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. 2022 Jan;24(1):29-40.
doi: 10.1016/j.gim.2021.08.003. Epub 2021 Nov 30.

Digenic inheritance of STUB1 variants and TBP polyglutamine expansions explains the incomplete penetrance of SCA17 and SCA48

Stefania Magri  1 , Lorenzo Nanetti  2 , Cinzia Gellera  1 , Elisa Sarto  1 , Elena Rizzo  1 , Alessia Mongelli  1 , Benedetta Ricci  1 , Roberto Fancellu  3 , Luisa Sambati  4 , Pietro Cortelli  4 , Alfredo Brusco  5 , Maria Grazia Bruzzone  6 , Caterina Mariotti  1 , Daniela Di Bella  1 , Franco Taroni  7
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Free article

Digenic inheritance of STUB1 variants and TBP polyglutamine expansions explains the incomplete penetrance of SCA17 and SCA48

Stefania Magri et al. Genet Med. 2022 Jan.
Free article

Abstract

Purpose: This study aimed to unravel the genetic factors underlying missing heritability in spinocerebellar ataxia type 17 (SCA17) caused by polyglutamine-encoding CAG/CAA repeat expansions in the TBP gene. Alleles with >49 CAG/CAA repeats are fully penetrant. Most patients, however, carry intermediate TBP41-49 alleles that show incomplete penetrance.

Methods: Using next-generation sequencing approaches, we investigated 40 SCA17/TBP41-54 index patients, their affected (n = 55) and unaffected (n = 51) relatives, and a cohort of patients with ataxia (n = 292).

Results: All except 1 (30/31) of the index cases with TBP41-46 alleles carried a heterozygous pathogenic variant in the STUB1 gene associated with spinocerebellar ataxias SCAR16 (autosomal recessive) and SCA48 (autosomal dominant). No STUB1 variant was found in patients carrying TBP47-54 alleles. TBP41-46 expansions and STUB1 variants cosegregate in all affected family members, whereas the presence of either TBP41-46 expansions or STUB1 variants individually was never associated with the disease.

Conclusion: Our data reveal an unexpected genetic interaction between STUB1 and TBP in the pathogenesis of SCA17 and raise questions on the existence of SCA48 as a monogenic disease with crucial implications for diagnosis and counseling. They provide a convincing explanation for the incomplete penetrance of intermediate TBP alleles and demonstrate a dual inheritance pattern for SCA17, which is a monogenic dominant disorder for TBP≥47 alleles and a digenic TBP/STUB1 disease (SCA17-DI) for intermediate expansions.

Keywords: CHIP; Digenic disease; Huntington disease-like phenotype; Polyglutamine; Spinocerebellar ataxia.

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