SAMD9 is a double-stranded nucleic acid-binding protein that functions as a critical antiviral factor and negative regulator of cell proliferation 1. It acts as a pattern-recognition receptor for cytosolic dsDNA and dsRNA, directly binding these ligands to trigger robust interferon and pro-inflammatory cytokine production 2. Loss of endogenous SAMD9 impairs interferon responses to viral nucleic acids and enhances pathogenic virus infectivity 2. SAMD9 contributes to cytoplasmic antiviral granule formation, a key component of innate immune defense 1. Heterozygous germline gain-of-function SAMD9 mutations cause MIRAGE syndrome, ataxia-pancytopenia syndrome, and myeloid leukemia syndrome with monosomy 7, characterized by multisystem manifestations including cytopenia, immunodeficiency, bone marrow failure, and myelodysplasia 1. Approximately 8% of pediatric myelodysplastic syndromes harbor germline SAMD9 mutations, with refractory cytopenia being the most prevalent manifestation 3. Notably, over 61% of patients with SAMD9 mutations undergo somatic genetic rescue, frequently involving monosomy 7 or adaptive somatic mutations 3. SAMD9/SAMD9L are now recognized in WHO 2022 classification as important predisposition factors for myeloid neoplasms 4.