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

## TL;DR

This study discovers a new genetic mutation in the LDLR gene that causes severe familial hypercholesterolemia and resistance to statin treatment in a Chinese family.

## Contribution

The study identifies a novel frameshift variant, c.89_92dup, in the LDLR gene associated with FH and statin resistance.

## Key findings

- A novel LDLR variant, c.89_92dup, was found in a three-generation Chinese family with FH.
- The variant causes a frameshift in the LDL receptor, leading to severe FH symptoms and statin resistance.
- Two FH patients and a possible third carried the variant, which was not previously known.

## Abstract

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.

The online version contains supplementary material available at 10.1186/s12944-024-02173-2.