Mechanisms of somatic genetic rescue in the SAMD9/9L syndromes. Pathogenic germline mutations in SAMD9 and SAMD9L are gain-of-function and have a growth suppressive effect on hematopoiesis. Cells that acquire adaptations that improve growth or survival are selected in the high turnover environment of the bone marrow. Somatic second-site loss-of-function mutations in cis or removal of the mutant allele via uniparental isodisomy of chromosome 7q or focal gene deletion are not associated with progression to MDS/AML. In contrast, the monosomy 7 clone often acquires additional leukemia driver mutations with high risk of disease progression. WT, wild type.