TBP Repeat Expansion Analysis in Patients Carrying Heterozygous STUB1 Variants

IF 7.6 1区医学 Q1 CLINICAL NEUROLOGY Movement Disorders Pub Date : 2025-02-14 DOI:10.1002/mds.30147

Jonathan De Winter MD, Liedewei Van de Vondel PhD, Kristof Van Schil PhD, Tine Deconinck MSc, Katrien Storm MSc, Karine Geens MD, Charlotte Sommeling MD, David Crosiers MD, PhD, Emke Marechal MD, Willem De Ridder MD, PhD, Peter De Jonghe MD, PhD, Jonathan Baets MD, PhD

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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.

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携带杂合子STUB1变异体患者TBP重复扩增分析。

背景：中间（40-49 CAG/CAA） TBP重复扩增与STUB1变异的共同发生，对单等位基因STUB1变异在小脑性共济失调中的致病性提出了质疑。目的：本研究的目的是描述具有或不具有中间TBP重复扩增的杂合STUB1变异的表型谱。方法：我们测定了6个小脑性共济失调家族中TBP重复扩增和STUB1变异的存在。结果：两个基因型在一个家族中同时发生导致小脑性共济失调，包括认知和锥体外系并发症。在四个携带杂合型STUB1变异和正常TBP等位基因的家族中发现了不同程度的小脑性共济失调和认知障碍。最后，我们报告了一名患有轻度迟发性小脑性共济失调的患者，该患者携带一种中间扩展的TBP等位基因，但不存在STUB1变异。结论：与与中间TBP等位基因共分离相比，杂合STUB1变异的表型更温和，外显率更低，导致小脑共济失调的完全渗透复杂形式。©2025国际帕金森和运动障碍学会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.