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. 2025 May;40(5):980-985.
doi: 10.1002/mds.30147. Epub 2025 Feb 14.

TBP Repeat Expansion Analysis in Patients Carrying Heterozygous STUB1 Variants

Jonathan De Winter  1   2   3 , Liedewei Van de Vondel  1   2 , Kristof Van Schil  4 , Tine Deconinck  4 , Katrien Storm  4 , Karine Geens  5 , Charlotte Sommeling  6 , David Crosiers  1   7 , Emke Marechal  7   8 , Willem De Ridder  1   2   3 , Peter De Jonghe  3 , Jonathan Baets  1   2   3
Affiliations

TBP Repeat Expansion Analysis in Patients Carrying Heterozygous STUB1 Variants

Jonathan De Winter et al. Mov Disord. 2025 May.

Abstract

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.

Keywords: autosomal recessive spinocerebellar ataxia type 16; digenic inheritance; reduced penetrance; spinocerebellar ataxia type 17; spinocerebellar ataxia type 48.

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