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GATA1-Related X-Linked Cytopenia

Includes: GATA1-Related Thrombocytopenia, GATA1-Related Anemia, GATA1-Related Anemia with Thrombocytopenia, GATA1-Related Thrombocytopenia with Beta-Thalassemia, GATA1-Related Neutropenia

, MD, , PhD, , MD, PhD, and , MD, PhD.

Author Information
, MD
Assistant Professor, Pediatrics
University of Pennsylvania School of Medicine
Division of Hematology
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
, PhD
Associate Professor, Department of Orthopaedic Surgery
Indiana University School of Medicine
Indianapolis, Indiana
, MD, PhD
Professor, Pediatrics
University of Pennsylvania School of Medicine
Division of Hematology
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
, MD, PhD
Professor, Departments of Medicine and Psychiatry and Behavioral Sciences
University of Washington Medical Center
Seattle, Washington

Initial Posting: ; Last Update: April 17, 2014.

Summary

Disease characteristics. GATA1-related cytopenia is characterized by thrombocytopenia and/or anemia ranging from mild to severe. One or more of the following may also be present: platelet dysfunction, mild β-thalassemia, neutropenia, and congenital erythropoietic porphyria (CEP) in males. Thrombocytopenia typically presents in infancy as a bleeding disorder with easy bruising and mucosal bleeding (e.g., epistaxis). Anemia ranges from minimal (mild dyserythropoiesis) to severe (hydrops fetalis requiring in utero transfusion). At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are life long; at the milder end, anemia and the risk for bleeding decrease spontaneously with age. Female carriers may have mild to moderate symptoms, such as menorrhagia.

Diagnosis/testing. Diagnostic laboratory findings usually include macrothrombocytopenia (low number of platelets that are larger than normal) and/or anemia with red cell indices that may be micro-, normo- or macrocytic. Defects in platelet aggregation in response to agonists may be seen. In some cases electron microscopy reveals reduced numbers of platelet alpha granules and dysplastic features in platelets and megakaryocytes. GATA1 is the only gene in which mutations are known to cause GATA1-related cytopenia.

Management. Treatment of manifestations: Platelet transfusions for moderate to severe epistaxis, gingival bleeding, or gastrointestinal bleeding; no specific treatment for mild symptoms (easy bruisability); erythrocyte transfusions when anemia is symptomatic (fatigue, tachycardia).

Prevention of primary manifestations: For severe cases, bone marrow transplantation (BMT) can be curative.

Surveillance: monitoring complete blood counts (with frequency depending on disease severity) to inform supportive care; monitoring those undergoing repeated erythrocyte transfusions for iron overload.

Agents/circumstances to avoid: Those with thrombocytopenia should avoid antiplatelet agents including aspirin and nonsteroidal anti-inflammatory agents (NSAIDs) (e.g., ibuprofen). Those with thrombocytopenia and/or platelet aggregation defects should avoid contact sports or activities with a high risk of trauma.

Evaluation of relatives at risk: If a GATA1 mutation has been identified in the family, complete blood counts and molecular genetic testing of at-risk relatives can be offered. At-risk relatives who choose not to have molecular genetic testing should have complete blood counts to evaluate for thrombocytopenia, anemia, or neutropenia.

Pregnancy management: For pregnancies in which a male fetus is known to be affected: monitoring by a high-risk obstetric practice; serial specialized ultrasounds to screen for signs of fetal anemia or bleeding; in utero transfusion if the affected fetus is severely anemic.

Genetic counseling. GATA1-related cytopenia is inherited in an X-linked manner. If the mother of an affected male has a GATA1-disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Affected males pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible once the disease-causing mutation has been identified in the family.

Diagnosis

Clinical Diagnosis

The diagnosis of GATA1-related cytopenia is suggested in males with the following:

  • Thrombocytopenia and/or anemia ranging from mild to severe (including fetal hydrops)
  • One or more of the following:
  • Family history consistent with X-linked inheritance
  • No evidence of Wiskott-Aldrich syndrome (WAS), an X-linked disorder of microthrombocytopenia that can present with or without immunodeficiency

The diagnosis of GATA1-related cytopenia is established when a GATA1 disease-causing mutation is detected.

Note: (1) Hematologic findings in GATA1-related cytopenia are variable and usually nonspecific (i.e., seen in numerous conditions and thus by themselves not indicative of a specific diagnosis). (2) Females may be affected but usually have milder symptoms.

