A Catalog of the Pathogenic Variants in ABCG5 and ABCG8 and Clinical Features in Sitosterolemia

Since comprehensive data on the pathogenic variants of ABCG5 and ABCG8 and clinical features in sitosterolemia remain limited, we aimed to compile a catalog through an extensive literature search of case reports from 2002 to 2024, as well as an evaluation of variants reported in review articles.

We compiled 155 cases of sitosterolemia from 133 families with nonsynonymous variants in ABCG5 and ABCG8, along with data on clinical information from case reports. Pathogenic variants were defined either as 1) protein-truncating variants, 2) classified as pathogenic or likely pathogenic variants according to the ACMG guidelines, or 3) serum sitosterol level of the case was measured at ≥ 1 mg/dL.

Xanthoma was observed in 69.2% of patients, ischemic heart disease in 14.2%, and hematologic abnormalities in 57.9%. Fifty-three variants in ABCG5 and 52 in ABCG8 were evaluated for their pathogenicity, in which 33 in ABCG5 and 29 in ABCG8 were protein-truncating variants. Additionally, based on the ACMG criteria and serum sitosterol levels, 50 variants in ABCG5 and 51 variants in ABCG8 were finally classified as pathogenic. Among them, the frequently observed R446X and R389H in ABCG5 were highly prevalent in East Asians, while W361X and S107X in ABCG8 were predominantly found in Europeans.

We provided the largest catalog of clinical features and pathogenic variants of ABCG5 and ABCG8 in the world. This study may help clarify the pathogenicity of variants in ABCG5 and ABCG8 and provide a valuable reference for the genetic diagnosis of sitosterolemia.