Independent Validation and Structural Characterization of Expanded HSF1 Intronic Variable Number Tandem Repeats in Essential Tremor.

BACKGROUND

Recent studies have reported associations between expanded HSF1 intronic variable number tandem repeats (VNTRs) and essential tremor (ET), necessitating independent validation.

METHODS

We analyzed HSF1 VNTR lengths in 720 ET patients and 507 controls using fluorescence amplicon length analysis. Sequence composition and interruption patterns were characterized using long-read sequencing (LRS) data from 26 ET patients and 29 controls harboring expanded VNTRs.

RESULTS

Expanded VNTRs showed similar frequencies in ET patients and controls at both 700 base pairs (bp) (5.9% vs. 4.3%, P = 0.22) and 550 bp thresholds (13.7% vs. 10.8%, P = 0.14). LRS refined the motif pattern from (CCCCGCNCCGCCT)n/(CCNCGCCT)n to (CNCCGCNCCGCCT)n/(CNNCGCCT)n. Both patients and controls showed identical repeat configurations with predominantly CC interruptions accompanied by CCCCG interruptions (75% in patients, 41.4% in controls). Self-organizing map analysis revealed no clustering differences between groups.

CONCLUSIONS

In our study, expanded HSF1 VNTRs are not enriched in ET patients, with no distinguishing sequence features between patients and controls. Further validation in additional large cohorts is warranted. © 2026 International Parkinson and Movement Disorder Society.