Identification of potential susceptibility genes in patients with Vestibular Migraine through whole exome sequencing
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Objective This study systematically analyzed the exonic regions of patients with vestibular migraine (VM) and healthy controls to identify VM-associated genetic variants and preliminarily map susceptibility genes. The findings aim to provide a theoretical foundation for elucidating the genetic mechanisms of VM and exploring potential therapeutic targets. Methods Whole-exome sequencing (WES) was performed on 59 VM patients (53 females, 6 males; mean age 49.27±12.77 years) recruited from Tianjin First Central Hospital and 280 healthy controls. All VM patients met the diagnostic criteria established by the Bárány Society, with exclusion of other peripheral vestibular disorders and central vertigo diseases. Result Through high-throughput sequencing and bioinformatics analysis, we identified 64 pathogenic/likely pathogenic variants across 56 genes. Notably, several key genes exhibited high mutation frequencies: The von Willebrand factor gene (VWF) showed variants in all patients (100%), providing direct evidence for the neurovascular hypothesis; The chromatin remodeler RSF1 demonstrated a 57.63% variant rate, implicating epigenetic regulation; Variants in nuclear pore protein NUP210L (54.24%) and cyclic nucleotide-gated channel CNGA1 (32.20%) suggested nuclear-cytoplasmic transport defects and ion channel dysfunction, respectively. These findings molecularly explain the co-occurrence of vestibular symptoms and migraines in VM patients. Notably, mutations in DNAH5 and STRC, associated with ciliary function and hearing loss, were detected in 8.47% of patients. Immune-related genes HLA-A (22.03%), HLA-B (10.17%), and metabolic gene UGT1A1 (23.73%) variants offered new genetic insights into VM-autoimmune disease comorbidity. Functional enrichment analysis revealed susceptibility genes significantly associated with clinical phenotypes: Sensorineural hearing loss (16.07%), Visual disturbances (16.07%), Hypertension (14.29%). Conclusion This study identified the key susceptibility gene profile of VM through WES and conducted functional enrichment analysis, indicating that its pathogenesis may involve pathways such as neurovascular regulation, epigenetic modification, and ion channel dysfunction. These findings provide important clues for understanding the molecular mechanism of the disease, with significant theoretical and clinical value. They lay a foundation for elucidating the complex clinical manifestations of VM, exploring the genotypic characteristics of different VM subtypes, and developing precise diagnostic markers and potential therapeutic targets.
