👤 Joseph Galvin

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, affecting 1 in 500 people. With growing access to genetic testing and incorporation of genetics in diagnosis and management of HCM, it is important to identify phenotypic predictors of HCM genotype, to improve genetic targeting and counselling as well as cascade testing for first-degree relatives. This was a retrospective analysis of consecutive probands, aged over 18 years referred to a tertiary centre for HCM gene panel testing. Demographic information was obtained from clinic data. Left ventricular hypertrophy (LVH) pattern was classified based on trans-thoracic echocardiogram (TTE). Pathogenicity of variants was classified per the American College of Medical Genetics (ACMG) criteria. 166 patients were included for analysis. Mean age was 53 years (SD 14.28). 128 (77%) were male. 59 had a history of hypertension and 19 had a family history of sudden cardiac death (SCD). The most frequent HCM pattern at baseline was concentric HCM (31.9% n = 53). 48 patients had a likely pathogenic (LP) or pathogenic (P) variant, giving a genetic testing yield of 28.9%. The most common sarcomeric genes were MYBPC3 and MYH7 accounting for 57% of cases. Younger age, female sex, and reverse curve LVH pattern were predictors of a LP or P gene variant identification. Reverse curve morphology was found to be a significant predictor for a sarcomere variant (p < 0.001). Genetic testing was appropriately offered in this cohort. Younger age, female sex, family history of SCD, normal/well controlled blood pressure and reverse pattern LVH on TTE predicted a higher yield of pathogenic variant identification. Reverse curve morphology was found to be a significant predictor for a sarcomere variant. This study has implications for supporting better phenotype-based genetic counselling and resource usage for HCM patients. Show less

Inherited cardiomyopathies (HCM, DCM, ACM) and cardiac ion channelopathies (long QT/Brugada syndromes, CPVT) are associated with significant morbidity and mortality; however, diagnosis of a familial pathogenic variant in a proband allows for subsequent cascade screening of their at-risk relatives. We investigated the diagnostic yield from cardiac gene panel testing and reviewed variants of uncertain significance from patients attending three specialist cardiogenetics services in Ireland in the years 2002 to 2020. Reviewing molecular genetic diagnostic reports of 834 patients from 820 families, the initial diagnostic yield of pathogenic/likely pathogenic variants was 237/834 patients (28.4%), increasing to 276/834 patients (33.1%) following re-evaluation of cases with variant(s) of uncertain significance. Altogether, 42/85 patients with VUS reviewed (49.4%) had a re-classification that could change their clinical management. Females were more likely to carry pathogenic/likely pathogenic variants than males (139/374, 37.2% vs 137/460, 29.8%, respectively, p = 0.03), and the diagnostic yields were highest in the 0 to < 2 years age group (6/12, 50.0%) and amongst those tested for cardiomyopathy gene panels (13/35, 37.1%). Variants in the MYBPC3/MYH7 (87/109, 79.8%) and KCNQ1/KCNH2 (91/100, 91.0%) genes were the predominant genetic causes for hypertrophic cardiomyopathy and long QT syndrome, respectively. Our study highlights the importance of collation and review of pre-ACMG genetic variants to increase diagnostic utility of genetic testing for inherited heart disease. Almost half of patients with pre-ACMG VUS reviewed had their variant re-classified to likely pathogenic/likely benign which resulted in a positive clinical impact for patients and their families. Show less