Whole-exome sequencing in obstructive coronary artery disease identifies rare and novel variants in cardiac arrhythmia and pulmonary arterial hypertension-associated genes.

PMID 41564389 | PMCID PMC13021037 | DOI 10.17305/bb.2026.13200 · Biomolecules & biomedicine · 2026

Coronary artery disease (CAD) represents a complex interplay of genetic, environmental, and lifestyle factors. In this study, we utilized whole-exome sequencing (WES) on 28 patients with obstructive CAD to identify rare variants that may influence clinical outcomes beyond conventional atherosclerotic risk. We examined 74 genes curated from the Genomics England PanelApp, focusing on familial hypercholesterolemia (FH), cardiac arrhythmias (CA), and pulmonary arterial hypertension (PAH), ultimately detecting 8,251 variants. After applying a stringent filtering process with a population maximum allele frequency (PopMax AF) threshold of <0.1%, we identified 68 candidate variants across 23 genes. The majority were associated with CA (47/68, 69%), followed by PAH (12/68, 18%) and FH (9/68, 13%). Notably, 30 variants (44%) were novel, and 18 were categorized as high-impact frameshift mutations. The highest burden of candidate variants was found in the sodium voltage-gated channel alpha subunit 10 (SCN10A), followed by the ryanodine receptor 2 (RYR2), mitochondrial seryl-tRNA synthetase 2 (SARS2), A-kinase anchoring protein 9 (AKAP9), and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4). Clinical evaluation revealed a pathogenic variant in the low-density lipoprotein receptor (LDLR) and likely pathogenic variants in sodium voltage-gated channel alpha subunit 5 (SCN5A) and potassium voltage-gated channel subfamily Q member 1 (KCNQ1); additionally, nine other variants were predicted to be deleterious, including five novel SCN10A variants. Functional annotation using Gene Ontology (GO) and Human Phenotype Ontology (HPO) highlighted mechanisms impacting cardiac structure, electrical conduction, and lipid homeostasis.