Germline Predisposition to MDS and AML

Familial predisposition to leukemia has been classically associated with inherited bone marrow failure syndromes such as Fanconi anemia, severe congenital neutropenia, or Schwachman–Diamond syndrome, which present with bone marrow failure progressing to myelodysplastic syndromes and leukemia. These childhood-onset conditions can be identified by clinical diagnosis due to the specific phenotype patterns, with genetics playing a confirmatory role. In recent years, many monogenic and mostly autosomal dominant MDS/AML (myelodysplastic syndrome/acute myeloid leukemia) predisposition syndromes have been identified. Due to the wide phenotype variability, incomplete penetrance, and lack of functional confirmation, genetics plays a crucial role in the diagnosis of such syndromes, which involve genes such as CEBPA, RUNX1, GATA2, ETV6, DDX41, or ERCC6L2. This chapter describes these newly characterized leukemia predisposition syndromes’ genetic, biological, and clinical features.