| Summary: | Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in <i>LDLR</i>, <i>APOB</i>, <i>PCSK9</i> and <i>APOE</i> 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 <i>CYP7A1</i>, p.(Val1382Phe) in <i>LRP6</i> and p.(Ser202His) in <i>LDLRAP1</i>. A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in <i>CYP7A1</i>; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in <i>LRP6</i>; and p.(Ser202LeufsTer19) in <i>LDLRAP1</i>. All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in <i>CYP7A1</i> showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four <i>LRP6</i> 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 <i>LDLRAP1</i> 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.
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