Distinct somatic genetic rescue mechanisms can be present within the same family and impact clinical course. Representative pedigrees of SAMD9/9L syndrome (A) and short telomere syndromes (B) showing that within 1 family carrying the same germline mutation, different somatic adaptations can arise. The consequence of these mutations influences subsequent risk of progression to MDS/AML, and the stochastic nature of these acquired changes on the cellular level may explain some of the variability in penetrance of MDS/AML in families with inherited bone marrow failure and MDS predisposition syndromes.