Genetic analysis and management of a familial hypercholesterolemia pedigree with polygenic variants: Case report

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder typically caused by low density lipoprotein receptor (LDLR) gene mutation. Herein, we reported a FH pedigree with polygenic variants: LDLR, apolipoprotein B (APOB), and epoxide hydrolase 2 (EPHX2).

A 10-year-old boy mainly presented multiple skin xanthomas and hypercholesterolemia. His family visited our hospital and was performed with pedigree whole exome sequencing (WES) at 20 + 3 weeks gestation of the mother's second pregnancy.

Based on the clinical features and genetic analysis, the pedigree was diagnosed with familial hypercholesterolemia.

After genetic counseling, the couple opted to continue the pregnancy. Treatment advice and follow-up were offered to them.

A novel compound heterozygous LDLR mutation: c.1009G>T and c.68-2A>G, derived from his parents respectively was revealed through pedigree WES, meanwhile, a maternal APOB gene variant: c.1670A>G and a paternal EPHX2 gene variant: c.548 dup of the proband were found together. Furthermore, the same compound heterozygous LDLR mutation as his was confirmed in his sister without APOB and EPHX2 variants in her fetal stage.

WES combined with clinical features is essential for the diagnosis of FH, however, prenatal genetic testing results might bring more challenges to prenatal genetic counseling. Furthermore, it is more important to provide the guidance and early intervention for such families in the long run.