Opportunistic Detection of Phytosterolemia During Genetic Testing for FH: Case Series and Contextual Review

Homozygous phytosterolemia is a rare autosomal recessive disorder that leads to severely elevated plasma levels of plant phytosterols, causing an increased risk of coronary artery disease (CAD) and mimicking the clinical presentation of familial hypercholesterolemia (FH). Integration of the genetic variants for homozygous phytosterolemia into the genetic panel for FH in clinical practice likely increases the detection of milder genetic forms of phytosterolemia, the implications of which in clinical practice, including cascade testing, remain unclear.

We report 3 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 phytosterolemia 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 (aged 31 and 29 years) 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 is 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) that had mild phytosterolemia 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%.

Phytosterolemia 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.