NHEJ1 Splice Variants Associated With Bone Marrow Failure and Hematologic Malignancy.

Area of Science:

• Genetics
• Hematology
• Immunology

Background:

• Nonhomologous end-joining (NHEJ)1 deficiency is a known cause of genome maintenance disorders (GMDs), typically presenting with severe combined immunodeficiency.
• However, the full spectrum of clinical manifestations, particularly hematologic implications beyond lymphoid abnormalities, remains incompletely understood.

Purpose of the Study:

• To highlight the under-recognized hematopoietic implications of NHEJ1 deficiency.
• To emphasize the diagnostic challenges posed by NHEJ1 omission in standard genetic testing panels for bone marrow failure syndromes.

Main Methods:

• Case report of two patients with confirmed NHEJ1 deficiency.
• Clinical and diagnostic evaluation, including genetic analysis and follow-up of hematologic parameters.

Main Results:

• One patient presented with recurrent cytopenias evolving into myelodysplasia, chronic myelomonocytic leukemia, and acute myeloid leukemia.
• The second patient exhibited cytopenias without overt immunodeficiency.
• Diagnosis was delayed in both cases due to NHEJ1's exclusion from common inherited bone marrow failure syndrome panels.

Conclusions:

• NHEJ1 deficiency presents with significant hematopoietic abnormalities, including myeloid malignancies, beyond lymphoid deficiencies.
• There is a need to include NHEJ1 in genetic testing for inherited bone marrow failure syndromes to ensure timely diagnosis and management.
• NHEJ1 deficiency contributes to the growing understanding of GMDs with combined myeloid and lymphoid concerns.