GATA2 Mutations In Pediatric Myelodysplastic Syndromes and Bone Marrow Failure

Inherited bone marrow failure syndromes (IBMFS), idiopathic aplastic anemia (AA), and myelodysplastic syndromes (MDS) represent a spectrum of bone marrow failure (BMF) conditions for which the underlying genetics and pathophysiology is still poorly understood. Heterozygous germline mutations in GATA2 have recently been described in three distinct conditions that include familial MDS/AML, Emberger syndrome and MonoMac syndrome, each of which exhibits great clinical heterogeneity.

The Pediatric MDS and BMF Registry was established in 2010 to carefully characterize clinical and histopathologic phenotypes and investigate the molecular basis for these disorders. To date 158 eligible patients/probands and 28 family members have been enrolled. The goal of this study was to determine the prevalence of GATA2 mutations in pediatric patients with MDS and BMF and characterize their clinical and histopathologic phenotypes.

Sanger sequencing of GATA2 was initially performed on 3 families with a history of familial MDS and 103 patients with sporadic appearing primary MDS, AA or an unclassified BMF enrolled in the Pediatric MDS and BMF Registry. Family members were assessed in patients with pathogenic mutation to determine if the disease was inherited or sporadic. Mutations were confirmed in somatic and germline tissue wherever possible. IBMFS were ruled out by molecular testing. Rigorous phenotype analysis included clinical and laboratory data, and standardized centralized pathology review. Whole exome sequencing (WES) was performed on a subset of patients to evaluate additional cooperating mutations and possible secondary somatic events and clonal evolution. Possible candidate genes were verified by Sanger sequencing.

We identified pathogenic GATA2 mutations in a total of 16 individuals, including 12 patients (7 familial MDS cases and 5 sporadic MDS/BMF cases) and 4 first-degree relatives from 5 kindreds. Most mutations clustered in zinc finger 2. Previously identified mutations such as N371K and R396Q as well as novel point and frame shift mutations were identified. The median age at diagnosis was 15 years. There was strong male predominance (n=11). The clinico-pathologic diagnoses were RAEB/AML (n=4), refractory cytopenia of childhood (n=6) and MonoMac/other (n=6). Two out of the four families presented with features of Emberger syndrome. Two individuals presented with characteristic features of MonoMac Syndrome, of which one also showed bone marrow failure and pulmonary fibrosis suggestive of telomere disease. Very short telomeres (below the first percentile) were detected in all lymphocyte subsets consistent with dyskeratosis congenita (DC). However, genetic analysis did not reveal any of the known DC associated genes. Other associated pathology included severe gastrointestinal bleeding (n=2), severe polyneuropathy (n=2) and other cancers (n=1). A morphologically distinctive megakaryocytic dysplasia was a characteristic finding on histopathology. Monosomy 7 was the most common acquired cytogenetic abnormalities (n=6). Given this association we identified several additional individuals with MDS and monosomy 7 from our pathology archives and identified 2 additional patients with pathogenic GATA2 mutations. Secondary somatic mutations identified by WES included ASXL1. Thirteen out of the 14 pediatric patients with GATA2 mutations underwent hematopoietic stem cell transplant (HSCT). Ten out of these 13 patients are alive.

GATA2 mutations occur at a higher frequency than previously anticipated in pediatric MDS, and BMF, often occur sporadically and are associated with monosomy 7. While the clinical presentation is heterogeneous, the histopathologic features are often unique. Somatic genetic alterations likely play a role in clonal evolution. Given its significant implications for treatment decisions and donor selection GATA2 mutation screening should be performed on all patients with MDS, AA, and BMF disorders excluding classical IBMFS, and potential related donors.

No relevant conflicts of interest to declare.