Submission Details

The relationship between ABCG8 and sitosterolemia, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of January, 2019. ABCG8 was reported in relation to sitosterolemia as early as 2001 (Berge et al, PMID: 11099417; Lee et al, 2001, PMID: 11138003). At least 16 unique variants including nonsense, splice site, frameshift and missense variants have been reported in humans. ABCG8 encodes an ATP-binding cassette half-transporter and functions to limit intestinal absorption and promote biliary excretion of sterols. Sitosterolemia is characterized by increased intestinal absorption and decreased biliary excretion of plant sterols, leading to extremely high plasma levels of plant sterols. Patients with the disorder can develop tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease (PMID: 11099417). The hematological presentation of sitosterolemia has been previously described as Mediterranean stomatocytosis/macrothrombocytopenia. Stomatocytic hemolysis, large platelets, splenomegaly and abnormal bleeding can be associated features in about 30% of cases (PMID: 32546081); however, hematologic manifestations can sometimes be the only clinical sign of sitosterolemia (PMID: 16029460). While the mechanisms underlying the hematological features shown by some sitosterolemia patients remains unknown, it is proposed that the accumulation of circulating plant sterols into blood cell membranes results in their altered morphology and dysfunction (PMID: 32546081).

Variants in both genes, ABCG8 and ABCG5, which share 28% homology, have been reported in relation to sitosterolemia (PMID: 11099417). Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 8 probands in 5 publications (PMID: 11099417, 28521186, 16029460, 24166850, 15210841, 32166861). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.

The mechanism for disease is biallelic loss of function (PMID: 11099417)

Summary of Experimental Data: 5.5 Points This gene-disease association is supported by mouse model evidence and in vitro functional assays. ABCG8 is strongly expressed in the liver and small intestine (PMID: 11099417). ABCG8 functions similar to and interacts with ABCG5 to form a heterodimer for transportation to the cell surface (PMID: 12208867, 14504269). ABCG8 knockout and ABCG5/ABCG8 knockout in mice recapitulates the sitosterolemia phenotype (PMID: 15040800, 12444248).

In summary, ABCG8 is definitively associated with Autosomal Recessive Sitosterolemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on July 10, 2020 (SOP Version 6).