening in 13%. We demonstrate the value of genomics in reaching an overall diagnosis and highlight inequities based on ancestry. Acknowledging our incomplete understanding of disease phenotypes, we propose a framework for prioritising likely monogenic cases to solve their underlying cause of disease.
(© 2022. The Author(s).)
Databáze: MEDLINE
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