Abstract
Telomere biology disorders (TBDs) are characterized by bone marrow failure (BMF) and dysfunctional telomeres. So far, inherited mutations in 18 genes have been identified in TBDs. Here, we describe a child presenting with early BMF, immunodeficiency, and severely short and defective telomeres, carrying a homozygous splicing mutation (c.409-2 A > G; p.Q136_K138del) in RPA2 – a known replication factor and telomerase accessory factor. The Q136_K138del mutation is predicted to compromise the binding of RPA2 to the single-stranded telomeric DNA. Sequencing of single telomeres revealed that telomere variant repeats (TVRs), present also in healthy individuals, became more prominent in the short telomeres of the patient. Such TVRs may aggravate the telomere dysfunction due to lower affinity to the shelterin proteins. The severe telomere shortening and the activation of DNA damage response at telomeres indicate that this RPA2 mutation causes TBD in a similar manner to other known mutations and should be considered in patients displaying clinical TBD features.
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Data availability
The exome and Sanger sequences (genomic and cDNA) datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
Code availability
The code used for filtering and processing Nanopore sequencing reads, termed Telomere Analyzer, is available at [Lichtental, D. TelomereAnalyzer. Zenodo (2023). https://doi.org/10.5281/zenodo.8379362].
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Acknowledgements
We thank the patient and his family for their participation in this study. We thank the Jeffrey Modell Foundation, the Israel Ministry of Health, and the Israeli Science Foundation for their support. This work was supported by the Israel Science Foundation grants 3115/19 to R.S. and 1342/23 to Y.T.
Funding
This work was supported by the Jeffrey Modell Foundation, the Israel Ministry of Health, and the Israeli Science Foundation grants 3115/19 and 1342/23 to Y.T.
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Contributions
Study conceptualization and design, analysis and interpretation of data, and manuscript writing: AJS, YT, and RS; Computational structure modeling and writing original draft: FB, ON, RK; Telomere analysis by NanoTelSeq and FISH, and writing original draft: MNB; Telomere analysis by in-gel hybridization: RS; Sanger sequencing and Western blot analysis: AL, SL; WES and bioinformatics analysis: OB; Patient diagnosis and treatment: AM, MR, EA; Pathology assessment: SN.
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A signed informed consent was obtained from the patient’s parents in accordance with the ethical standards and approved by our institutional ethics committee at Sheba Medical Center (reference number 8842-11-SMC). Clinical data were collected and reviewed from digital hospital-based data.
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Simon, A.J., Neustadter-Blackman, M., Lev, A. et al. A homozygote mutation in RPA2 associated with bone marrow failure, immunodeficiency, and telomere biology disorder. Eur J Hum Genet (2026). https://doi.org/10.1038/s41431-026-02035-8
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DOI: https://doi.org/10.1038/s41431-026-02035-8
