**7. Sitosterolemia and/or Familial Hypercholesterolemia**

Challenges in the proper diagnosis of sitosterolemia include heterogeneity of the clinical presentation of the disease, the lack of genotype–phenotype correlations, and the inability of clinical laboratory assays to distinguish phytosterols from cholesterol [28,141,142]. Studies among hypercholesterolemic subjects suggest sitosterolemia is significantly underdiagnosed [143,144]. Genome and exome sequence analysis of large populations indicates that carriers of loss of function mutations are far more common than previously thought and are at an elevated risk of coronary artery disease [72,80]. Exome sequence analysis of over 60,000 individuals across multiple populations reveals 57 and 58 predicted loss of function alleles for *ABCG5* and *ABCG8*, respectively (https://gnomad.broadinstitute.org/ (accessed on 3 January 2021) v2.1.1) [145]. This analysis did not include missense variants, 37 of which have been described for sitosterolemia [141]. At the time of the preparation of this review, 619 and 1307 missense variants have been catalogued in dbSNP for *ABCG5* and *ABCG8*, respectively. Most are predicted to be benign, but virtually none of those likely to be pathogenic or of uncertain significance have been experimentally or clinically validated. The number of *ABCG5 ABCG8* variants will undoubtedly grow as additional genomes and exomes are sequenced, as will the need for better tools to predict which variants are pathogenic.

An analysis of selected missense mutants of *ABCG5* and *ABCG8* suggests that the majority of dysfunctional alleles are due to the inability of *ABCG5 ABCG8* to heterodimerize and traffic beyond the endoplasmic reticulum [127]. The development of correctors and potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR, *ABCC7*, OMIM: 602421) and the rescue of mutants of *ABCB4*, defective in progressive familial intrahepatic cholestasis type 3 (PFIC3, OMIM: 602347), suggest these or perhaps other small molecule chaperones may facilitate maturation and rescue function of G5G8 [146,147]. However, no systematic approach to classify the types of mutations that cause sitosterolemia has been made. We propose a draft of such a classification system for sitosterolemia (Table 1). We based our initial draft on the system established for PFIC3 due to the fact that both are biliary lipid transporters [148]. Our system may need future revision as additional mutations are identified and the impact of these variants/mutants on G5G8 formation, trafficking, and activity are determined. Nonetheless, this classification system provides a framework for characterizing *ABCG5 ABCG8* mutants that cause sitosterolemia and a basis for the systematic investigation of compounds that may potentially rescue G5G8 function.


**Table 1.** Classification system for experimentally verified sitosterolemia mutations.

https://gnomad.broadinstitute.org/ (accessed on 3 January 2021) and Reference [127].
