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How to manage patients with germline DDX41 variants: Recommendations from the Nordic working group on germline

Panagiotis Baliakas1, Bianca Tesi2,3,4, Jörg Cammenga5,6

  • 1Department of Immunology, Genetics and Pathology Uppsala University Uppsala Sweden.

Hemasphere
|August 14, 2024
PubMed

Insights

Germline DDX41 variants increase risk for myeloid neoplasms, including myelodysplastic syndrome and acute myeloid leukemia. This study offers specific guidance for diagnosing and managing these rare but significant hematologic malignancies.

Area of Science:

  • Hematology
  • Genetics
  • Oncology

Background:

  • Germline variants in the DEAD-box helicase 41 (DDX41) gene are increasingly recognized as predisposing factors for hematological malignancies.
  • These variants are particularly associated with myeloid neoplasms (MNs), including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

Purpose of the Study:

  • To establish specific recommendations for the diagnosis, surveillance, and treatment of patients with germline DDX41 variants.
  • To characterize the unique clinical features of DDX41-associated MNs.

Main Methods:

  • Review of existing literature and clinical data on germline DDX41 variants in hematological malignancies.
  • Analysis of the prevalence, clinical presentation, and genetic landscape of DDX41-associated MNs.
  • Development of evidence-based guidelines for clinical management.

Main Results:

  • Approximately 3%-5% of MDS or AML patients harbor a pathogenic germline DDX41 variant, often with a second somatic hit.
  • DDX41-associated MNs typically occur in older individuals, present with an indolent clinical course, and are more common in males.
  • Hypoplastic bone marrow and preceding cytopenias are characteristic findings.

Conclusions:

  • Germline DDX41 variants represent a distinct subtype of inherited predisposition to MNs.
  • Tailored diagnostic, surveillance, and treatment strategies are crucial for affected individuals.
  • Further research is warranted to fully elucidate the pathogenesis and optimize management of DDX41-associated MNs.

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