Targeted sequencing provides genetic insights into familial cardiovascular disease among young adults in a high consanguinity population

BACKGROUND: Cardiovascular diseases (CVDs) account for approximately 19.8 million deaths annually, with coronary artery disease (CAD) as a major contributor. Genetic factors play an important role in CVD development. Genetic risk can be attributed to monogenic and polygenic risk variants. Patients with rare, Mendelian monogenic CVDs have been shown to have mutations in many causative genes, including LRP6, MEF2A, CYP27A1, and ST6GALNAC5. METHODS: A case-control study was conducted at two tertiary care hospitals in Peshawar, Pakistan, Lady Reading Hospital and Peshawar Institute of Cardiology. The study included 20 patients with familial CVDs diagnosed through clinical and laboratory investigations and 20 matched healthy controls. Whole blood and relevant clinical-demographic data were collected, with matched control samples selected by age, gender, and family background, with minimizing variability to ensure accurate comparison. A total of 5 mL of blood was drawn from each patient and transported to the Molecular and Genomic Laboratory (IPDM) at Khyber Medical University. DNA was extracted from the collected samples, and targeted PCR and Sanger sequencing were performed. The sequencing data were analyzed using bioinformatics tools such as FinchTV and BioEdit. RESULTS: The analysis demonstrated the presence of mutations in 12 out of 20 patient's DNA, including LRP6 gene variants (146344T > A in two patients, 146345A > G in three, and 92497C > A and 94776T > A in one each), MEF2A gene variants (113826A > T in one patient and 113802T > A in two), and CYP27A1 gene variants (5924G > C and 6016G > A in one patient each). CONCLUSION: This study identified genetic variants in the LRP6, MEF2A, and CYP27A1 genes among young patients with familial CVD using targeted PCR and Sanger sequencing. The detection of these variants in a proportion of cases suggests a possible genetic contribution within the studied cohort. However, further studies with larger sample sizes and advanced sequencing approaches (WGS/NGS) are required to confirm the clinical significance of these findings.