Clinical and genetic analysis of an early-onset sitosterolemia family caused by a novel compound heterozygous ABCG5 mutation.

BACKGROUND

Sitosterolemia (STSL) is a rare autosomal recessive disorder caused by biallelic mutations in ABCG5 or ABCG8, which encode sterolin efflux transporters. Defective transport leads to intestinal hyperabsorption and reduced biliary excretion of plant sterols and cholesterol, causing their accumulation and heterogeneous phenotypes often misdiagnosed as familial hypercholesterolemia.

METHODS

Whole-exome sequencing was performed in a 3-year-old child with early-onset hypercholesterolemia. Candidate variants were validated by Sanger sequencing of family members, followed by genotype-phenotype analysis. Plasma plant sterols were quantified by gas chromatography-mass spectrometry, and structural modeling was used to predict the impact of variants.

RESULTS

The proband developed multiple xanthomas over the knees, elbows, ankles, finger joints and skin folds at 2 years of age. Her father and grandfather had obesity and hypercholesterolemia with fatty liver but no xanthomas. Genetic analysis identified a novel compound heterozygous ABCG5 mutation: c.1337G > A (p.Arg446Gln), inherited from the father and classified as likely pathogenic, and c.1396G > C (p.Ala466Pro), inherited from the mother and classified as a variant of uncertain significance according to ACMG guidelines. Segregation supported the genotype-phenotype correlation. Plasma sterol profiling showed elevated cholestanol, desmosterol, campesterol, stigmasterol and sitosterol with normal squalene and lathosterol. Ezetimibe plus a low-plant-sterol diet improved xanthomas and biochemical parameters. Structural modeling demonstrated conformational changes and reduced hydrogen bonding for both variants, suggesting impaired protein stability.

CONCLUSION

The missense variants c.1337G > A (p.Arg446Gln) and c.1396G > C (p.Ala466Pro) in exon 10 of ABCG5 likely represent the molecular genetic basis of STSL in this family.