Journal Article

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

Bagnall, Richard D., Nowak, Natalie, Ryan, Mark P., Raju, Hariharan, Ingles, Jodie, Gray, Belinda, Medi, Caroline, Richmond, David, Butters, Alexandra, Sy, Raymond W., Isbister, Julia C., Yeates, Laura, Stafford, Fergus, Krishnan, Neesha, Semsarian, Christopher, Hespe, Sophie, Richardson, Ebony, Singer, Emma S., Burns, Charlotte

2022

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cardiovascular diseases / Care and treatment / Diagnosis / Genetic screening / Genetic Testing / Genomics / Heart / Heart Diseases - diagnosis / Heart Diseases - genetics / Heart Diseases - therapy / Human Genetics / Humans / Inherited cardiac conditions / Medical tests / Medicine/Public Health / Metabolomics / Phenotype / Retrospective Studies / Sudden cardiac death / Systems Biology