Testing

Diagnostic laboratory findings in males with GATA1-related cytopenia include the following:

  • Complete blood count
    • Platelet counts are usually low (10-100 x 103/µL), but vary considerably with specific mutations. Normal counts have also been reported (150-400 x 103/µL), including individuals with a mutation that results in production of truncated GATA-1, causing congenital anemia [Hollanda et al 2006, Sankaran et al 2012]. The platelets are typically larger than normal (macrothrombocytopenia).
    • Anemia (hematocrit 16%-35%; normal: 35%-45%) may be present; the severity is associated with the specific mutation. Red cell indices are normochromic but may be mildly microcytic (75-79 fL) or macrocytic (101-103 fL) (normal: 80-99 fL).
    • Significant persistent neutropenia (0.5-2.8 x 103/µL; normal 1.9-8.0 x 103/µL) was observed in one family with a specific GATA1 mutation [Hollanda et al 2006].

Note: Thrombocytopenia, anemia, and neutropenia are usually defined as two standard deviations below values observed in the normal population.

  • Peripheral blood smear may show the following:
    • Some platelets that are larger and more spherical than the typical discoid morphology. Platelets may be pale, reflecting reduced granularity.
    • Variation in erythrocyte size and shape and hypochromia, reflecting low hemoglobin content.
    • Decreased neutrophils with abnormal morphology; this rare finding was reported in one family with an unusual germline mutation that results in exclusive production of truncated GATA-1 (erythroid transcription factor) protein (GATA-1s) [Hollanda et al 2006].
  • Bone marrow biopsy may show the following:
    • Hyper- or hypocellularity
    • Increased or decreased numbers of megakaryocytes
    • Small, dysplastic megakaryocytes with signs of incomplete maturation
    • Dyserythropoiesis
    • Hypocellularity of erythroid and granulocytic lineages
  • Platelet function abnormalities. Defects in platelet aggregation in response to agonists, such as ristocetin, adenosine diphosphate, epinephrine or collagen occur in some cases [Thompson et al 1977, Freson et al 2001, Balduini et al 2004, Hollanda et al 2006]. These studies can be normal in some affected individuals.
  • Electron microscopy. Findings in some cases include reduced numbers of platelet alpha granules and dysplastic features in megakaryocytes and platelets.
  • In subtypes associated with globin chain imbalance, findings consistent with mild hemolysis, including mild reticulocytosis, elevated LDH, and low haptoglobin, may be present. In addition, HbA2 and HbF may be elevated.

Note: In female carriers, two distinct platelet morphologies can be observed on peripheral blood smear, reflecting mosaicism secondary to random X-chromosome inactivation.

Definitions of terms used to describe this disorder
  • Thrombocytopenia. Reduced platelet count
  • Macrothrombocytopenia. Thrombocytopenia with large platelets
  • Dyserythropoiesis. Impaired production and maturation of erythrocytes (red blood cells)
  • Thalassemia. An inherited form of anemia associated with unbalanced globin chain synthesis
  • Hemoglobin. The oxygen-carrying compound of red blood cells, made up of heme, α-globin, and β-globin. β-thalassemia is associated with decreased β-globin synthesis in red blood cells.

Molecular Genetic Testing

Gene. GATA1 is the only gene in which mutations are known to be associated with GATA1-related cytopenia.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in GATA1-Related Cytopenias

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
Affected Males Carrier Females
GATA1Sequence analysis 4Sequence variants 5>95% 6>95% 7
Deletion/duplication analysis 8(Multi)exon or whole-gene deletion/duplicationUnknown; none reported 9Unknown; none reported 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Most GATA1 mutations identified in GATA1-related cytopenias have been missense mutations. Mutations predicting a splicing abnormality that results in the loss of the first 83 coding amino acids of GATA-1 have been reported [Hollanda et al 2006, Sankaran et al 2012].

6. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

7. Sequence analysis of genomic DNA cannot detect deletion or duplication of one or more exons or the entire X-linked gene in a heterozygous female.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. Some laboratories offer deletion/duplication analysis of GATA1; however, no exonic or whole-gene deletions or duplications have been reported as a cause of GATA1-related cytopenia. Complete loss of GATA1 through deletion is expected to be embryonic lethal in males. Copy number variation of GATA1 may be detected by a variety of methods (Table 1).

