Key result
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 an additional 5%.
Why the study?
The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and primarily used for screening relatives, but its role in diagnosis, management, and identifying individuals with the highest likelihood of monogenic disease in a specialised clinic required evaluation.
Does genetic testing improve the diagnostic yield and clinical management of individuals with inherited cardiac conditions?
Observational (n=888)
No
Does genetic testing improve the diagnostic yield and clinical management of individuals with inherited cardiac conditions?
Genetic testing provides a diagnostic yield of 37% for pathogenic variants in inherited cardiac conditions, with research-focused efforts adding 5% and findings altering clinical diagnosis in 13% of cases.
Genetic testing clarifies diagnosis in 13% of solved cases; leaves open optimal prioritization strategies and ancestry equity in routine care.
Background The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and 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 highest likelihood of having a monogenic disease. Methods Retrospective audit of 1697 consecutive, unrelated probands referred to a specialised, multidisciplinary clinic between 2002 and 2020. 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 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 15-20%, 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. Conclusion 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 likely pathogenic or pathogenic (LP/P) 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 an additional 5%.