Journal Article

Genomic and clinical predictors of cardiovascular disease in Familial dyslipidemia: risk stratification in Egyptian adolescents and young adults

Ashaat, Neveen A, Ashaat, Engy A, Abbas, Mohamed H, Dimitry, Mark O, Basha, Walaa A, Reda, Ashraf, Kamel, Iman H, Metwally, Ammal M, Elaraby, Nesma M, Ezzat, Wafaa M, El Mawardy, Tarek R, Elshaarawy, Ghada A, Bendary, Ahmed

2025

Overview

Familial dyslipidemia (FD), particularly familial hypercholesterolemia (FH), is a major contributor to premature cardiovascular disease (CVD), especially in regions with high consanguinity and underutilized genetic screening, such as Egypt. This study aimed to assess clinical, biochemical, and genetic factors that differentiate FD patients with and without CVD, and to develop a composite risk score for individualized stratification. A cross-sectional study was conducted on 60 Egyptian patients aged 15–25 years with genetically confirmed FD, equally divided based on CVD status. All participants underwent detailed clinical assessment, lipid profiling, and targeted next-generation sequencing of LDLR, APOB, and PCSK9 genes. Missense variants were evaluated using SIFT, PolyPhen-2, CADD, and ΔΔG stability scores, and classified according to ACMG criteria. Compared to non-CVD patients, those with CVD had significantly higher triglyceride levels (median: 356.5 vs. 236.5 mg/dL; p < 0.001) and a higher frequency of heterozygous pathogenic LDLR variants (30.0% vs. 3.3%; p = 0.006), while homozygous variants were more common in non-CVD patients (26.7% vs. 0%; p = 0.002). Deleterious missense variants were notably more frequent in the CVD group (56.7% vs. 10.0%; p < 0.001). A 10-variable composite risk score integrating clinical, lipid, and bioinformatic predictors effectively distinguished high- and moderate-risk cases (AUC = 0.742; p = 0.022), with 89.5% sensitivity and 81.8% negative predictive value. The study highlights the importance of combining clinical and genomic data for early risk stratification and introduces a pragmatic tool for identifying high-risk youth in resource-limited, consanguineous populations.

• Publisher: Springer Nature B.V
• Subject: Anthropometry / Atherosclerosis / Bioinformatics / Cardiovascular disease / Cardiovascular diseases / Cholesterol / Chronic illnesses / Clinics / Congenital diseases / Consanguinity / Diabetes / Disease prevention / Dyslipidemia / Family medical history / Genetic factors / Genetic screening / Genetic testing / Genomics / Genotype & phenotype / Hypercholesterolemia / Hyperlipidemia / Lipids / Metabolic disorders / Next-generation sequencing / Patients / Population / Sample size / Young adults