Genetic analysis in a compound heterozygote family with familial hypercholesterolemia

Homozygous familial hypercholesterolemia (FH) is rare, with an incidence of ~one in a million and commonly presents with a genetic mutation. The genetic variations of families with FH were clinically analyzed to investigate the association between the phenotype and genotype of patients. Direct sequencing was conducted for the proband and her parents to detect mutations in the fragment of 18 exons of the low‑density lipoprotein receptor (LDLR) and apolipoprotein B100 Q3500R in the peripheral blood genomic DNA. The gene sequences were compared with normal ones to find mutations using GenBank. The QX200 Droplet Digital PCR system was used to detect target DNA copy number variations of the proband and her parents. The functional alterations resulting from the novel mutations were verified by quantitative polymerase chain reaction, western blotting and flow cytometric analyses. The lipid levels of the proband and her parents were all elevated. Genetic testing results indicated that the proband and her mother had a novel heterozygous missense mutation (C377G, 28893T>G) in exon 8 of the LDLR gene, whereas the proband and her father had LDLR gene DNA fragment deletions in exon 18. Clinically, the proband was of a compound heterozygous genotype and her parents were of the simple heterozygous genotype. Furthermore, both mutations led to impaired expression and LDL binding and internalization function of LDLR in vitro. The proband's genotype was confirmed to be compound heterozygous FH, leading to clinical manifestations in line with the homozygous FH phenotype. The phenotype is highly associated with the genotype in this type of compound heterozygous FH.