Testing Strategy

To confirm/establish the diagnosis in a proband. Initial testing should include complete blood count, examination of the blood smear, and bone marrow aspirate and biopsy to confirm that cytopenia results from ineffective hematopoiesis rather than peripheral destruction or sequestration. The diagnosis should be confirmed by molecular genetic testing, as the hematologic abnormalities can be seen with other disorders.

Platelet function studies or electron microscopy may also be informative, as specific abnormalities are reported in some affected individuals.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Males. GATA1-related thrombocytopenia typically presents in infancy as a bleeding disorder. Affected individuals have easy bruising and mucosal bleeding, such as epistaxis. Physical examination may reveal petechiae, ecchymoses, or splenomegaly. Excessive hemorrhage and/or bruising can occur either spontaneously or after trauma or surgery. Some affected individuals may be recognized only after incidental findings of mild to moderate cytopenias on blood count analysis.

Anemia, the other major clinical problem in males with GATA1-related cytopenia, ranges from minimal with only mild dyserythropoiesis [Freson et al 2001] to severe hydrops fetalis requiring in utero transfusions [Nichols et al 2000]. Anemia can be so severe that affected males are red blood cell transfusion-dependent after birth [Freson et al 2002].

Variable mild to moderate neutropenia with macrocytic anemia and normal platelet counts was reported in one extended family (with a germline mutation leading to exclusive GATA-1s production); family members with severe neutropenia were predisposed to infection [Hollanda et al 2006].

In one family, moderately severe anemia was associated with congenital erythropoietic porphyria (CEP) [Phillips et al 2005]. The affected individual also had bullous skin lesions associated with porphyria.

The long-term course depends on disease severity. At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are life long. At the milder end, the risk for bleeding decreases spontaneously with age, despite continued thrombocytopenia [Mehaffey et al 2001, Del Vecchio et al 2005].

Splenomegaly is commonly present in one form of GATA1-related disease (see Genotype-Phenotype Correlations).

Typically, no other physical anomalies are present.

Carrier females. Females who carry a GATA1 mutation may manifest platelet abnormalities [White 2007] and mild to moderate symptoms such as menorrhagia, presumably related to the proportion of relevant cells that contain the mutant GATA1 allele on the active X chromosome [Nichols et al 2000; Raskind et al 2000; Balduini et al 2004; Del Vecchio et al 2005; Raskind, unpublished observations].

Of note, females who carry a GATA1 mutation may have normal platelet counts or be mildly to moderately thrombocytopenic [Nichols et al 2000]. This may depend on the nature of the mutation or other modifiers either genetic or environmental. Morphologic abnormalities of platelets can be detected by electron microscopy (mutation c.622_623delGGinsTC) [White 2007] and in some instances on peripheral blood smears (mutation c.647G>A) [Tubman et al 2007].

Genotype-Phenotype Correlations

To a large extent, disease severity depends on the nature of the GATA1 mutation. GATA-1 (erythroid transcription factor) is a transcription factor containing two zinc fingers. The carboxyl terminal finger (C-f) is essential for binding to DNA at most or all target genes. The amino terminal finger (N-f) stabilizes GATA-1 binding to a subset of DNA target sites and also participates in critical protein interactions. Most importantly, the N-f is required for interaction with the critical essential GATA-1 cofactor FOG-1.

Most GATA1 mutations associated with inherited thrombocytopenia/anemia occur within the N-f and affect DNA binding, FOG-1 interactions, or perhaps both. The extent to which these functions are impaired can be linked to clinical severity.

For example, two different amino acid substitutions occur at GATA-1 amino acid position 218:

In four families, two different mutations are described at amino acid position 216, which forms part of the DNA binding face of GATA-1. The phenotypic variability observed between different families illustrates how different mutations in GATA-1 protein could selectively impair its ability to recognize specific elements in cis configuration.

Specific genotype-phenotype correlations are illustrated further by individuals with congenital anemia and germline mutations that result in the exclusive production of an amino terminal truncated GATA-1s protein. In one family, affected individuals exhibit a unique phenotype that includes macrocytic anemia, variable neutropenia, and trilineage dysplasia in the bone marrow [Hollanda et al 2006]. Similar mutations were identified in two unrelated pedigrees with Diamond Blackfan anemia (DBA) (see Allelic Disorders).

