[Analysis of clinical phenotypes and variants of LDLR gene in two Chinese patients with familial hypercholesterolemia].

OBJECTIVE
To explore the correlation between clinical phenotypes and pathogenic variants in two patients with familial hypercholesterolemia.


METHODS
Both patients were subjected to whole exome sequencing (WES) with a focus on the analysis of genes associated with dyslipidemia. Candidate variants were verified by Sanger sequencing of the patients and their family members.


RESULTS
WES revealed that the proband 1 has harbored two heterozygous variants of the LDLR gene, namely c.1360G>A (p.D454N) and c.292G>A (p.G98S), whilst proband 2 has harbored a heterozygous c.321T>G (p.C107W) variant of the LDLR gene. Based on the guidelines from the American College of Medical Genetic and Genomics (ACMG), the above variants were respectively predicted to be likely pathogenic (PM1+PM2+PP2+PP3+PP4+PP5), variant of unknown significance (PM1+PP2+PP3), and likely pathogenic (PM1+PM2+PP2+PP4+PP5). Treatment with PCSK9 inhibitor has attained a significant effect in proband 1 but no apparent effect in proband 2.


CONCLUSION
Variants of the LDLR gene probably underlay the familial hypercholesterolemia in the two pedigrees. The difference in the severity of the clinical phenotypes and response to PCSK9 inhibitor treatment between the two probands may be attributed to the different genotypes of the LDLR gene. Genetic testing not only can provide a basis for clinical diagnosis, but also facilitate the choice of lipid-lowering drugs.