Myeloid neoplasms risks for germline DDX41 pathogenic variants carriers

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.