Hypothetical model of the pathophysiology of germ line SAMD9L GoF mutations in relation to hematopoietic stem and progenitor cell proliferation and differentiation. Healthy individuals, with 2 wild-type SAMD9L copies (top row), have (1) normal, steady-state hematopoiesis and (2) increased cellular output upon infection-induced, demand-adapted hematopoiesis. In contrast, carriers of heterozygous SAMD9L GoF mutations (middle row) may (1) display grossly normal (subclinical?) hematopoiesis for some time, but (2) experience cytopenias and immunodeficiency upon infections early in life. In this setting, interferons can promote SAMD9L expression, with SAMD9L GoF mutants acting as potent suppressors of cell proliferation, dramatically impairing hematopoiesis and immunity. The ensuing hematopoietic crisis can facilitate (3) selection and expansion of revertant mutants, by uniparental disomy (UPD) of 7q, SAMD9L loss-of-function (LoF) mutations in cis, or monosomy 7. Whereas UPD(7q) and in cis SAMD9L, LoF mutations can support clonal hematopoiesis and recovery from cytopenia, monosomy 7 is associated with development of myelodysplastic syndrome. Finally, carriers of combined SAMD9L GoF mutation and rare LoF variants in trans (bottom row) are asymptomatic, suggesting they have normal (1) steady-state and (2) demand-adapted hematopoiesis. As such, pathogenic effects of SAMD9L GoF mutations may be balanced by SAMD9L LoF mutations.