Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Mov Disord. 2024 Sep;39(9):1636-1640. doi: 10.1002/mds.29912. Epub 2024 Jul 7.
Monoallelic, pathogenic STUB1 variants cause autosomal dominant cerebellar ataxia (ATX-STUB1/SCA48). Recently, a genetic interaction between STUB1 variants and intermediate or high-normal CAG/CAA repeats in TBP was suggested, indicating digenic inheritance or a disease-modifying role for TBP expansions.
To determine the presence and impact of intermediate or high-normal TBP expansions in ataxic patients with heterozygous STUB1 variants.
We describe 21 patients with ataxia carrying a heterozygous STUB1 variant and determined TBP repeat length.
A total of 15 of 21 patients (71%) carried a normal TBP allele, 4 (19%) carried an intermediate TBP allele, and two carried a high-normal TBP allele (9.5%). Five of six carriers (83%) of both STUB1 variants and TBP alleles showed marked cognitive impairment.
SCA48 is predominantly a monogenic disorder, because most patients carried an isolated, heterozygous STUB1 variant and presented with the typical combined phenotype of ataxia and cognitive dysfunction. Still, co-occurrence of TBP or high-normal TBP alleles was relatively frequent and associated with marked cognitive defects (28.5%), suggesting a modifying effect on clinical expression in some cases.
单等位基因、致病性 STUB1 变异导致常染色体显性小脑共济失调（ATX-STUB1/SCA48）。最近，STUB1 变异与 TBP 中中度或高度正常 CAG/CAA 重复之间的遗传相互作用被提出，表明双等位基因遗传或 TBP 扩展具有疾病修饰作用。
确定携带杂合 STUB1 变异的共济失调患者中是否存在中度或高度正常的 TBP 扩展及其影响。
我们描述了 21 例携带杂合 STUB1 变异的共济失调患者，并确定了 TBP 重复长度。
21 例患者中，共有 15 例（71%）携带正常 TBP 等位基因，4 例（19%）携带中度 TBP 等位基因，2 例携带高度正常 TBP 等位基因（9.5%）。携带 STUB1 变异和 TBP 等位基因的 6 例患者中的 5 例（83%）表现出明显的认知障碍。
SCA48 主要是一种单基因疾病，因为大多数患者携带孤立的杂合 STUB1 变异体，并表现出典型的共济失调和认知功能障碍联合表型。然而，TBP 或高度正常 TBP 等位基因的共同发生相对频繁，并与明显的认知缺陷（28.5%）相关，这表明在某些情况下对临床表达具有修饰作用。
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