Variable Clinical Presentation in Individuals with Truncating Variants in DDX41

Defects in DDX41 have previously been associated with increased risk of myeloid neoplasms, lymphoid neoplasms, cytopenia, and red blood cell macrocytosis. DDX41-related phenotypes have a variable age of onset typically in the 60 s. A previous study analyzed a cohort of 1,385 individuals with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), identifying 33 individuals with a pathogenic variant in DDX41, 9 of whom had a familial history of MDS/AML. In our cohort of 6,103 participants with diverse clinical manifestations, we identified 7 individuals with truncating variants in DDX41. We sought to characterize age-related penetrance and the phenotypic spectrum of individuals with DDX41 truncating variants. We performed exome or genome sequencing on DNA extracted from blood, saliva, fibroblasts, or EBV-transformed cell lines in individuals referred to the Centralized Sequencing Program at the NIH for immune-related, neurological, psychiatric, and other clinical indications. We identified 7 subjects with truncating variants in DDX41, including 3 different frameshift variants in 5 subjects and 2 different nonsense variants in the other 2 subjects. The average age of subjects was 37 years old, ranging from 5 to 76 years old at time of enrollment. There were 3 males and 4 females. Family history of DDX41-related phenotypes was not reported in the families; furthermore, there were no familial cases, thought segregation data was incomplete. Clinical features were highly variable, ranging from a healthy volunteer to an individual with JAK2 p. Val617Phe-associated eosinophilic myeloid neoplasm. Previously associated DDX41-related phenotypes were not observed in the 7 subjects even include those above 60. Here, we report 7 subjects with truncating variants in DDX41. These individuals have variable immune phenotypes and further studies are necessary to delineate whether they are attributed to DDX41 truncating variants. Detection of DDX41-defects in younger individuals prior to symptom onset poses genetic counseling challenges given the long latency period and minimal evidence-based management guidelines at present. Nonetheless, current expert-based clinical recommendations for management and monitoring may provide clinical benefit upon further study. Additional studies of clinical and sub-clinical features in expanded cohorts are warranted to further delineate DDX41-related disease risk.