Intermediate repeat expansions of TBP and STUB1: genetic modifier or pure digenic inheritance in spinocerebellar ataxias? - Sorbonne Université Access content directly
Journal Articles Genetics in medicine : official journal of the American College of Medical Genetics Year : 2022

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

Claire-Sophie Davoine
  • Function : Author
Emilien Petit
  • Function : Author
Maximilien Porche
  • Function : Author
Léna Guillot-Noel
  • Function : Author
Sabrina Sayah
  • Function : Author
Anne-Laure Fauret
  • Function : Author
Jean-Philippe Neau
  • Function : Author
Lucie Guyant- Marechal
  • Function : Author
Didier Deffond
  • Function : Author
Christine Tranchant
  • Function : Author
Cyril Goizet
  • Function : Author
Giulia Coarelli
  • Function : Author
Anna Castrioto
  • Function : Author
Stephan Klebe
  • Function : Author
Claire Ewenczyk
  • Function : Author
Anna Heinzmann
  • Function : Author
Perrine Charles
  • Function : Author
Maya Tchikviladzé
  • Function : Author
Christine van Broeckhoven
  • Function : Author
Alexis Brice
  • Function : Author
Alexandra Durr
  • Function : Author
  • PersonId : 1078003
Pr Alexandra Durr
  • Function : Author

Abstract

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.
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hal-03997720 , version 1 (20-02-2023)

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Mathieu Barbier, Claire-Sophie Davoine, Emilien Petit, Maximilien Porche, Léna Guillot-Noel, et al.. Intermediate repeat expansions of TBP and STUB1: genetic modifier or pure digenic inheritance in spinocerebellar ataxias?. Genetics in medicine : official journal of the American College of Medical Genetics, 2022, ⟨10.1016/j.gim.2022.10.009.⟩. ⟨hal-03997720⟩
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