Myeloid neoplasms risks for germline DDX41 pathogenic variants carriers

Area of Science:

• Hematology
• Genetics
• Oncology

Background:

• Monoallelic germline DDX41 pathogenic variants (PV) are the most common cause of inherited predisposition to myeloid neoplasms (MN).
• Myeloid neoplasms, including myelodysplastic syndrome and acute myeloid leukemia, are rare clonal hematopoietic disorders.
• Hematopoietic stem cell transplantation is a curative approach for MN, necessitating genetic screening of relatives of affected individuals.

Purpose of the Study:

• To determine the penetrance of germline DDX41 PV in families with MN.
• To assess the risk of developing MN in relatives who carry familial DDX41 PV.
• To establish monitoring guidelines for unaffected relatives who are carriers of DDX41 PV.

Main Methods:

• Utilized the Genotype-Restricted-Likelihood (GRL) approach to estimate risk.
• Identified 63 families with MN probands carrying germline DDX41 PV (ACMG class 4 or 5) from 11 French centers.
• Genotyped 160 relatives, with 80 (50%) identified as carriers of the familial DDX41 PV.

Main Results:

• The cumulative risk of MN by age 70 for DDX41 PV carriers was estimated at 19.5% (95% CI: 5.8%-62.5%).
• This represents a 55-fold increased relative risk of MN compared to the general population (95% CI: 16.4-176.5).
• The risk appeared higher in males, though not statistically significant, and MN cases were observed before age 50 in females.

Conclusions:

• Germline DDX41 PV carriers have a substantially elevated lifetime risk of developing myeloid neoplasms.
• Yearly complete blood count screening is suggested for DDX41 PV carriers from age 50.
• Sex-differentiated monitoring may be warranted due to potential sex-based differences in risk and age of onset.