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Article Abstract
Background: 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.
Objective: To determine the presence and impact of intermediate or high-normal TBP expansions in ataxic patients with heterozygous STUB1 variants.
Methods: We describe 21 patients with ataxia carrying a heterozygous STUB1 variant and determined TBP repeat length.
Results: 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.
Conclusions: 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.
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