Myelodysplastic syndrome (MDS) typically presents in older adults with the acquisition of age-related somatic mutations, whereas MDS presenting in children and younger adults is more frequently associated with germline genetic predisposition. Germline predisposition is increasingly recognized in MDS presenting at older ages as well. Although each individual genetic disorder is rare, as a group, the genetic MDS disorders account for a significant subset of MDS in children and young adults. Because many patients lack overt syndromic features, genetic testing plays an important role in the diagnostic evaluation. This review provides an overview of syndromes associated with genetic predisposition to MDS, discusses implications for clinical evaluation and management, and explores scientific insights gleaned from the study of MDS predisposition syndromes. The effects of germline genetic context on the selective pressures driving somatic clonal evolution are explored. Elucidation of the molecular and genetic pathways driving clonal evolution may inform surveillance and risk stratification, and may lead to the development of novel therapeutic strategies.
© 2019 by The American Society of Hematology.