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 type 17 (SCA17).We previously detected co-segregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in two families.This co-segregation questions the existence 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≥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 = 0.0129) and the faster the disease progression until death (p = 0.0003).Importantly, thirteen 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.