Synergic combination of the monogenic ANGPTL3 p.H343R variant and a polygenic predisposition in a family with hypobetalipoproteinemia

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BACKGROUND AND AIMS: Primary hypobetalipoproteinemia (HBL) is mostly due to a polygenic origin or to monogenic disorders including loss of function (LOF) variants in APOB, much less frequently Angiopoietin-like 3 gene (ANGPTL3). A new heterozygous variant of uncertain significance (VUS), p.H343R missense variant in ANGPTL3 cosegregated with HBL in a family. The aim of the present study was to assess in vitro the functionality of this variant and to establish its causality in this family. METHODS: ). The effect of the variant was investigated by assessing the ANGPTL3 protein secretion in vitro. A replication study was performed in the UK-biobank. RESULTS: below the first decile, supporting a polygenic HBL. Six family members also carrying the p.H343R variant (n = 6) had a significantly lower LDL-C than the polygenic members non-carriers of the p.H343R (n = 2) (p=0.012). In vitro, p.H343R variant significantly decreased ANGPTL3 concentration in the medium (-82 %, p=0.029) and the ratio of secretion (0.28 ± 0.06 vs. 1.00 ± 0.30 p=0.029, n = 3) compared to the wild-type. The synergistic combination of the p.H343R ANGPTL3 variant and a polygenic HBL predisposition was confirmed in the UK biobank. CONCLUSIONS: This study shows that the novel ANGPTL3-p.H343R variant decreases ANGPTL3 secretion in vitro and can now be considered as a LOF variant. The lipid phenotype in this family results from a synergistic combination of the p.H343R ANGPTL3 variant and a polygenic HBL predisposition.

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