Population enrichment of ABCG5/ABCG8 variants in Qatar and genetic estimates of sitosterolemia burden.

Sitosterolemia is a rare autosomal recessive disorder caused by pathogenic variants in ABCG5 or ABCG8, leading to plant sterol buildup and variable low-density lipoprotein cholesterol levels. Its symptoms often mimic familial hypercholesterolemia (FH), making diagnosis difficult since standard lipid panels do not measure plant sterols. We aimed to estimate the genetic burden of sitosterolemia in Qatar using pathogenic ABCG5/ABCG8 variants METHODS: We interrogated the ABCG5/ABCG8 variation in 14,060 Qatar Genome Program participants linked to Qatar Biobank phenotypes. Variants were annotated using ClinVar and gnomADv4.1 and classified according to American College of Medical Genetics and Genomics criteria. The carrier frequency was estimated in 5385 unrelated Qataris, incorporating a recessive disease burden model that accounted for inbreeding. We observed 7 pathogenic/likely pathogenic variants (3 in ABCG5; 4 in ABCG8) and identified 4 novel predicted loss‑of‑function variants in ABCG8. Estimated carrier frequencies were ∼1:215 (ABCG5) and ∼1:192 (ABCG8), yielding a combined ∼1:102 and an overall disease burden of ∼1:7509 in Qatar, markedly exceeding gnomAD estimates (∼1:251 carrier frequency; ∼1:383,744 disease burden). Several variants had homozygous individuals with abnormal lipid profiles and self‑reported hypercholesterolemia, suggestive of a potential FH-like phenotype. ABCG5/ABCG8 variants are enriched in Qatar relative to global datasets, consistent with population structure and consanguinity. Given the phenotypic overlap with FH but distinct therapeutic implications (notably superior response to ezetimibe and dietary sterol restriction), we propose integrating ABCG5/ABCG8 into dyslipidemia diagnostic workflows, especially in FH clinics, pediatrics, and ancestry-informed screening programs in the Middle-East and North Africa (MENA) region. These data highlight the potential value of plant-sterol testing and ABCG5/ABCG8 screening to reduce misdiagnosis, guide treatment, and enable cascade testing.