A number of genes that are targets of recurrent somatic mutation in AML are also mutated in the germline in families with predisposition to myeloid malignancy without a prodrome of bone marrow failure. These include mutations in RUNX1, CEBPA, DDX41, and GATA2. Predisposition to AML is also associated with germline variants in ANKRD26, SRP72, ETV6, and SAMD9/SAMD9L. Because gene panel testing (see box on Molecular Diagnostics in Acute Myeloid Leukemia) of unpaired tumor samples cannot reliably discriminate germline from somatic mutations, detection of a known pathogenic mutation in one of these genes in a bone marrow or peripheral blood sample should prompt referral for genetic counseling and germline testing. Although these familial syndromes are rare, they are important to recognize because affected individuals and asymptomatic carriers require specific clinical management. In particular, asymptomatic carriers require counseling about risks to themselves and their offspring, and they should be deferred as graft donors for allogeneic stem cell transplantation. The prevalence and risk of MDS/AML development has not been defined for most of these syndromes due to ascertainment bias in most of the reported series (Table 1).
Table1. Familial Acute Myeloid Leukemia Syndromes
Familial platelet disorder with predisposition to acute myelogenous leukemia (OMIM 601399) is associated with autosomal dominant inheritance of germline mutations in RUNX1. Mutation carriers frequently present with easy bruising/bleeding due to quantitative or qualitative platelet dysfunction and have an approximately 40% life time risk of developing AML, typically in the third or fourth decade. The most frequently reported mutant alleles in RUNX1 are loss-of function nonsense, frameshift, or missense mutations in the DNA binding domain. The second copy of RUNX1 is frequently mutated in cases that evolve to MDS/AML.
Germline mutations in CEBPA are a rare cause of autosomal dominant familial predisposition to AML (OMIM 116897). The germline mutations are typically truncating at the N-terminus of the protein, whereas somatic acquisition of mutations affecting the C-terminus is a nearly invariant event in the development of AML among these patients. These cases have a relatively favorable prognosis, similar to de novo AML with somatically acquired biallelic CEBPA mutations.
Germline mutations in GATA2 cause a spectrum of disor ders with overlapping features, including Emberger syndrome (OMIM 614038) and immunodeficiency 21 (IMD21) (OMIM 614172), also described as monocytopenia with susceptibil ity to mycobacterial, fungal, and papillomavirus infection and myelodysplasia (MonoMAC syndrome) or dendritic cell, mono cyte, B-lymphocyte, and natural killer lymphocyte deficiency (DCML). Patients with IMD21 have decreased monocyte counts and natural killer and B-cell deficiency and are at an increased risk of developing viral and nontuberculous mycobacterial infections. Emberger syndrome patients have a similar presentation but also have deafness and lymphedema and often develop pancytopenia. More than 100 germline GATA2 mutations have been described, most commonly deletions, nonsense, or missense substitution affecting the C-terminal zinc finger of GATA2, in addition to intronic mutations and substitutions at a 5′ enhancer. AML or MDS arises in approximately 70% of carriers and is associated with cooperating genetic events, such as mutations in ASXL1, SETBP1, STAG2, or hemizygous deletions involving chromo some 7.
SAMD9 and SAMD9L are paralogous genes on chromosome 7q. Inherited missense mutations in both genes appear to confer gain-of function growth suppressive activity in hematopoietic cells. A variety of compensatory somatic events have been described that allow cells to escape from this antiproliferative pressure, including acquisition of loss-of-function mutations in cis that abrogate the effects of the germline allele, gene correction by homologous recombination, and loss of the chromosome arm harboring the mutant allele—a phenomenon termed “adaptation by aneuploidy.” The latter is associated with increased risk of MDS/AML development, whereas the former mechanisms are protective. Affected individuals may present with MDS/AML without prior sequelae or may have preceding stigmata of ataxia-pancytopenia (SAMD9L; OMIM 159550) or the MIRAGE syndrome (SAMD9; OMIM 617053).
Germline mutations in DDX41 on chromosome 5q are associated with autosomal dominant predisposition to MDS/AML with a long latency (OMIM 616871). Affected individuals may present with cytopenias prior to diagnosis of MDS/AML, but often a family history of hematologic malignancies is the only feature that raises suspicion of an inherited syndrome. Pathogenic germline DDX41 alleles include deletions, frameshift, nonsense, or missense mutations. Somatic mutations in the remaining DDX41 allele are acquired in nearly half of individuals who progress to MDS/AML.
