Molecular analysis of APOB, SAR1B, ANGPTL3, and MTTP in patients with primary hypocholesterolemia in a clinical laboratory setting : Evidence supporting polygenicity in mutation-negative patients

Background and aims: Primary hypobetalipoproteinemia is generally considered a heterogenic group of monogenic, inherited lipoprotein disorders characterized by low concentrations of LDL cholesterol and apolipoprotein B in plasma. Lipoprotein disorders include abetalipoproteinemia, familial hypobetalipoproteinemia, chylomicron retention disease, and familial combined hypolipidemia. Our aim was to review and analyze the results of the molecular analysis of hypolipidemic patients studied in our laboratory over the last 15 years. Methods: The study included 44 patients with clinical and biochemical data. Genomic studies were performed and genetic variants were characterized by bioinformatics analysis. A weighted LDL cholesterol gene score was constructed in order to evaluate common variants associated with impaired lipid concentrations and their distribution among patients. Results: Twenty-three patients were genetically confirmed as affected by primary hypobetalipoproteinemia. In this group of patients, the most prevalent mutated genes were APOB (in 17 patients, with eight novel mutations identified), SAR1B (in 3 patients, with one novel mutation identified), ANGPTL3 (in 2 patients), and MTTP (in 1 patient). The other 21 patients could not be genetically diagnosed of hypobetalipoproteinemia despite presenting suggestive clinical and biochemical features. In these patients, two APOB genetic variants associated with lower LDLc cholesterol were more frequent than in controls. Moreover, the LDL cholesterol gene score, calculated with 11 SNPs, was significantly lower in mutation-negative patients. Conclusion: Around half of the patients could be genetically diagnosed. The results suggest that in at least some of the patients without an identified mutation, primary hypobetalipoproteinemia may in fact have a polygenic origin