Key result
Genetic testing identifies pathogenic variants in 37% of probands with inherited cardiac conditions.
Why the study?
Genetic testing for inherited cardiac diseases yields up to 40% diagnostic success and is primarily indicated for relative screening, prompting an evaluation of genomics in patient diagnosis and management to identify those most likely to have monogenic disease.
Observational (n=888)
No
Comprehensive genetic testing, including research-focused efforts, provides a diagnostic yield of over 40% in inherited cardiac conditions and alters clinical management in a significant subset of patients.
May support expanded genetic testing in inherited cardiac conditions; extends diagnostic yields but remains hypothesis-generating pending prospective validation.
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.
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Stafford et al. (2022) conducted an observational in Inherited cardiac conditions (n=888). Genetic testing was evaluated on Diagnostic yield of genetic testing (identification of likely pathogenic or pathogenic variants). Genetic testing identified likely pathogenic or pathogenic variants in 37% of probands with inherited cardiac conditions, with research-focused efforts increasing the diagnostic yield by up to 5%.
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