Whole-Exome Sequencing in Multiple Sclerosis: A Systematic Review of Candidate Genes, Replication and Evidence Strength

Whole-exome sequencing (WES) has been used to investigate rare variation in multiple sclerosis (MS), particularly in multiplex families and selected clinical cohorts. This systematic review examines candidate findings, replication, participant overlap and the distinction between susceptibility, Mendelian causation and diagnostic mimicry. Thirty-six reports published between 2011 and 2026 were included, identified through database and citation searches, a supplementary Embase search and eligibility reassessment during revision. Family-based studies nominate biologically plausible genes and pathways, but independent confirmation is limited. Follow-up studies challenge several prominent claims, including high-penetrance NR1H3 causation and the initial CYP27B1 association. Susceptibility alleles, disease-course modifiers, gene-set burdens and alternative diagnoses require distinct interpretive frameworks; a Mendelian gene-validity grade cannot serve as a common scale. Larger studies provide important negative evidence within their tested populations, genes and outcomes, without excluding all rare-variant contributions to MS. The assembled evidence does not establish a high-penetrance monogenic explanation for typical MS. Genomic testing may nevertheless identify alternative inherited disorders in selected atypical presentations. Heterogeneous designs, incomplete replication and participant overlap limit the strength of inference. Future studies should prioritise independent replication, ancestry-aware analysis, transparent variant-level results and disease-relevant functional validation.