Association Analysis of HSF1 Variable Number Tandem Repeat Expansion and Coding Variants with Essential Tremor Risk in a Large Cohort

BACKGROUND: A variable number tandem repeat (VNTR) expansion in HSF1 has recently been linked to essential tremor (ET). METHODS: We analyzed the VNTR in an existing HiFi cohort (n = 159) and subsequently in an expanded prospective case-control cohort (n = 2121) using fluorescent polymerase chain reaction (PCR). Ten size-matched case-control pairs were newly HiFi-sequenced to further characterize sequence details. A gene-burden analysis of HSF1 used retrospective whole-genome sequencing data (n = 5147). RESULTS: Fluorescent PCR genotyping showed no case-control difference in VNTR length distribution (range: 135-847 bp; P = 0.63) and no association with disease status (P = 0.93). HiFi sequencing of existing (n = 159) and new (n = 20) samples identified two core VNTR motifs (13-bp [CCGCNCCGCCTCC]n and 8-bp [CCGCCTCC]n), but no significant case-control differences in fine-scale sequence composition. Gene-burden analysis showed no enrichment of rare damaging coding variants in ET. CONCLUSION: Our data do not support HSF1 VNTR or rare damaging coding variants as major risk factors for ET. © 2026 International Parkinson and Movement Disorder Society.