Clinical utility of gene panel-based testing for hereditary myelodysplastic syndrome/acute leukemia predisposition syndromes

Myelodysplastic syndrome (MDS) and acute leukemia (AL) are clinically diverse and genetically heterogeneous groups of hematological malignancies. Hereditary forms of MDS/AL were considered rare, but have been increasingly recognized in recent years. 1 , 2 , 3 Pathogenic variants in a single gene can predispose carriers to an increased lifetime risk of primary MDS and/or AL. Hereditary MDS/AL can occur in the context of familial MDS/AL that have MDS/AL as the principal clinical feature, or arise from inherited bone marrow failure syndromes (IBMFS), such as Fanconi anemia (FA), dyskeratosis congenita/telomerase biology disorders (TBD), Diamond–Blackfan anemia and severe congenital neutropenia. 1 , 4 Within the past decade, nearly a dozen adult-onset familial MDS/AL syndromes have been defined. These include thrombocytopenia with associated myeloid malignancies caused by germ line mutations in RUNX1 , ANKRD26 and ETV6 ; GATA2 -associated syndromes (Emberger syndrome; MonoMAC syndrome; immunodeficiency); familial MDS and acute myeloid leukemia caused by mutations in CEBPA , DDX41 and SRP72 ; and TBD due to mutations in TERT or TERC. 2 Although the majority of patients with classic IBMFS are diagnosed in childhood, some patients have no or only subtle extra hematopoietic manifestations and may present in adulthood with MDS or AL. 2 , 5