Somatic variation in multiple sclerosis: from blood to brain

Multiple sclerosis (MS) is a progressive autoimmune disease of the central nervous system (CNS) that affects nearly 3 million people worldwide. Pathologically, MS is characterised by inflammation, demyelination and neurodegeneration, leading to declining neurological function and increasing disability. To date, investigations of somatic variation in MS have focused primarily on peripheral immune cells and, more recently, neurons. Deep targeted and exome sequencing of blood‑derived T cells have not demonstrated enrichment of somatic driver mutations in individuals with MS compared with controls. In contrast, whole‑genome sequencing of single neurons from chronic MS lesions has revealed a markedly elevated, age-adjusted somatic mutation burden, suggesting a mechanistic link between inflammation and neurodegeneration. Together, these findings provide support for further investigation of somatic mosaicism across both peripheral and CNS‑resident cell types in MS. Future studies will benefit from advances in genome sequencing that enable more accurate detection of ultra-rare somatic variants, combined with single-cell and complementary genomic technologies, to more definitively assess the role of somatic variation in MS pathogenesis. Ultimately, it is anticipated that insights from this work will translate into novel therapeutic targets and interventions to alleviate MS progression.