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

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.

Keywords: Genetic testing; Inherited cardiac conditions; Sudden cardiac death.

Fig. 1

A Monogenic disease score, B diagnostic yield of genetic testing based on monogenic disease scores, and C frequency and diagnostic yield among individuals with different clinical features suggesting monogenic disease. Abbreviations: LP/P, likely pathogenic and pathogenic; S-VUS, suspicious variant of uncertain significance; ICD, implantable cardioverter defibrillator

Fig. 2

Flow diagram of included probands and their outcomes. Abbreviations: LP/P, likely pathogenic and pathogenic variants; VUS, suspicious variant of uncertain significance

Fig. 3

Diagnostic yield of genetic testing among all patients. Abbreviations: P, pathogenic; LP, likely pathogenic; S-VUS, suspicious variant of uncertain significance

Fig. 4

Impact of genomics in clarifying or changing the overall diagnosis. Baseline phenotype of ARVC included those who met the 2010 Task Force Criteria. Abbreviations: ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; LVNC, left-ventricular non-compaction; CPVT, catecholaminergic polymorphic ventricular tachycardia; ACM, arrhythmogenic cardiomyopathy

Fig. 5

Diagnostic yield of genetic testing by major ancestry groups. ‘Other ancestry’ includes Oceanian and People of the Americas. The proportion of suspicious VUS compared between ancestry groups using chi-square. Abbreviations: LP/P, likely pathogenic and pathogenic variants; VUS, variant of uncertain significance