# Role of Next-Generation Sequencing in Diagnosis of Familial Hypercholesterolemia in Serbia

## TL;DR

This study used next-generation sequencing to identify genetic variants in Serbian patients with familial hypercholesterolemia, finding that most mutations were in the LDLR gene.

## Contribution

The study is the first to explore the genetic basis of FH in Serbia using NGS and highlights the importance of multi-gene testing.

## Key findings

- A mutation detection rate of 43.6% was achieved, with 93.2% of detected variants in the LDLR gene.
- The most common LDLR variant was c.858C>A p.(Ser286Arg), found in 26% of LDLR-positive patients.
- Genetically confirmed FH patients had significantly different lipid profiles compared to FH-negative patients.

## Abstract

Objectives: Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipid metabolism characterized by high levels of low-density lipoprotein (LDL). This study aimed to identify variants in the LDLR, APOB, PCSK9 and LDLRAP1 genes and to identify the genotype–phenotype correlation in Serbian FH patients. Method: This study included a total of 101 patients suspected of having FH based on clinical criteria. Genetic analysis was performed by the next-generation sequencing (NGS) method. Results: An overall mutation detection rate of 43.6% was achieved. Thirteen distinct variants were detected in the LDLR gene (93.2%). The most frequently observed variant was c.858C>A p.(Ser286Arg), which was present in 26% of the LDLR-positive patients. Additional variants were detected in the APOB gene. No pathogenic variants were detected in the PCSK9 or LDLRAP1 genes. Comparing genetically FH-positive and FH-negative patients, statistical significance was observed in terms of age (p < 0.001), total cholesterol (TC) (p < 0.001), low-density-lipoprotein cholesterol (LDL-C) (p < 0.001) and triglyceridemia (p < 0.001). Conclusions: This study represents the first insight into the genetic basis of FH in Serbia. Taking into consideration that variants were detected in more than one gene and that the variants in the LDLR gene were distributed across nearly all exons, the FH diagnostics in Serbia ought to be based on NGS methodology.