Abstract
Genetic studies have contributed to our understanding of the complex mechanisms involved in cholesterol homeostasis in familial hypercholesterolemia (FH). Recently, computational modeling in silico have provided a useful tool for structure-function predictions of mutant protein. However, there is still much to unravel in FH, and further investigations are needed. In this study, we aimed to further characterize these mutations in the Vietnamese population and to provide structure-function predictions for protein modeling. In total, 28 FH variants were identified—21 LDLR, 6 APOB, and 1 PCSK9 variants—with a detection rate of 43.6% in the patient cohort. Three novel LDLRmutations (Gly396_Glu714del, Pro476Arg, and Asp843Glufs*86) and one novel APOB mutation (His3583Leu) were identified. LDLR mutations, such as Asp227Glu and His583Tyr, affected protein stability and interactions and consequently impacted cholesterol metabolism. Similarly, other mutations in less conserved regions, like Gln660Ter and Cys318Arg, disrupted stability and interactions. APOB mutations, including Arg1386Trp and Phe2469Cys, modified protein stability and interactions, potentially affecting APOB–LDLR binding. These findings provide valuable insights into the genetic diversity and dynamic nature of FH, furthering our understanding of the molecular basis of FH and aiding the development of potential therapeutic interventions.