1. The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic.
- Author
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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, and Ingles, Jodie
- Subjects
GENETIC testing ,GENETIC disorder diagnosis ,MEDICAL screening ,TESTING laboratories ,GENETIC disorders ,PHENOTYPES ,AGE of onset - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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