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.

TDP2编码有效修复DNA拓扑异构酶II（TOP2）的流产诱导的双链断裂（DSB）所需的5'-酪氨酰DNA磷酸二酯酶。迄今为止，在来自四个不相关谱系的患有脊髓小脑共济失调23（SCAR23）的六名患者中，仅报告了TDP2的三个纯合变异体。通过全外显子组测序，我们确定了一种新型的TDP2两个意大利同胞（分别为40岁和45岁）的剪接位点变异（c.636 + 3_636 + 6del），表现为进行性共济失调，智力残疾，言语延迟，难治性癫痫发作和各种身体异常。该变异体导致外显子5跳跃，随之而来的是无意义的介导的mRNA衰变和TOP2诱导的DSBs修复缺陷，如对患者成纤维细胞的功能分析所证实。我们的发现进一步证明了TDP2双等位基因功能缺失变异体在SCAR23发病机理中的致病作用。考虑到我们患者的年龄，迄今报道的最年长患者以及他们的广泛随访，我们的研究更详细地描述了与TDP2活性降低有关的临床表型。