Genetic Landscape of Inherited Cardiovascular Diseases and Risk Stratification in the Russian Population Using a Targeted Next-Generation Sequencing Panel and the Local GDBPop Database

Background: Sudden cardiac death (SCD) is a major contributor to cardiovascular mortality, frequently stemming from undiagnosed genetic predispositions. In clinical practice, underlying genetic risks are often masked by prevalent conditions such as ischemic heart disease and hypertension, necessitating precise molecular characterization of inherited cardiovascular conditions. Objectives: This study aims to evaluate the diagnostic yield of a targeted next-generation sequencing (NGS) panel in a cohort of patients with diverse cardiovascular pathologies and to refine variant interpretation using a population-specific genetic database. Methods: We conducted a prospective, observational cohort study involving targeted NGS on 270 DNA samples from patients with documented cardiovascular disease. The cohort presented with a broad spectrum of phenotypes, including ischemic heart disease, hypertension, conduction disorders, arrhythmias, cardiomyopathies, and dyslipidemias. Genetic variants were classified according to ACMG/AMP guidelines. To minimize false-positive findings, we implemented a bioinformatic pipeline leveraging the Russian Population Genetic Variant Frequency Database (GDBPop) to filter out benign variants common in the local population but rare in global repositories like gnomAD. Results: Seventeen pathogenic or likely pathogenic (P/LP) genetic variants spanning 13 different genes across 15 distinct molecular loci were identified in 15 subjects out of 270 subjects (5.56%), with two individuals carrying concurrent alterations (Patient 6326 with two variants in LDLR, and Patient 6284 with variants in FHOD3 and KCNH2). The identified genetic spectrum was predominantly driven by alterations within the KCNH2, LDLR, and LMNA genes. Conclusions: A targeted NGS panel combined with regional genetic databases provides a robust strategy for identifying potential genetic predispositions to cardiovascular disorders. This observational screening approach effectively captures clinically relevant variants across a broad phenotypic spectrum, supporting personalized variant interpretation in the Russian population.