Abstract
Monoallelic germline DDX41 pathogenic variants (PV) are responsible for the most frequent monogenic predisposition to myeloid neoplasms (MN), i.e., to myelodysplastic syndrome and acute myeloid leukemia. MN are rare clonal diseases affecting hematopoietic tissues, and curative approaches frequently implicate hematopoietic stem cell transplantation, requesting testing for relatives of DDX41-mutated MN patients. Establishing the penetrance of germline DDX41 PV is crucial to determine how to monitor the unaffected relatives who carry the familial DDX41 PV. Our study aims to assess the risk of MN in relatives of affected DDX41 carriers using the Genotype-Restricted-Likelihood (GRL) approach. We identified 63 families with probands carrying a germline DDX41 PV (ACMG class 4 or class 5 variant) affected with MN, from 11 French centers. One hundred and sixty relatives, including 73 males (46%), were genotyped at the median age of 51 [range: 15–84] years, 80 of them (50%) being carriers of the familial DDX41 PV. The cumulative risk of MN at 70 years for DDX41 PV carriers was estimated at 19.5% [95% CI: 5.8%–62.5%], corresponding to a relative risk compared to the general population of 55 [95% CI: 16.4–176.5]. This risk appeared higher in males, although the difference did not reach statistical significance. Based on these findings, we suggest yearly complete blood count from the age of 50 for DDX41 PV carriers. Of note, we observed cases before the age of 50 in females, which could suggest sex-differentiated monitoring.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Code availability
All calculations were performed using R version 4.4.1 [13] and the open-source generisk package version 0.1.1 available at https://github.com/youenndrouet/generisk.
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The authors would like to thank the patients and their families.
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MCV, CC, DSL, and MS designed the project. MCV, BD, LFr, MMA, LFe, SN, MW, EL, DL, ML, OI, NG, TC, ML, JS, PFG, PT, LV, LP, and BB collected the clinical, genetic and familial data. YV, LL, ND, and EC analyzed the molecular genetic data. YD and MCV performed the statistical analyses. MCV, YD, and MS wrote the manuscript and designed the figures and tables. All authors revised the manuscript critically and approved the version of the manuscript to be published.
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Ethical approval was not sought for the present study because all data were obtained as part of routine care. All probands and relatives gave their written consent for genetic testing and for use of their data for research purposes. The data used for this study comes from a database approved by a National Review Board, in accordance with the Declaration of Helsinki and French ethics regulations.
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Villy, MC., Drouet, Y., Larcher, L. et al. Myeloid neoplasms risks for germline DDX41 pathogenic variants carriers. Eur J Hum Genet (2025). https://doi.org/10.1038/s41431-025-01952-4
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DOI: https://doi.org/10.1038/s41431-025-01952-4
