Novel Genetic Contributors to Premature Coronary Artery Disease: Insights from Whole-Exome Sequencing in Families with Early Onset Disease

Coronary artery disease (CAD) is a leading global cause of mortality, with genetic predisposition conferring a more than two-fold increased risk in individuals with a family history of premature disease. This study aimed to identify rare genetic variants underlying inherited premature CAD (PCAD) in familial cases. Fifty unrelated Iranian families with early-onset familial CAD/MI were recruited. Inclusion required at least two affected members with PCAD (< 45 years in men, < 55 years in women) across generations. Whole-exome sequencing (WES) was performed using the Illumina DRAGEN Bio-IT platform for alignment and variant-calling, and Ilyome for annotation. Sanger sequencing was used for co-segregation analysis in additional family members. The study identified novel and rare variants potentially linked to CAD in eight genes, all of which co-segregated with familial premature CAD in eight unrelated families. Among the novel candidates, PIKFYVE emerged as the most compelling primary candidate, supported by its established role in cardiac calcium homeostasis, platelet function, and vascular biology. Three additional genes ( PKP2 , CAPN5 , OBSCN ) represent secondary novel findings that warrant further investigation. These findings expand the genetic architecture of familial PCAD and highlight the value of WES in early-onset familial cases. GTEx expression data supported the biological relevance of candidate genes. Functional studies are warranted to confirm pathogenicity of the identified variants.