Key result
Targeted NGS identifies pathogenic variants in ~6% of cardiovascular disease patients, led by KCNH2, LDLR, and LMNA.
Why the study?
Sudden cardiac death frequently stems from undiagnosed genetic predispositions that are often masked by prevalent conditions like ischemic heart disease and hypertension. This necessitates precise molecular characterization and population-specific variant interpretation for inherited cardiovascular conditions.
Does a targeted next-generation sequencing panel combined with the Russian Population Genetic Variant Frequency Database improve the diagnostic yield and variant interpretation of inherited cardiovascular diseases in the Russian population?
Cohort (n=270)
Does a targeted next-generation sequencing panel combined with the Russian Population Genetic Variant Frequency Database improve the diagnostic yield and variant interpretation of inherited cardiovascular diseases in the Russian population?
Combining a targeted NGS panel with a local Russian population genetic database (GDBPop) identifies pathogenic or likely pathogenic cardiovascular variants in 5.56% of patients across a broad spectrum of cardiovascular phenotypes while minimizing false-positive findings.
May aid molecular diagnosis in unexplained SCD; leaves open optimal panel use and prospective validation before routine adoption.
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.
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Shipulin et al. (2026) conducted a cohort in Cardiovascular diseases (ischemic heart disease, hypertension, conduction disorders, arrhythmias, cardiomyopathies, and dyslipidemias) (n=270). Targeted next-generation sequencing (NGS) panel and Russian Population Genetic Variant Frequency Database (GDBPop) was evaluated on Diagnostic yield of pathogenic or likely pathogenic (P/LP) genetic variants. Targeted NGS combined with the GDBPop database identified 17 pathogenic or likely pathogenic variants in 5.56% (15/270) of cardiovascular disease patients, primarily in KCNH2, LDLR, and LMNA.
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