Whole Exome/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia

Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in , , and genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes by focusing on a French family with affected and non-affected members who presented a high ADH polygenic risk score (wPRS). Linkage analysis, whole exome and whole genome sequencing resulted in the identification of variants p.(Pro398Ala) in , p.(Val1382Phe) in and p.(Ser202His) in . A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in ; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in ; and p.(Ser202LeufsTer19) in . All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four mutants in HEK293T cells resulted in contradictory results excluding a major effect of each variant alone. Within the family, none of the heterozygous for only the p.(Ser202His) variant presented ADH. Altogether, each variant individually does not result in elevated LDL-C; however, the oligogenic combination of two or three variants reveals the ADH phenotype.