摘要BACKGROUND Familial hypercholesterolemia(FH)is a common autosomal dominant hereditary disease.Its early diagnosis and intervention significantly improve the patient's quality of life.However,there are few types of research on the FH pathogen-ic genes in China.METHODS In this study,we recruited a family diagnosed with FH and used whole exome sequencing(WES)to analyze the proband variants.Intracellular cholesterol level,reactive oxygen species(ROS)level,and the expression of pyroptosis-related genes were detected after overexpression of wild-type or variant LDLR in L02 cells.RESULTS A heterozygous missense variant predicted to be deleterious to LDLR(c.1879G>A,p.Ala627Thr)was identified in the proband.Mechanistically,intracellular cholesterol level,ROS level,and the expression of pyroptosis-related genes,nucleotide-binding oligomerization domain-like receptor family protein 3(NLRP3)inflammasome and components(caspase 1,apoptosis-as-sociated speck-like protein containing a caspase recruitment domain(ASC)and NLRP3),gasdermin D(GSDMD),interleukin(IL)-18,IL-1β was elevated in the variant LDLR group,which was attenuated by inhibition of ROS.CONCLUSIONS FH is associated with a variant(c.1879G>A,p.Ala627Thr)in the LDLR gene.Regarding the mechanism,the ROS/NLRP3-mediated pyroptosis in hepatic cells may contribute to the pathogenesis of the LDLR variant.