Myeloid neoplasms risks for germline DDX41 pathogenic variants carriers.

IF 4.6 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
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
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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.

种系DDX41致病变异携带者患髓系肿瘤的风险。
单等位种系DDX41致病变异(PV)是最常见的髓系肿瘤(MN)的单基因易感性,即骨髓增生异常综合征和急性髓系白血病。MN是影响造血组织的罕见克隆性疾病,治疗方法往往涉及造血干细胞移植,因此需要对ddx41突变MN患者的亲属进行检测。建立种系DDX41 PV的外显率对于确定如何监测携带家族DDX41 PV的未受影响的亲属至关重要。本研究旨在利用基因型限制似然(GRL)方法评估DDX41携带者亲属罹患MN的风险。我们从法国11个中心鉴定了63个先证携带MN影响的种系DDX41 PV (ACMG 4级或5级变体)的家庭。160例亲属,其中男性73例(46%),中位年龄51岁[范围:15-84],其中80例(50%)为家族性DDX41型PV携带者。DDX41 PV携带者70岁时MN的累积风险估计为19.5% [95% CI: 5.8%-62.5%],与一般人群相比的相对风险为55 [95% CI: 16.4-176.5]。这种风险在男性中似乎更高,尽管差异没有达到统计学意义。基于这些发现,我们建议DDX41 PV携带者从50岁开始每年进行一次全血计数。值得注意的是,我们观察到50岁之前的女性病例,这可能提示性别区分监测。
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来源期刊
European Journal of Human Genetics
European Journal of Human Genetics 生物-生化与分子生物学
CiteScore
9.90
自引率
5.80%
发文量
216
审稿时长
2 months
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
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