Clinical Guidance

GATA1 pathogenic variants that result in truncation of the first 83 amino acids of erythroid transcription factor (GATA-1) (i.e., GATA-1 short [GATA-1s]) are associated with macrocytic anemia of varying severity. Findings that have only been reported in association with GATA-1s are neutropenia, thrombocytosis, and progression to myelodysplastic syndromes and acute myeloid leukemia. GATA1 missense variants affecting either the amino- or carboxy-terminus zinc finger domain that affect its ability to bind either GATA1 sites in DNA, the cofactor friend of GATA (FOG)-1, or both are associated with macrothrombocytopenia and dyserthryopoiesis but not necessarily anemia.

Source: GeneReviews — "GATA1-Related Cytopenia"

Diagnostic Criteria

Suggestive Findings

GATA1-related cytopenia should be suspected in a male or female proband with any combination of the following clinical and laboratory findings and family history.

Clinical findings

• Excessive bruising

• Mucosal bleeding (e.g., gingival bleeding, epistaxis)

• Petechiae

• Hydrops fetalis in some infants

Laboratory findings

Source: GeneReviews — "GATA1-Related Cytopenia"

Differential Diagnosis

GATA1-related cytopenia must be distinguished from other acquired and hereditary thrombocytopenias (e.g., Wiskott-Aldrich syndrome, which is also X-linked), platelet function abnormalities, and anemias . Algorithms exist to help differentiate among these disorders . However, the clinical phenotypes of GATA1-related cytopenias vary greatly and overlap considerably with other genetic causes of cytopenia. Hence, a genetic diagnosis is almost always required for confirmation. A multigene panel is often used to establish the diagnosis of a hereditary thrombocytopenia and thereby facilitate appropriate surveillance (some types of hereditary thrombocytopenia are associated with increased malignancy risk) and genetic counseling. Of note: • Numerous congenital thrombocytopenias may be considered in the differential diagnosis . In GATA1-related thrombocytopenia, platelets are usually large and may be hypogranular. There may be associated platelet aggregation defects and/or a prolonged bleeding time. Relatively common congenital causes of macrothrombocytopenia that could be confused with GATA1-related disorders are described in . • Thrombocytopenia may be the initial manifestation of bone marrow failure in individuals with a telomere biology disorder (e.g., dyskeratosis congenita). • Cryptorchidism and/or hypospadias may suggest the involvement of GATA1 but are not always present. • Congenital causes of anemia that could potentially be confused with GATA1-related disorders are described in . Table 3. Selected Genes of Interest in the Differential Diagnosis of GATA1-Related Cytopenia

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GATA1-related cytopenia, the following are recommended:

• Complete blood count (CBC) and examination of the peripheral blood smear to assess the degree of cytopenia(s) and morphologic abnormalities

• Detailed history of the disease course, including the age at which hematologic disease was detected and the associated symptoms

• Documentation of abnormal/unexpected bleeding episodes and platelet counts obtained at the time of the episodes to help determine whether platelet function is abnormal and whether disease severity has changed over time

Note: Platelet aggregation studies may identify functional abnormalities that predict a greater risk of bleeding for any given platelet count, but studies can be difficult to interpret when platelet counts are lower than 100,000/L.

• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of GATA1-related cytopenia for medical and personal decision making

Treatment of Manifestations

Targeted Therapy

Source: GeneReviews — "GATA1-Related Cytopenia"

Clinical Guidance

Individuals with thrombocytopenia and/or platelet aggregation defects should avoid antiplatelet agents including aspirin and nonsteroidal anti-inflammatory drugs (e.g., ibuprofen). Individuals with thrombocytopenia and/or platelet aggregation defects should avoid contact sports or activities with a high risk of trauma. Individuals with severe neutropenia should avoid close contact with persons who have a communicable disease to minimize risk of infection. Individuals with significant splenomegaly should avoid contact sports, which increase the risk of traumatic splenic rupture.

Source: GeneReviews — "GATA1-Related Cytopenia"

Therapies Under Investigation

Correction of the GATA1 pathogenic variant by genome editing of autologous hematopoietic stem cells may offer a viable cure in the future, although this will require individualized "n-of-few" therapy since there is no single common pathogenic variant . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "GATA1-Related Cytopenia"

Surveillance Guidelines

The frequency of CBCs should be tailored to disease severity.

• Individuals with mild cytopenias should have annual CBCs.

• Individuals with severe cytopenias who require transfusions should have monthly CBCs or as indicated by clinical signs and symptoms.

• Additional surveillance with bone marrow aspirate and biopsy may be indicated in those with a phenotype similar to Diamond-Blackfan anemia.

• Individuals undergoing repeated erythrocyte transfusions should be monitored for iron overload.

Source: GeneReviews — "GATA1-Related Cytopenia"