Marie-Charlotte Villy, Youenn Drouet, Lise Larcher, Yoann Vial, Benjamin Dauriat, Léa Veyrune, Laurène Fenwarth, Marie-Mathilde Auboiroux, Lucie Freiman, Sophie Nambot, Léa Patay, Marjolaine Willems, Emma Lachaier, Bénédicte Bonte, Delphine Lebon, Mathis Lepage, Olivier Ingster, Nathalie Gachard, Thomas Cluzeau, Michael Loschi, Jean Soulier, Pascale Flandrin-Gresta, Pascal Turlure, Nicolas Duployez, Emmanuelle Clappier, Dominique Stoppa-Lyonnet, Christine Lasset, Chrystelle Colas, Marie Sebert
{"title":"Myeloid neoplasms risks for germline DDX41 pathogenic variants carriers.","authors":"Marie-Charlotte Villy, Youenn Drouet, Lise Larcher, Yoann Vial, Benjamin Dauriat, Léa Veyrune, Laurène Fenwarth, Marie-Mathilde Auboiroux, Lucie Freiman, Sophie Nambot, Léa Patay, Marjolaine Willems, Emma Lachaier, Bénédicte Bonte, Delphine Lebon, Mathis Lepage, Olivier Ingster, Nathalie Gachard, Thomas Cluzeau, Michael Loschi, Jean Soulier, Pascale Flandrin-Gresta, Pascal Turlure, Nicolas Duployez, Emmanuelle Clappier, Dominique Stoppa-Lyonnet, Christine Lasset, Chrystelle Colas, Marie Sebert","doi":"10.1038/s41431-025-01952-4","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6000,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Human Genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41431-025-01952-4","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
The European Journal of Human Genetics is the official journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports and reviews in the rapidly expanding field of human genetics and genomics. It covers molecular, clinical and cytogenetics, interfacing between advanced biomedical research and the clinician, and bridging the great diversity of facilities, resources and viewpoints in the genetics community.
Key areas include:
-Monogenic and multifactorial disorders
-Development and malformation
-Hereditary cancer
-Medical Genomics
-Gene mapping and functional studies
-Genotype-phenotype correlations
-Genetic variation and genome diversity
-Statistical and computational genetics
-Bioinformatics
-Advances in diagnostics
-Therapy and prevention
-Animal models
-Genetic services
-Community genetics