Double heterozygosity for variants in ABCG8 and ABCG5 and potential association with sitosterolemia

Abstract

Background/Synopsis

Sitosterolemia is a rare autosomal recessive lipid disorder caused by pathogenic variants in the ABCG5 and/or ABCG8 genes. These genes encode ATP-binding cassette transporters responsible for the regulation of sterol absorption and excretion. Sitosterolemia leads to the accumulation of plant sterols in the blood, resulting in hypercholesterolemia, xanthomas, premature atherosclerosis, and other complications. We present the case of an individual with abnormal plant sterol levels and heterozygous variants in both genes. This case supports nascent evidence that double heterozygosity in ABCG5 and ABCG8 could lead to sitosterolemia.

Objective/Purpose

Very few cases of double heterozygosity in ABCG5 and ABCG8 leading to sitosterolemia have been reported in the literature. This case adds to the growing body of evidence supporting this association.

Methods

Comprehensive cholesterol balance panel including plant sterols was performed through a commercial laboratory (Boston Heart Diagnostics). Genetic testing was performed through a direct-to-consumer (DTC) testing platform and results validated through a CLIA-approved laboratory. The effectiveness of interventions was assessed through biochemical markers and clinical assessment.

Results

A 24-year-old female with syncope episodes and gastrointestinal symptoms underwent comprehensive testing including a cholesterol panel that showed elevated low-density lipoprotein (125 mg/dL) and considerably elevated plant sterol levels (Beta-sitosterol 244 µmol x 100/mmol and Campesterol 345 µmol x 100/mmol) suggestive of sitosterolemia. Genetic testing identified a pathogenic heterozygous variant in the ABCG8 gene (rs137852987 G>A), as well as a heterozygous variant of uncertain significance in the ABCG5 gene (rs778605187 G>C). Based on laboratory results and clinical findings, the patient received a presumptive diagnosis of sitosterolemia. Dietary changes and ezetimibe therapy resulted in significant symptom improvement, reduction in LDL levels, and normalization of plant sterol levels.

Conclusions

This case underscores the need for further research into the clinical impact of heterozygous and VUS mutations in ABCG5/ABCG8. It highlights the importance of personalized dietary and pharmacologic interventions in managing sitosterolemia-like presentations. The findings have implications for the evaluation and management of patients with rare genetic disorders, particularly those involving sterol metabolism.