ABCG5-related dysregulation of phytosterol metabolism and growth impairment: a family-based observational study.

Sitosterolemia is classically described as an autosomal recessive disorder caused by biallelic pathogenic variants in ABCG5 or ABCG8. Emerging evidence suggests that heterozygous carriers may exhibit subtle biochemical or clinical features, prompting a re-evaluation of its inheritance paradigm. This study aimed to characterize the clinical and biochemical phenotypes-particularly childhood linear growth and plasma phytosterol levels-in individuals harboring ABCG5 variants, and to explore the association between specific genotypes and phytosterol accumulation. Clinical and genetic data from three families with ABCG5 variants were retrospectively analyzed, and childhood height was evaluated relative to mid-parental target height. In one family with unexplained markedly elevated sitosterol, whole-genome sequencing (WGS) was performed to investigate potential noncoding variants. A candidate variant, c.-162 T > C (p.( =)), was annotated using the Ensembl Variant Effect Predictor (VEP) and functionally evaluated by dual-luciferase assays. Participants were stratified by genotype into wild-type (WT), heterozygous (Het), and compound heterozygous (cHet) groups to compare plasma sitosterol levels. Four children with ABCG5 variants had elevated plasma sitosterol and heights below mid-parental targets, with their heights all falling between the 3rd and 20th percentile; individuals with biallelic ABCG5 variant combinations showed more pronounced growth impairment. Their parents all had normal adult heights. Sitosterol levels varied by genotype: heterozygous c.1336C > T (p.Arg446Ter) (41.7 μmol/L); a compound heterozygote with c.1336C > T (p.Arg446Ter) and ABCG5 exons 1-4 deletion (668.4 μmol/L); a trans-heterozygote carrying c.1336C > T (p.Arg446Ter) and c.-162 T > C (p.( =)) (193.9 μmol/L); and a heterozygous carrier of c.-162 T > C (p.( =)) showing mildly elevated sitosterol (19.2 μmol/L). The c.-162 T > C (p.( =)) variant is a 5' UTR variant in the second most abundant ABCG5 liver isoform; dual-luciferase assays showed a modest, non-significant reduction in promoter activity, but combined clinical, genetic, and biochemical data support its potential pathogenicity. Sitosterol levels exhibited a trend consistent with gene dosage, with the highest concentrations in the cHet group, intermediate levels in the Het group, and the lowest in the WT group. Biallelic ABCG5 variants are associated with childhood growth impairment. The c.-162 T > C (p.( =)) variant is likely pathogenic, though its role requires further validation. Integrated sterol profiling and comprehensive genetic analysis in familial contexts are essential for clarifying clinical status and inheritance.