Analysis of a deeply-phenotyped familial hypercholesterolemia cohort from Mexico shows a role for both rare and common alleles across known dyslipidemia genes and reveals structural variation in a novel locus.

ABSTRACT: Familial hypercholesterolemia (FH) is a genetic disorder driven in part by mutations in three genes that encode components of the cholesterol pathway: LDLR, APOB, and PCSK9. However, the majority of FH genetics has been performed in individuals of European descent. Here, we leveraged a cohort of 300 patients from the Mexican FH registry to understand how rare, high liability alleles and common variants might contribute to shaping individual risk. Using a combination of whole exome and of short- and long-read whole genome sequencing, we report three key findings. First, we observed that rare pathogenic point mutations and structural variants in all known FH genes, together with variants in APOE, CREB3L3, and PLIN1, contribute to a molecular FH diagnosis in 67% of families, including novel g

SUBMITTER: Katsanis N 

PROVIDER: S-EPMC12642200 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature