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Updated: May 12, 2026
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Genetic screening and response to drug therapy in familial hypercholesterolemia
Yuzhi Lu1,2,3, Qianwen Chen1,2,3,4, Wenjuan Zhang1,2,3,5
1Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Insights
A novel mutation in the LDLR gene was identified in a Chinese family with familial hypercholesterolemia (FH). This genetic finding aids in diagnosing FH and guides personalized treatment with statins and PCSK9 inhibitors.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Molecular Biology
Background:
- Familial hypercholesterolemia (FH) is an underdiagnosed autosomal genetic disorder.
- Early diagnosis and intervention are crucial for preventing cardiovascular events in FH patients.
Purpose of the Study:
- Identify the genetic cause of FH in a Chinese family.
- Clarify clinical diagnosis and establish a personalized treatment plan.
- Investigate the impact of a novel LDLR mutation.
Main Methods:
- Recruited a three-generation Chinese FH family.
- Performed Whole Exome Sequencing and Sanger Sequencing.
- Utilized bioinformatics tools (SIFT, Polyphen-2, AlphaFold) and ACMG/AMP guidelines for mutation analysis.
Main Results:
- Identified a novel pathogenic frameshift insertion mutation (c.2517_2518insCA, p. C839fs) in the LDLR gene.
- The mutation, classified as pathogenic, affects RNA stability and protein structure (loss-of-function).
- Proband showed good response to statins, ezetimibe, and PCSK9 inhibitors; three additional carriers identified.
Conclusions:
- Identified a novel LDLR mutation contributing to FH in a Chinese family.
- This finding expands knowledge of FH genotype-phenotype correlations.
- Emphasizes the importance of genetic testing for FH diagnosis, intervention, and cascade screening.
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.
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