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High Prevalence of Sitosterolemia in the Middle East: Insights from Genetic Prevalence Estimates

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Population Genetics
  • Secondary Categories:
    • Population Genetics
Introduction:
Sitosterolemia (also known as phytosterolemia, MIM 210250) is an autosomal recessive condition caused by homozygous or compound heterozygous mutations in ABCG5 (sitosterolemia 1) or ABCG8 (sitosterolemia 2) genes.  Affected individuals have elevated levels of plant sterols, primarily beta-sitosterol and campesterol, due to increased intestinal absorption and impaired biliary excretion caused by defects in the ABCG5 or ABCG8 genes. Sitosterolemia is often misdiagnosed as familial hypercholesterolemia due to overlapping clinical features, including xanthomas, premature cardiovascular disease, and normal or moderately elevated plasma cholesterol levels. Other clinical manifestations include arthralgia and hematological abnormalities such as hemolytic anemia with stomatocytosis and macrothrombocytopenia. Approximately 110 cases of molecularly confirmed sitosterolemia have been documented worldwide. Since routine plasma lipid panels do not measure plant sterols, the condition is likely underdiagnosed. In our study, we aimed to estimate the genetic prevalence of sitosterolemia in the Middle East population using Qatar Biobank (QBB) and Qatar Genome Program (QGP) data.

 

Methods:
Genome sequencing data of 14,060 Qatari participants from QGP were examined for disease-causing variants in ABCG5 and ABCG8 genes. Carrier frequency and disease burden were estimated using a cohort of 5,385 unrelated individuals. Carrier frequency for variant x was calculated as follows: carrier frequency (x) = (number of occurrences of x in the heterozygous state) / (total number of samples screened – number of occurrences of x in the homozygous state). Due to the inbred nature of our population, we applied the inbreeding coefficient (qF) to estimate the disease burden. The global genetic prevalence of ABCG5 and ABCG8 genes were obtained using the GeniE (the Genetic Prevalence Estimator) tool. GeniE utilizes allele frequencies from the gnomAD database to estimate the prevalence of autosomal recessive diseases using the Hardy-Weinberg principle .



 

Results:
We found eight known pathogenic//likely pathogenic (PLP) SNVs, including three in ABCG5 associated with sitosterolemia 1 and five in ABCG8 associated with sitosterolemia 2. Among these eight variants, two of them have minor allele frequency (MAF) greater than 0.1% (ABCG5 c.1336C>T p. (Arg446Ter) – MAF 0.2%; ABCG8 c.965-1G>C – MAF 0.2%). Using ACMG classification, we identified four novel predicted loss-of-function (LOF) variants in ABCG8. Based on the eight known PLP variants, we estimated the carrier frequency to be 1:215 for sitosterolemia 1 and 1:180 for sitosterolemia 2. Disease burden estimation indicates a prevalence of 1:15,920 for sitosterolemia 1 and 1:13,267 for sitosterolemia 2. The combined carrier frequency of sitosterolemia (including sitosterolemia 1 and sitosterolemia 2) in the Qatari population is estimated at 1 in 98, with a disease burden of 1 in 7,237. We observed a homozygous pathogenic variant (ABCG8 c.1720G>A p.(Gly574Arg)) in a 47-year-old male participant with self-reported hypercholesterolemia. Notably, we identified a participant with a double heterozygous variant in ABCG5 (c.1336C>T p.(Arg446Ter)) and ABCG8 (c.965-1G>C) presenting with elevated cholesterol and LDL-C levels. We used GeniE to estimate the genetic prevalence of known PLP for ABCG5 and ABCG8 genes in the gnomADv4 database across eight out of nine gnomAD subpopulations (excluding the Middle Eastern population), to compare the prevalence of sitosterolemia in the Middle East with global estimates. We found 32 PLP in ABCG5 and 31 PLP in ABCG8 genes and estimated the combined carrier frequency of 1:430 and disease burden of 1:423,370 for sitosterolemia.

 

Conclusion:
Our findings demonstrate a substantially higher prevalence of sitosterolemia in Qatar, estimated to be around 60 fold higher than the prevalence reported in the gnomAD database. This elevated prevalence may be attributed to the high rates of consanguinity in the region, which increase the likelihood of autosomal recessive disorders. With cardiovascular diseases (CVDs) being the leading cause of death worldwide, a thorough understanding of their genetic basis and accurate diagnosis is essential.

 

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