Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?

Purpose: CAG/CAA repeat expansions in TBP>49 are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the exis-tence of SCA48 as a monogenic disease.Methods: We systematically sequenced TBP repeats in 34 probands of dominant ataxia families with STUB1 variants. In addition, we searched for pathogenic STUB1 variants in probands with expanded alleles of TBP>49 (n = 2) or intermediate alleles of TBP & GE;40 (n = 47). Results: STUB1 variants were found in half of the TBP40-49 cohort. Mirroring this finding, TBP40-49 alleles were detected in 40% of STUB1 probands. The longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P = .0129) and the faster the disease progression until death (P= .0003). Importantly, 13 STUB1 probands presenting with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode.Conclusion: We show that intermediate TBP40-49 alleles act as disease modifiers of SCA48 rather than a STUB1/TBP digenic model. This distinction from what has been proposed before has crucial consequences for genetic counseling in SCA48.& COPY; 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Automated summary

Through systematic sequencing of STUB1 variants in 36 dominant ataxia families, half of the TBP40-49 samples were found to have STUB1 variants. Additionally, TBP40-49 alleles were detected in 40% of STUB1 probands. The study found that the longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P=0.0129) and the faster the disease progression (P=0.0003). Importantly, 13 STUB1 probands with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode.