Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies

Blood. 2016 Feb 25;127(8):1017-23. doi: 10.1182/blood-2015-10-676098. Epub 2015 Dec 28.

Abstract

Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Aged
  • Aged, 80 and over
  • DEAD-box RNA Helicases / genetics*
  • DNA Mutational Analysis
  • Female
  • Fluorescent Antibody Technique
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Germ-Line Mutation*
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / genetics*
  • Pedigree
  • Phenotype

Substances

  • DDX41 protein, human
  • DEAD-box RNA Helicases