Genetic variants associated with cardiac hypertrophy-related sudden cardiac death and cardiovascular outcomes in a Finnish population

• Published in: Heart (British Cardiac Society) Vol. 111; no. 2; pp. 55 - 61
• Main Authors: Doedens, Anne, Skarp, Sini, Holmström, Lauri, Pakanen, Lasse, Saarimäki, Samu, Kerkelä, Risto, Pylkäs, Katri, Huikuri, Heikki V, Junttila, Juhani
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Cardiovascular Society 01.01.2025; BMJ Publishing Group LTD
• Subjects: Adult; Aged; Arrhythmias and sudden death; Autopsies; Autopsy; Body mass index; Cardiomyopathy; Cardiomyopathy, Hypertrophic - complications; Cardiomyopathy, Hypertrophic - genetics; Cardiovascular disease; Coronary vessels; Death, Sudden, Cardiac - epidemiology; Death, Sudden, Cardiac - etiology; Disease prevention; Enzymes; Exome Sequencing; Female; Fibrosis - genetics; Finland - epidemiology; Genes; Genetic Predisposition to Disease; Genetic Variation; Genetics; Genomes; Genomics; Health risk assessment; Heart; Humans; Hypertension; Hypertension - complications; Hypertension - genetics; Hypertrophy, Left Ventricular - genetics; Ischemia; Male; Middle Aged; Proteins; Sudden cardiac death; Finland; Hypertension; Sudden cardiac death; Genetics
• ISSN: 1355-6037; 1468-201X; 1468-201X
• DOI: 10.1136/heartjnl-2024-324623

BackgroundHypertrophic cardiomyopathy is a common cause of non-ischaemic sudden cardiac death (SCD). Left ventricular hypertrophy (LVH) without cardiomyopathy-related myocardial disarray is a common autopsy finding and is often associated with prior hypertension in SCD subjects. Our aim was to investigate novel rare gene variants among SCD subjects with presumably hypertension-related LVH and myocardial fibrosis at autopsy.MethodsWhole exome sequencing was used to study rare variants (minor allele frequency<0.005) estimated to be deleterious in 96 non-ischaemic SCD subjects with presumably hypertension-related LVH and myocardial fibrosis. Associations of the identified variants with cardiac disease endpoints were replicated in the Finnish national genetic study (FinnGen) dataset.Results18 variants were estimated likely to affect protein function and 14 of these were associated with cardiomyopathies, heart failure, conduction abnormalities, hypertension and/or cardiac arrest in Finnish population (FinnGen). Three of the variants were classified as pathogenic or likely pathogenic. These include the splice site variant NM_000449.3:c.234-1G>A in regulatory factor X5 and frameshift variants NM_000449.3:c.234-1G>A in dehydrogenase/reductase 7C and NM_015873.3:c.1164del in villin like.ConclusionsWe identified rare deleterious variants associated with LVH in SCD subjects. Several of the identified rare variants associated with cardiovascular endpoints including heart failure, cardiomyopathies, cardiac arrest and hypertension in general population.