# Exome Sequencing Uncovers Genetic Drivers of Multiple Sclerosis in a Multiplex Family

## TL;DR

Exome sequencing in a family with multiple MS cases identified rare genetic variants linked to the disease, suggesting an oligogenic model of susceptibility.

## Contribution

The study identifies novel candidate genes for MS through exome sequencing in a multiplex family.

## Key findings

- 47 co-segregating rare variants were identified in the family.
- Three missense variants in RTN4, JAK2, and DUOX2 genes were highlighted as promising candidates.
- Protein modeling suggests these variants may significantly impact protein function.

## Abstract

Background: Multiple Sclerosis (MS) is a chronic, autoimmune, multifactorial, and complex disorder of the central nervous system (CNS), affecting more than 2 million individuals globally. Genome-wide association studies (GWAS) have explained only a small fraction of its high heritability, highlighting the need for alternative approaches to identify rare genetic variants that contribute to its etiology. To address this, we performed whole-exome sequencing (WES) in a multi-affected family. Methods: WES was performed in a MS multigenerational family comprising two affected sisters, their two healthy brothers, and one affected son. Results: Bioinformatics analysis identified 47 co-segregating rare variants. Three missense variants in genes involved in inflammation, autoimmunity, and demyelinization were identified as the most promising candidates: c.443 C>T, p.Pro148Leu in the RTN4 gene, c.1678 T>G, p.Phe560Val in the JAK2 gene, and c.3449 A>G, p.Tyr1150Cys in the DUOX2 gene. Protein modeling and in silico tools suggest that the three selected variants may have a significant impact on protein function. Conclusions: We identified novel candidate genes for MS in a multiplex family, providing evidence for an oligogenic model of disease susceptibility. Further replication and functional studies are required to validate these preliminary results.