Background: Homozygous phytosterolaemia, is a rare autosomal recessive disorder which lead to severely elevated plasma levels of plant phytosterols causing an increased risk of coronary artery disease (CAD) and mimics the clinical presentation of familial hypercholesterolaemia(FH). Integration of the genetic variants for homozygous phytosterolaemia into the genetic panel for FH in clinical practice likely increases the detection of milder genetic forms of phytosterolaemia, of which the implications to clinical practice including cascade testing remain unclear.
Results: We report three families with pathogenic loss-of-function variants in ABCG5 and/or ABCG8, in which probands were identified incidentally when genetically testing them for FH. The proband of the first family was a 35-year-old man with a homozygous ABCG5 loss-of-function variant (c.1336C > T, p.Arg446*) causing severe phytosterolaemia and premature CAD on cardiac imaging; his younger brother was heterozygous for the same variant with mildly elevated phytosterol levels. The second family included 2 sisters (31 and 29-year-old) with digenic variants in ABCG5 (c.1336C > T, p.Arg446*) and ABCG8 (c.1269G > T, p.Glu423Asp with uncertain significance) with moderately elevated plasma phytosterol levels and premature CAD on cardiac imaging. The third family referred to a 68-year-old man and his 44-year-old daughter who were both heterozygous for a pathogenic ABCG5 variant (c.1166G > A, p.Arg389His), had mild phytosterolaemia and CAD on cardiac imaging. Treatment with ezetimibe alone or in combination with colesevelam reduced elevated plasma sitosterol and campesterol concentrations by 30 to 80%.
Conclusion: Phytosterolaemia is specific genetic disorder that can mimic FH, cause premature atherosclerosis, and require specific pharmacotherapy. Cascade testing for pathogenic ABCG5/G8 variants can lead to earlier detection and treatment of affected family members.
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