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Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23)
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  • Edoardo Errichiello,
  • Guido Zagnoli-Vieira,
  • Romana Rizzi,
  • Livia Garavelli,
  • Keith Caldecott,
  • Orzetta Zuffardi
Edoardo Errichiello
University of Pavia
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Guido Zagnoli-Vieira
University of Sussex
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Romana Rizzi
Azienda USL di Reggio Emilia
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Livia Garavelli
Azienda USL di Reggio Emilia
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Keith Caldecott
University of Sussex
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Orzetta Zuffardi
University of Pavia
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Abstract

TDP2 encodes a 5′-tyrosyl DNA phosphodiesterase that is required for the efficient repair of double-strand breaks (DSBs) induced by the abortive activity of TOP2. To date, only two homozygous variants in TDP2 have been reported in five patients from three unrelated pedigrees with spinocerebellar ataxia 23 (SCAR23). By whole-exome sequencing, we identified a novel TDP2 splice-site variant (c.636+3_636+6del) in two Italian siblings (aged 39 and 43) showing progressive ataxia, intellectual disability, speech delay, refractory seizures, and various physical anomalies. The variant caused exon 5 skipping with consequent nonsense-mediated mRNA decay and defective repair of TOP2-induced DSBs, as demonstrated by the functional assays performed on the patients’ fibroblasts. Our findings further support the pathogenic role of biallelic loss-of-function variants of TDP2 in SCAR23 pathogenesis. Considering the adult age of our patients and their extensive follow-up, our study delineates in more detail the clinical phenotype related to the loss of TDP2 activity.