Association of TRPM7 gene mutation with familial vestibular migraine.

Vestibular migraine (VM) is a common neurological disorder characterized by headache and vestibular symptoms, with its genetic mechanism not yet fully elucidated. We aimed to explore the association of TRPM7 gene mutation with familial vestibular migraine. A three-generation VM pedigree from Jinhua, China (4 affected individuals/2 healthy controls) was enrolled for neurological examinations and clinical differential diagnosis. Peripheral blood DNA was extracted using the QIAamp DNA extraction kit, followed by quality control and whole-exome sequencing (WES) performed with the Agilent SureSelect V7 platform. Variant calling was conducted using GATK (v4.3) HaplotypeCaller. Candidate variants were filtered by gnomAD East Asian population frequency (MAF < 0.01) and co-segregation analysis. Pathogenicity was assessed and the TRPM7 c.3526 C > T mutation was ultimately validated by Sanger sequencing. All four VM patients manifested recurrent pulsatile headaches (unilateral/bilateral, lasting 4–48 h) accompanied by nausea/vomiting or photophobia/phonophobia. Among them, two cases presented visual aura and one exhibited concomitant tinnitus. Vestibular symptoms included rotational vertigo (duration: 5 min to 6 h). WES identified a heterozygous nonsense mutation (TRPM7 c.3526 C > T, gnomAD East Asian MAF = 0.000006) in all affected individuals. Bioinformatics analysis revealed that this mutation resulted in C-terminal truncation of the protein, affecting the coiled-coil and kinase domains. Pathogenicity prediction scores unanimously supported its disease-causing potential (CADD = 35.2, MutationTaster = 1.0). Structural modeling demonstrated that the mutation reduced protein stability (ΔΔG = − 2.1 kcal/mol) and impaired Mg²⁺ binding affinity. The TRPM7 c.3526 C > T mutation is associated with familial VM and results in protein truncation that is predicted to affect ion channel–kinase function.