Co-segregation of WFS1 p.Gly494Ser variant with recurrent vasovagal syncope in a multigenerational family: a candidate susceptibility variant needing independent validation.

INTRODUCTION: Vasovagal syncope (VVS) is the most prevalent subtype of reflex syncope. However, the genetic etiology underlying familial recurrent VVS has not been fully elucidated. METHODS: We recruited a multigenerational Chinese pedigree with three-generation recurrent early-onset VVS. Whole-exome sequencing was performed to screen pathogenic variants. Variant interpretation was conducted following the ACMG-AMP 2015 criteria, and multiple in-silico prediction tools were applied to evaluate variant pathogenicity. Clinical laboratory indicators of affected family members were collected and analyzed. RESULTS: The heterozygous WFS1 c.1480G>A (p.Gly494Ser) variant was identified and found to co-segregate with the syncope phenotype within this family. This variant is rare in public population databases and predicted to be potentially damaging to wolframin protein structure. It was classified as a Variant of Uncertain Significance (VUS) with moderate-strength evidence of PM2 and PP3. Concurrent hyperinsulinemia was detected in affected individuals, which may be confounded by obesity-related insulin resistance. DISCUSSION: Our results hypothesize that WFS1 p.Gly494Ser may serve as a candidate susceptibility variant for VVS. This finding broadens the phenotypic spectrum of heterozygous WFS1 variants and provides preliminary evidence linking endoplasmic-reticulum-related and autonomic regulatory pathways to VVS predisposition. Further validation using large independent cohorts and comprehensive cellular functional experiments is required to confirm the causal role of this variant in VVS.