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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).

Abstract：

: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.

journal_name

J Hum Genet

journal_title

Journal of human genetics

authors

Errichiello E,Zagnoli-Vieira G,Rizzi R,Garavelli L,Caldecott KW,Zuffardi O

doi

10.1038/s10038-020-0800-4

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

1135-1141

issue

12

eissn

1434-5161

issn

1435-232X

pii

10.1038/s10038-020-0800-4

journal_volume

65

pub_type

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