Genetic Spectrum and Lipid Profiles of 46 Chinese Children With Dyslipidemia Analyzed by Whole-Exome Sequencing: A 10-Year Single-Center Retrospective Study

Objective To characterize the genetic spectrum and lipid phenotypes of Chinese children with dyslipidemia using whole-exome sequencing (WES) and to explore genotype–phenotype correlations. Methods We retrospectively analyzed 46 children with dyslipidemia who underwent WES at Shanghai Children’s Medical Center between June 2015 and September 2025. Clinical characteristics, seven lipid parameters, and family histories were collected. Based on WES findings, patients were classified into five subgroups: (1) WES-negative, (2) FH-pathway variants ( LDLR , PCSK9 , APOB ), (3) ABCG5/8 mutations, (4) triglyceride-related variants ( APOA5 , LPL ), and (5) other rare mutations ( LIPC , JAG1 , APOE ). Comparative analyses were performed among the first three major groups, and longitudinal lipid changes were evaluated in patients with ≥ 6-month follow-up to assess post-diagnostic management outcomes. Results Among 46 children (18 males, 28 females; mean age 7.88 ± 4.00 years), 33 of 40 (82.5%) had a positive family history of hyperlipidemia, and tendon xanthomas were detected in 8 of 39 (20.5%). The overall molecular diagnostic yield of WES was 84.8% (39/46). Variants in the FH-related pathway were most common (58.7%, 27/46), followed by ABCG5/8 mutations (13.0%), triglyceride-related variants (6.5%), and other rare variants (6.5%). Median TC, LDL-C, and ApoB levels tended to be higher in both FH-pathway and ABCG5/8 subgroups compared with WES-negative cases, though the differences were not statistically significant. Notably, children carrying heterozygous ABCG5/8 variants showed lipid patterns closely resembling those with heterozygous LDLR mutations. Thirteen patients completed approximately 6 months of follow-up (9 pharmacologic, 4 lifestyle interventions), showing a modest, nonsignificant decrease in LDL-C levels. Conclusions This 10-year cohort revealed a high molecular diagnostic yield of WES and defined the genetic landscape of pediatric dyslipidemia in Chinese children. Beyond confirming LDLR as the predominant causal gene, our findings highlight that heterozygous ABCG5/8 variants can manifest LDLR -like biochemical profiles, suggesting clinically relevant phenotypic effects despite their recessive nature. Incorporating WES into the routine evaluation of children with severe or unexplained dyslipidemia may refine genetic classification, enable targeted interventions, and improve family-based prevention strategies.