Sitosterolemia via the ABCG5 Gene

Sitosterolemia is a disorder hallmarked by a 30-100 fold increase in plasma plant sterols. Heightened levels are due to defects in the adenosine triphosphate-binding cassette transporter protein which effluxes free sterols from hepatocytes and enterocytes into the gut lumen. The primary clinical features of sitosterolemia patients are tendon or tuberous xanthomas and accelerated atherosclerosis which have been reported in individuals as young as 4 years of age (Mymin et al. 2003). Hemolytic anemia, stomatocyte formation, and macrothrombocytopenia are common hematologic findings and may be the only clinically observed symptoms in patients (Wang et al. 2014; Escolá-Gil et al. 2014). Clinical colormetric enzyme assays to quantify sterols cannot discriminate between cholesterol and plant sterols making diagnosis difficult (Kidambi and Patel 2008). Genetic testing is helpful in the differential diagnosis of sitosterolemia from cerebrotendinous xanthomatosis, cardiovascular disease, and familial hypercholesterolemia. Ezetimibe, an inhibitor of intestinal cholesterol absorption, has been shown to be effective in reducing plasma sterol levels (Othman et al. 2015).

Sitosterolemia is inherited in an autosomal recessive manner with pathogenic variants in the ABCG5 and ABCG8 genes being responsible for 1/3 and 2/3 of cases respectively (Lee et al 2001; Escolá-Gil et al. 2014; Hubacek et al. 2001). The ABCG5 and ABCG8 genes encode the heterodimer adenosine triphosphate-binding cassette transporter protein present on enterocytes and hepatocytes. In enterocytes, the transporter is located on the apical membrane and promotes efflux of plant sterols back into the intestinal lumen. In the liver, the transporter is responsible for excretion of plant sterols into the bile (Lee et al. 2001). Pathogenic variants in the ABCG5 and ABCG8 genes impair transporter function or surface expression and result in elevated plasma plant sterol levels.

Loss of function pathogenic variants are most commonly found in the ABCG5 gene and include nonsense, frameshift, splice site alterations and gross deletions of exon 3. Missense variants, primarily occurring in exon 9, have also been reported to be causative for sitosterolemia (Lee et al. 2001; Escolá-Gil et al. 2014; Lu et al. 2001). ABCG5 pathogenic variants are more commonly found in patients of Chinese, Japanese, or Indian decent (Kidambi and Patel 2008).

To date, only about 100 cases of sitosterolemia have been reported (Escolá-Gil et al. 2014). In a series of 25 unrelated families with a diagnosis of sitosterolemia based on elevated plasma sitosterol levels, pathogenic variants in the ABCG5 and ABCG8 genes were found in 9 of 25 and 16 of 25 families respectively (Lu et al. 2001). Analytical sensitivity for detection of pathogenic variants in the ABCG5 and ABCG8 genes is >95%. Two cases of a deletion of exon 3 in the ABCG5 gene have been reported that are not predicted to be detected by sequencing (Lu et al. 2001).

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the ABCG5 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.