Independent Severe Cases of Heterozygous Familial Hypercholesterolemia Caused by the W483X and Novel W483G Mutations in the Low-Density Lipoprotein Receptor Gene That Were Clinically Diagnosed as Homozygous Cases.

Background and Aims: The genetic spectrum underlying familial hypercholesterolemia (FH) remains unclear, especially in northeastern China. The aim of this study was to delineate the FH genetic spectrum and identify specific characteristics of FH patients in this region. Materials and Methods: The family history, personal medical history, and lifestyle habits of two unrelated patients clinically diagnosed with homozygous FH were recorded. DNA samples of the patients and their relatives were subjected to a newly designed next-generation sequencing panel using an Illumina Miseq platform. Detected variants were annotated and functionally predicted with in silico algorithms, and protein structures were modeled. Results: The patients' cholesterol levels were effectively reduced to 33.8% and 17.2% of the original level under conventional ezetimibe and statin treatment. Two pathogenic mutations, W483X and the novel mutation W483G, in the low-density lipoprotein receptor (LDLR) gene were identified. Both patients were heterozygous for the respective mutations. Under a high cholesterol/carbohydrate diet, these mutations could trigger a severe FH phenotype, but both patients responded well to regular medical treatments and dietary control. The W483X mutation results in a premature stop codon, leading to incomplete protein formation. Although the W483G mutation results in translation of the complete protein with no apparent structural difference, it still led to a severe FH phenotype similar to W483X. Conclusions: Identification of the novel W483G mutation expands the genetic spectrum of FH. Both mutations cause a severe FH phenotype under certain conditions, suggesting that W483 is important for LDLR function, highlighting potential targets for genetic screening or drug development.