Investigation of pathogenic and truncated variants of RUNX1 and DDX41 in all of us

Authors

• VD Bhat
• Q Chen
• B Lackford
• G Hu

Abstract

Myeloid neoplasms associated with germline disposition can be caused by inherited variants involving multiple genes such as RUNX1, DDX41, CEBPA, GATA2, ETV6, TP53, ANKRD26s. Inherited pathogenic/likely pathogenic (P/LP) variants of RUNX1 lead to familial platelet disorder with predisposition to myeloid malignancy (FPDMM), and those of DDX41 lead to late onset MDS/AML. However, previous generated data has mostly focused on clinically ascertained probands and their families and thus may be subjected to ascertainment biases. Here, we used a genotype-first strategy to investigate the natural behaviors of the pathogenic and likely pathogenic (P/LP) variants involving RUNX1 and DDX41 in a phenotypically unselected population on the All of Us Research Platform.
In RUNX1, we identified ?20 individuals who carry P/LP variants, all located in the RUNT domain. Phenotypes included undiagnosed persistent thrombocytopenia, myeloid neoplasm, and absence of significant hematological diseases in different carrying individuals.
In DDX41, we identified 33 individuals with P/LP variants with a median age of 53 years. The prevalence of cytopenia was similar to non-carriers (anemia 65.2% in carriers compared to 54.5% in non-carriers; thrombocytopenia 5.8% compared to 20%, neutropenia 33% compared to 28.7%; all statistically non-significant). However, we observed that among the < 20 male carriers with CBC data, 75% of them had documented anemia with first onset at ages of 49-64 years old. There were no diagnosed myeloid neoplasms among the carriers, which might be due to the younger ages of the All of Us participants.

Scientific Focus Area: Genetics and Genomics

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