TBP Repeat Expansion Analysis in Patients Carrying Heterozygous STUB1 Variants.

BACKGROUND

The cooccurrence of intermediate (40-49 CAG/CAA) TBP repeat expansions with STUB1 variants questions the pathogenicity of monoallelic STUB1 variants in cerebellar ataxia.

OBJECTIVE

The objective of this study was to describe the phenotypic spectrum of heterozygous STUB1 variants with or without intermediate TBP repeat expansions.

METHODS

We determined the presence of TBP repeat expansions and STUB1 variants in six families with cerebellar ataxia.

RESULTS

Cooccurrence of both genotypes in one family resulted in cerebellar ataxia, involving cognitive and extrapyramidal complications. Variable degrees of cerebellar ataxia and cognitive impairment were found in four families carrying a heterozygous STUB1 variant and normal TBP alleles. Finally, we report one patient with a mild late-onset cerebellar ataxia carrying an intermediate expanded TBP allele without the presence of a STUB1 variant.

CONCLUSIONS

Heterozygous STUB1 variants are associated with a milder phenotype and reduced penetrance compared with the cosegregation with intermediate TBP alleles, which causes a fully penetrant complicated form of cerebellar ataxia. © 2025 International Parkinson and Movement Disorder Society.