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- Title
The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic.
- Authors
Stafford, Fergus; Krishnan, Neesha; Richardson, Ebony; Butters, Alexandra; Hespe, Sophie; Burns, Charlotte; Gray, Belinda; Medi, Caroline; Nowak, Natalie; Isbister, Julia C.; Raju, Hariharan; Richmond, David; Ryan, Mark P.; Singer, Emma S.; Sy, Raymond W.; Yeates, Laura; Bagnall, Richard D.; Semsarian, Christopher; Ingles, Jodie
- Abstract
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.
- Subjects
GENETIC testing; GENETIC disorder diagnosis; MEDICAL screening; TESTING laboratories; GENETIC disorders; PHENOTYPES; AGE of onset
- Publication
Genome Medicine, 2022, Vol 14, Issue 1, p1
- ISSN
1756-994X
- Publication type
Article
- DOI
10.1186/s13073-022-01149-0