TDP2 encodes a 5'-tyrosyl DNA phosphodiesterase required for the efficient repair of double-strand breaks (DSBs) induced by the abortive activity of DNA topoisomerase II (TOP2). To date, only three homozygous variants in TDP2 have been reported in six patients from four 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 40 and 45) 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 on the patients' fibroblasts. Our findings further demonstrate the pathogenic role of TDP2 biallelic loss-of-function variants in SCAR23 pathogenesis. Considering the age of our patients, the oldest reported to date, and their extensive follow-up, our study delineates in more detail the clinical phenotype related to the loss of TDP2 activity.

Department of Genome Dynamics Institute of Molecular Genetics of the ASCR v v i Prague Czech Republic

Genome Damage and Stability Centre University of Sussex Falmer Brighton UK

Medical Genetics Unit Department of Maternal and Child Health Azienda USL IRCCS Reggio Emilia Reggio Emilia Italy

Medical Genetics Unit Department of Molecular Medicine University of Pavia Pavia Italy

Neurology Unit Department of Neuro Motor Diseases Azienda USL IRCCS Reggio Emilia Reggio Emilia Italy

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