{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T15:12:31Z","timestamp":1778857951512,"version":"3.51.4"},"reference-count":49,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Australian National Health and Medical Research Council","award":["NHMRC-APP1122387"],"award-info":[{"award-number":["NHMRC-APP1122387"]}]},{"name":"Migraine Research Foundation","award":["NHMRC-APP1122387"],"award-info":[{"award-number":["NHMRC-APP1122387"]}]},{"name":"Australian International Science Linkages","award":["NHMRC-APP1122387"],"award-info":[{"award-number":["NHMRC-APP1122387"]}]},{"name":"Australian Government EIF Super Science Funds","award":["NHMRC-APP1122387"],"award-info":[{"award-number":["NHMRC-APP1122387"]}]},{"name":"PhD scholarship provided by Queensland University of Technology","award":["NHMRC-APP1122387"],"award-info":[{"award-number":["NHMRC-APP1122387"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with a complex genetic basis. Although pathogenic variants in CACNA1A, ATP1A2, and SCN1A 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. Objective: 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. Methods: 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 \u2264 0.05), location (exonic\/splice site), and predicted pathogenicity using in silico tools. Statistical comparisons to gnomAD\u2019s Non-Finnish European population were made using chi-square tests. Results: Significant variants were identified in several SVD-related genes, including LRP1 (p.Thr4077Arg), COL4A1 (p.Pro54Leu), COL4A2 (p.Glu1123Gly), and TGFBR2 (p.Met148Leu and p.Ala51Pro). The LRP1 variant showed the strongest association (p &lt; 0.001). All key variants demonstrated pathogenicity predictions in multiple computational models, implicating them in vascular dysfunction relevant to migraine mechanisms. Conclusions: 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.<\/jats:p>","DOI":"10.3390\/genes16080895","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T14:50:03Z","timestamp":1753714203000},"page":"895","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Insights into Hemiplegic Migraine: Whole Exome Sequencing Highlights Vascular Pathway Involvement via Association Analysis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2917-6251","authenticated-orcid":false,"given":"Zizi","family":"Molaee","sequence":"first","affiliation":[{"name":"Genomics Research Centre, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Genomics Research Centre, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia"},{"name":"Genomics Research Centre, Research Infrastructure, Faculty of Sciences, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4891-4333","authenticated-orcid":false,"given":"Neven","family":"Maksemous","sequence":"additional","affiliation":[{"name":"Genomics Research Centre, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia"},{"name":"Genomics Research Centre, Research Infrastructure, Faculty of Sciences, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-5475","authenticated-orcid":false,"given":"Lyn R.","family":"Griffiths","sequence":"additional","affiliation":[{"name":"Genomics Research Centre, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s10194-024-01795-2","article-title":"GBD2021: Headache disorders and global lost health\u2014A focus on children, and a view forward","volume":"25","author":"Steiner","year":"2024","journal-title":"J. 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