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.