👤 Neveen A Ashaat

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. Show less

Early childhood obesity is a real public health problem worldwide. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Measurement of serum leptin levels is helpful in the diagnosis of congenital leptin and leptin receptor deficiencies which are considered important rare causes of early childhood obesity. The main aim of this study was to investigate the frequency of LEP, LEPR, and MC4R gene variants among a cohort of Egyptian patients with severe early onset obesity. The current cross-sectional study included 30 children who developed obesity during the first year of life with BMI > 2SD (for age and sex). The studied patients were subjected to full medical history taking, anthropometric measurements, serum leptin and insulin assays, and genetic testing of LEP, LEPR and MC4R. Disease causing variants in LEP and LEPR were identified in 10/30 patients with a detection rate of 30%. Eight different homozygous variants (two pathogenic, three likely pathogenic, and three variants of uncertain significant) were identified in the two genes, including six previously unreported LEPR variants. Of them, a new frameshift variant in LEPR gene (c.1045delT, p.S349Lfs*22) was recurrent in two unrelated families and seems to have a founder effect in our population. In conclusion, we reported ten new patients with leptin and leptin receptor deficiencies and identified six novel LEPR variants expanding the mutational spectrum of this rare disorder. Furthermore, the diagnosis of these patients helped us in genetic counseling and patients' managements specially with the availability of drugs for LEP and LEPR deficiencies. Show less