NHEJ1 Splice Variants Associated With Bone Marrow Failure and Hematologic Malignancy

Nonhomologous end-joining (NHEJ)1 deficiency causes a genome maintenance disorder (GMD), classically associated with severe combined immunodeficiency. Here, we describe two cases of NHEJ1 deficiency presenting with cytopenias. One patient was an adolescent with recurrent cytopenias and frank immunodeficiency that evolved into bone marrow failure with myelodysplasia, then chronic myelomonocytic leukemia and ultimately treatment-refractory acute myeloid leukemia. The second patient was a preadolescent with only cytopenias. In both cases, diagnosis was not achieved by sending an inherited BMF syndrome panel because of the omission of NHEJ1. Our cases further emphasize that NHEJ1 deficiency harbors additionally under-recognized hematopoietic implications beyond lymphoid abnormalities, adding to the emerging evidence for coexistent myeloid and lymphoid concerns in GMDs.