Abstract

Recently our group and others have identified DDX41 mutations both as germline and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome and/or acute myeloid leukemia (MDS/AML), suggesting that DDX41 acts as a tumor suppressor. To determine if novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our groups screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine with DDX41 mutations (3%). As previously observed, MDS/AML were the most common malignancies, often of the erythroblastic subtype, and one 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 germline 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.

View details for DOI 10.1182/blood-2015-10-676098

View details for PubMedID 26712909