Genetic Insights into Hemiplegic Migraine: Whole Exome Sequencing Highlights Vascular Pathway Involvement via Association Analysis.

: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with a complex genetic basis. Although pathogenic variants in , , and explain some familial cases, a significant proportion of patients remain genetically undiagnosed. Increasing evidence points to an overlap between migraine and cerebral small vessel disease (SVD), implicating vascular dysfunction in HM pathophysiology. : This study aimed to identify rare or novel variants in genes associated with SVD in a cohort of patients clinically diagnosed with HM who tested negative for known familial hemiplegic migraine (FHM) pathogenic variants. : We conducted a case-control association analysis of whole exome sequencing (WES) data from 184 unrelated HM patients. A targeted panel of 34 SVD-related genes was assessed. Variants were prioritised based on rarity (MAF ≤ 0.05), location (exonic/splice site), and predicted pathogenicity using in silico tools. Statistical comparisons to gnomAD's Non-Finnish European population were made using chi-square tests. : Significant variants were identified in several SVD-related genes, including (p.Thr4077Arg), (p.Pro54Leu), (p.Glu1123Gly), and (p.Met148Leu and p.Ala51Pro). The variant showed the strongest association ( < 0.001). All key variants demonstrated pathogenicity predictions in multiple computational models, implicating them in vascular dysfunction relevant to migraine mechanisms. : This study provides new insights into the genetic architecture of hemiplegic migraine, identifying rare and potentially deleterious variants in SVD-related genes. These findings support the hypothesis that vascular and cellular maintenance pathways contribute to migraine susceptibility and may offer new targets for diagnosis and therapy.