LDLR c.89_92dup: a novel frameshift variation in familial hypercholesterolemia

• Published in: Lipids in health and disease 2024-06, Vol.23 (1), p.182-8
• Main Authors: Deng, Jialing, Zhang, Ju, Meng, Shirui, Ding, Nan, Hao, Yu, Zeng, Hui, Lin, Jie
• Format: Article
• Language: English
• Subjects: Adult; Analysis; Analysis and chemistry; Blood; c.89_92dup variant; Care and treatment; Complications and side effects; Dosage and administration; Exome Sequencing; Familial hypercholesterolemia; Female; Frameshift Mutation - genetics; Genetic screening; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II - diagnosis; Hyperlipoproteinemia Type II - genetics; Ligand-binding domain; Low-density lipoprotein receptor; Male; Middle Aged; Pedigree; Receptors, LDL - genetics; Statins; Whole-exome sequencing
• ISSN: 1476-511X; 1476-511X
• DOI: 10.1186/s12944-024-02173-2

Familial hypercholesterolemia (FH) is a common inherited metabolic disease that causes premature atherosclerosis, cardiovascular disease, and even death at a young age. Approximately 95% of FH-causing genetic variants that have been identified are in the LDLR gene. However, only 10% of the FH population worldwide has been diagnosed and adequately treated, due to the existence of numerous unidentified variants, uncertainties in the pathogenicity scoring of many variants, and a substantial number of individuals lacking access to genetic testing. The aim of this study was to identify a novel variant in the LDLR gene that causes FH in a Chinese family, thereby expanding the spectrum of FH-causing variants. Patients were recruited from Beijing Anzhen Hospital, Capital Medical University. FH diagnosis was made according to the Dutch Lipid Clinical Network (DLCN) criteria. Whole-exome sequencing (WES) was conducted to identify the FH-causing variant in the proband, and amplicon sequencing was used to verify the variant in his family members. A three-generation Chinese family was recruited, and two FH patients were clinically diagnosed, both without known FH-causing variants. These two FH patients and another possible patient carried a novel variant, NC_000019.9(NM_000527.5):c.89_92dup (NP_000518.1:p.Phe32Argfs*21), in the ligand-binding domain of the low-density lipoprotein (LDL) receptor that led to a frameshift. The FH adults in the family showed severe clinical symptoms and statin therapy resistance. This study identified a novel pathogenic LDLR variant, c.89_92dup, associated with severe FH clinical manifestations and statin therapy resistance.