**Background:** Dyslipidemia, particularly hypercholesterolemia, is a growing concern in children and adolescents and is a recognized risk factor for premature atherosclerotic cardiovascular disease (ASCVD). Precise diagnosis, especially through genetic testing, is crucial for pediatric patients because it influences prognosis and treatment decisions. In China, genetic diagnosis of hypercholesterolemia in children is underutilized. This study aimed to identify molecular defects using whole-exome sequencing (WES) in a cohort of Chinese pediatric patients with hypercholesterolemia to improve diagnostic accuracy and guide management.
**Methods:** This single-center retrospective study included pediatric patients (<18 years) with dyslipidemia from the Department of Endocrinology and Metabolism at Shanghai Children’s Medical Center (2015–2021). Inclusion criteria were: (1) persistent hypercholesterolemia (LDL-C ≥3.60 mmol/L on two occasions ≥3 months apart), (2) premature ASCVD, (3) tendon xanthomas, or (4) hypercholesterolemia with family history. Exclusion criteria included secondary causes (e.g., diabetic ketoacidosis, severe liver/kidney disease). After screening 35 patients, 30 were enrolled (13 males, 17 females; mean age 6.42±3.20 years). Clinical data, including lipid profiles (TC, LDL-C, HDL-C, TG, ApoA1, ApoB, Lp(a)), were collected. WES was performed on peripheral blood, and variants were filtered by minor allele frequency <1% and classified per ACMG guidelines. Sanger sequencing confirmed variants in patients and parents. Statistical comparisons used t-tests, Mann-Whitney U, or Fisher exact tests as appropriate.
**Key Results:** Positive genetic results were found in 63.33% (19/30) of patients. A total of 25 variants were identified, 7 of which were novel. The most frequently mutated gene was LDLR (13 patients), followed by ABCG5/ABCG8 (5 patients), and less commonly LIPC, LPL, and CETP. Two patients had variants in two different genes. Patients with positive genetic results had significantly higher mean levels of TC (8.56±2.12 vs. 6.33±1.15 mmol/L, p<0.001), LDL-C (6.48±2.27 vs. 4.30±1.01 mmol/L, p=0.002), ApoB (1.74±0.57 vs. 1.26±0.32 g/L, p=0.002), and Lp(a) (67.01±63.86 vs. 26.74±39.85 nmol/L, p=0.018) compared to those with negative results. Family history of hypercholesterolemia was present in 86.67% of the positive group vs. 0% in the negative group (p<0.001). No significant differences were found between LDLR and ABCG5/8 heterozygous subgroups in lipid levels or clinical features. Tendon xanthomas were present in 6 patients (20%), of whom 5 had positive genetic results (83.33% diagnostic rate).
**Clinical Implications:** This study demonstrates that WES can identify a genetic cause in a substantial proportion (63.33%) of Chinese pediatric patients with persistent hypercholesterolemia, with LDLR and ABCG5/8 being the most common. The findings underscore the importance of genetic testing beyond traditional FH gene panels, as variants in ABCG5/8, LPL, LIPC, and CETP were identified, which are often missed. Notably, heterozygous ABCG5/8 variants may be underestimated, especially in patients with xanthomas. Elevated ApoB and Lp(a) levels in genetically positive patients may serve as biomarkers for monogenic hypercholesterolemia. Genetic diagnosis can guide treatment decisions, as some conditions (e.g., sitosterolemia due to ABCG5/8 variants) require specific management. Limitations include small sample size, lack of a control group, and potential selection bias due to inclusion of patients with xanthomas. Larger studies are needed to validate these findings and establish screening guidelines.