Genetics in Inherited Bone Marrow Failure Disorders

The classical Inherited Bone Marrow Failure Syndromes (IBMFS) such as Fanconi anemia, Dyskeratosis Congenita, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia are a heterogeneous group of disorders, all of which are characterized by impaired hematopoiesis, varying degrees of peripheral cytopenias and marrow hypoplasia and dysplasia.  Many of these are associated with an increased risk of clonal dominance and evolution to myelodyplastic syndrome (MDS) and acute myeloid leukemia (AML).   For the purposes of this talk, the familial MDS and acute leukemia predisposition syndromes are also included in the broad term IBMFS.  The genes responsible for a subset of IBMFS have been identified and will be reviewed.  However, the causative mutations in many patients presenting with seemingly inherited marrow failure remain unknown.  Gene discovery in IBMFS has been difficult in large part due to the phenotypic heterogeneity of these syndromes.  Some patients with IBMFS display a distinct clinical phenotype with associated syndromic abnormalities, others are variable and overlap with one another or with acquired MDS or idiopathic acquired aplastic anemia, and additional cases are more obscure and have evaded classification altogether.  Accurate diagnosis of IBMFS inform patient care as it allows appropriate screening of siblings to avoid choosing an affected donor if marrow transplant is indicated and the selection of an appropriate transplant conditioning regiment to avoid undue toxicity. Additionally, accurate diagnosis allows appropriate medical monitoring and early intervention to successfully treat disease-specific non-hematologic medical complications.  The application of next generation sequencing approaches for comprehensive genetic screening of IBMFS, including these cryptic or atypical presentations will be reviewed.  In addition to providing accurate diagnoses in a subset of patients, genetic characterization in small family kindreds or even in single individuals presents unique opportunities to discover new genes and pathways contributing to dysfunctional hematopoiesis and clonal progression.  The frequency of inherited mutations in known IBMFS genes among seemingly idiopathic acquired aplastic anemia patients or pediatric and younger adults with MDS referred for hematopoietic stem cell transplant will be reviewed.  Future genetic studies are needed to characterize the secondary genetic events that lead to disease progression in IBMFS.