A Maltese landscape of cardiac genetics

Abstract

Abstract Introduction Advances in human genetics have improved our understanding of various inherited cardiovascular conditions (ICC). Genetic testing is now an important pillar in the management of patients suffering from cardiomyopathies, channelopathies and aortic and other vascular disorders. Existing population databases may not cater for the local gene pool. The local genetic yield of ICCs has never been explored. Objective The aim of this study was to evaluate the population referred for genetic testing and to assess the genetic yield according to the referring phenotype. Methodology Probands referred for genetic testing between 2018-2022 were included. Data was retrospectively reviewed in close liaison with the molecular genetics lab at a university. Variants classified as pathogenic or likely pathogenic by ACMG criteria were labelled as ‘gene positive’ for the purpose of this study. Results 328 patients were referred for genetic testing (63.7% Male, 51.3±18.7 years). The majority were referred because of a cardiomyopathy phenotype (64.02%) followed by arrhythmic disorders (20.7%), aortic/vascular disorders (12.5%), familial hyperlipidaemia (1.5%) and complex congenital heart disease (0.6%). Two (0.6%) did not have a reason specified. 94 (28.7%) probands were gene positive, 5 patients (1.5%) had two mutations, 41.4% of all mutations were novel. The highest genetic yield was seen in cardiomyopathy patients (34.8%), followed by aortic/vascular disorders (24.4%) and arrhythmic disorders (14.7%). A separate analysis was also performed for each individual phenotype (Table 1). The dominant genes for each condition: MYH7 (24.4%) and MYBPC3 (22.0%) for hypertrophic cardiomyopathy; TTN (52.9%) and FLNC (23.5%) for dilated cardiomyopathy; DSG2 (45.5%) and FLNC (18.2%) for arrhythmogenic cardiomyopathy; TTN (40.0%) and MYH7 (40.0%) for left ventricular non-compaction cardiomyopathy; TTR (100%) for cardiac amyloid; SCN5A (37.5%) for non-specific cardiomyopathy; KCNH2 (50.0%) and KCNQ1 (50.0%) for long QT syndrome; SCN5A (37.5%) for Brugada Syndrome; FBN1 (40.0%) for skeletal phenotype; FBN1 (33.3%) for aortic phenotype; and LDL-R (100.0%) for familial hyperlipidaemia Conclusion The overall ICC genetic yield in Malta is 28.7%. A substantial proportion were novel mutations. The highest genetic yield is in the cardiomyopathy group. The yield for most phenotypes is comparable to other labs. The proportion of gene positive LQTS patients is surprisingly very small, a phenotype with an established high genetic yield in various studies (up to 80%). Clinicians caring for patients with ICCs now have local diagnostic yield data to better counsel patients when referred for genetic testing.