Year: 2026
Type: article
Study design: Case Report
Abstract: Objectives Familial hypercholesterolemia (FH) is an autosomal genetic disorder, which is significantly underdiagnosed. Here, we aimed to identify the genetic causes of a FH family and clarify the clinical diagnosis of the patient and then provide personalized treatment plan. Materials and Methods We recruited a three-generation Chinese family with a history of FH and conducted genetic testing by Whole exome sequencing and Sanger sequencing. The potential effect of mutation identified was predicted using various software such as SIFT, Polyphen-2, Mutation Taster, RNAfold, AlphaFold and the conservation was tested using multiple sequence alignments by ClustalX. The pathogenicity of the identified mutation was evaluated according to the 2015 ACMG/AMP Standards and Guidelines. Results A frame shift insertion mutation (c.2517_2518insCA, p. C839fs) in LDLR was identified in proband, which showed to have a deleterious effect and has not been reported before. According to the 2015 ACMG/AMP, this nonsense pathogenic mutation was classified as “pathogenic”. This LOF mutation was thought to influence RNA stability by changing the free energy dynamics of the RNA molecule, while it also changes protein structure by removing an essential LDLR functional domain. With personalized drug treatment, such as statins, ezetimibe, and PCSK9 inhibitor, the serum lipids of the proband were well controlled and the prognosis was good. The further cascade screening of family members identified three carriers of the mutation, who need close follow-up and regular monitoring of lipid changes to prevent future cardiovascular events. Conclusion Here, we identified a novel mutation in LDLR (c.2517_2518insCA, p. C839fs) for FH. Hyperlipidemia patients carrying this mutation will respond favorably to statins and PCSK9 inhibitor. The finding expanded our understanding of Phenotype–Genotype Correlations of FH with LDLR gene mutations and emphasized the important role of genetic testing and genetic screening in the diagnosis and intervention of FH.
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7155551744