Rare Coding Variation Identified by Whole-Exome Sequencing in Multiple Sclerosis: A Systematic Review of Candidate Genes, Replication, and Evidence Strength

Genome-wide association studies have identified more than 200 common-risk loci for multiple sclerosis (MS), but common variants do not fully explain familial aggregation. Whole-exome sequencing (WES) has therefore been applied to multiplex families and clinical cohorts to identify rare protein-altering variants. We systematically searched five databases from inception to 10 August 2026, supplemented by citation searching. Of 663 unique records screened, 33 primary reports were identified between 2011 and 2026, representing approximately 15 distinct participant collections. Study quality was appraised with the validated Quality of Genetic Studies (Q-Genie) instrument, and each principal gene-disease claim was classified using the Clinical Genome Resource (ClinGen) clinical validity framework. At study level, 27 of 33 reports were rated Good, four Moderate, and two Poor. Of 21 gene-disease claims, none reached Definitive, Strong, or Moderate validity: 16 were Limited, two Disputed, two Refuted, and one No Known Disease Relationship entry comprised NOTCH3 and PYGM, genes with definitive validity for other disorders but no established relationship with MS. No gene-disease relationship in this literature meets the evidence threshold recommended for diagnostic panel inclusion, and the largest contemporary cohort studies are negative. WES retains a narrow diagnostic role in atypical presentations but is not supported as a population-level test in typical MS.