Uncovering Rare Genetic Variants in Familial Multiple Sclerosis through Whole Exome Sequencing

Whole exome sequencing (WES) has become a powerful tool in uncovering genetic variants linked to multiple sclerosis (MS), particularly in families with multiple affected individuals. While most genetic studies on MS have focused on common variants, WES allows researchers to explore rare variants that may play a critical role in familial MS cases.

Recent studies have highlighted key findings through WES in familial MS. In one study involving 132 patients from 34 multi-incident families, 12 candidate genes were identified, many of which are involved in immune system regulation, particularly in pathways like fibrinolysis, complement, and inflammasome assembly. Some notable genes include PLAU, NLRP12, and C2, which are linked to inflammatory responses crucial to MS pathophysiology​.

Another study conducted WES on multiple generations in nine multi-incident families, identifying rare variants in genes such as MBP, MECP2, and CPT1A. These genes, already known to be implicated in MS, were shown to interact within biological processes essential for myelination and immune regulation. Interestingly, this research suggests that some of these rare variants could directly affect disease progression by influencing the integrity of myelin sheaths and promoting autoimmune responses​.

Overall, these findings emphasize the potential of WES to uncover novel genetic contributors to MS in familial settings, shedding light on rare but impactful variants that drive disease susceptibility and progression. This knowledge could pave the way for more personalized therapeutic approaches targeting these specific pathways.

References:
Vilariño-Güell, C., Zimprich, A., Martinelli-Boneschi, F., Herculano, B., Wang, Z., Matesanz, F., et al. (2019). Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease. PLOS Genetics, 15(6), e1008180. https://doi.org/10.1371/journal.pgen.1008180 Kornek, B., Schneider, C., Rommer, P., Berger, T., & Zimprich, A. (2020). Exome sequence analyses of four multi-incident multiple sclerosis families. MDPI Genes, 11(9), 988. https://doi.org/10.3390/genes11090988