Molaee Zizi, Smith Robert A, Maksemous Neven, Griffiths Lyn R
Genomics Research Centre, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia.
Genomics Research Centre, Research Infrastructure, Faculty of Sciences, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia.
Genes (Basel). 2025 Jul 28;16(8):895. doi: 10.3390/genes16080895.
: 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.
偏瘫性偏头痛（HM）是一种罕见且严重的偏头痛亚型，具有复杂的遗传基础。尽管在[具体基因1]、[具体基因2]和[具体基因3]中的致病变异解释了一些家族性病例，但仍有相当一部分患者在基因方面未得到诊断。越来越多的证据表明偏头痛与脑小血管疾病（SVD）存在重叠，这意味着血管功能障碍参与了HM的病理生理过程。
本研究旨在在一组临床诊断为HM且已知家族性偏瘫性偏头痛（FHM）致病变异检测呈阴性的患者中，鉴定与SVD相关基因中的罕见或新变异。
我们对184名无亲缘关系的HM患者的全外显子测序（WES）数据进行了病例对照关联分析。评估了一个由34个与SVD相关基因组成的靶向基因panel。根据稀有性（MAF≤0.05）、位置（外显子/剪接位点）以及使用计算机工具预测的致病性对变异进行优先级排序。使用卡方检验与gnomAD的非芬兰欧洲人群进行统计学比较。
在几个与SVD相关的基因中鉴定出了显著变异，包括[具体基因4]（p.Thr4077Arg）、[具体基因5]（p.Pro54Leu）、[具体基因6]（p.Glu1123Gly）以及[具体基因7]（p.Met148Leu和p.Ala51Pro）。[具体基因4]变异显示出最强的关联（p<0.001）。所有关键变异在多个计算模型中均显示出致病性预测，表明它们与偏头痛机制相关血管功能障碍有关。
本研究为偏瘫性偏头痛的遗传结构提供了新见解，鉴定出了与SVD相关基因中的罕见且可能有害的变异。这些发现支持了血管和细胞维持途径导致偏头痛易感性的假说，并可能为诊断和治疗提供新靶点。