Table 2. Genotype-Phenotype Correlations

Pathogenic Allelic VariantFOG-1 BindingDNA BindingPlatelet Phenotype 1 Red Cell PhenotypePlatelet AggregationOther FeaturesReference
p.Val205Met↓↓Normal
Large

Dyserythropoietic, fetal hydrops
Not studiedCryptorchidism 2 Nichols et al [2000]
p.Gly208SerNormal
Large
NormalDecreasedMehaffey et al [2001] 3, 4
p.Gly208ArgNot studiedNot studied↓↓
Large

Dyserythropoietic
Not studiedCryptorchidism in proband but also in two sibs with wild type GATA1 2 Del Vecchio et al [2005], Kratz et al [2008] 3, 4
p.Arg216GlnNormal↓ 5
Large
Mild β-thalassemiaNormal, but prolonged bleeding timeSplenomegalyThompson et al [1977], Raskind et al [2000], Yu et al [2002], Balduini et al [2004], Hughan et al [2005], Tubman et al [2007], Campbell et al [2013]
p.Arg216TrpNot studied↓ 5Mild β -thalassemiaNot reportedCongenital erythropoietic porphyria, splenomegalyHindmarsh [1986], Phillips et al [2007], Ged et al [2009], Campbell et al [2013]
p.Asp218GlyNormal
Large
Dyserythropoiesis without anemiaDecreasedFreson et al [2001], White [2007], White et al [2007]
p.Asp218Tyr↓↓Normal↓↓
Large
Severe anemiaNot studiedPlatelets in carrier female expressed only wild type alleleFreson et al [2002]
p.Ter414ArgextTer42 6Not studiedNot studied
Large
NormalNot studiedLu(a-b-) red cellsSingleton et al [2013]
p.Gly332CysNot studiedNot studiedNormal counts, but dysplastic megakaryocytesMacrocytic anemia of variable severityDecreasedNeutropeniaHollanda et al [2006]
p.Val74Leu 6Not studiedNot studiedNormal or ↓Macrocytic anemia of variable severityNot studiedSankaran et al [2012]
c.220+1delG 7Not studiedNot studiedNormalAnemiaNot studiedSankaran et al [2012]
p.Met1_Cys83del 6Not studiedNot studiedAnemiaNot studiedParrella et al [2014]

1. Decreased platelet alpha granules are observed in all affected males studied.

2. Cryptorchidism has been reported in several males with GATA1 mutations [Nichols et al 2000, Del Vecchio et al 2005]. Although Gata1 is expressed in mouse testis, knockout of Gata1 in Sertoli cells within the testis had no effect, suggesting that Gata1 is not essential for Sertoli cell function [Lindeboom et al 2003]. The independent segregation of cryptorchidism and GATA1 mutations in one of the two families [Del Vecchio et al 2005], in conjunction with the mouse data, make the mechanistic relationship between GATA1 mutations and cryptorchidism unclear at this point.

3. No response to splenectomy and/or steroids

4. Decreased bleeding episodes with age, despite persistence of thrombocytopenia

5. In vitro DNA binding only

6. See Table 4 for details

7. Frameshift predicted because the deletion affects the canonic splice donor site.

For further information on murine and in vitro experiments involving GATA-1, see Management, Other.

Nomenclature

Until GATA1 mutations were shown to underlie this heterogeneous disorder, a variety of terms were coined for the different clinical presentations. The first term used was X-linked thrombocytopenia with thalassemia (XLTT) [Raskind et al 2000]. Other terms used in the past and still in the current literature are "familial dyserythropoietic anemia and thrombocytopenia" [Nichols et al 2000, Del Vecchio et al 2005] and "X-linked macrothrombocytopenia" [Freson et al 2001].

Debate is ongoing regarding the classification of patients with a clinical diagnosis of Diamond-Blackfan anemia in whom GATA1 mutations are identified and ribosomal protein mutations are absent. The authors suggest the phrase “variant DBA associated with GATA1 mutation.”

Prevalence

GATA1-related cytopenia is rare; the prevalence is not known. To date, hematopoietic disease caused by inherited pathogenic variants in GATA1 has been reported in fourteen families [Nichols et al 2000, Freson et al 2001, Mehaffey et al 2001, Freson et al 2002, Yu et al 2002, Balduini et al 2004, Del Vecchio et al 2005, Phillips et al 2005, Hollanda et al 2006, Sankaran et al 2012, Singleton et al 2013, Parrella et al 2014].

GATA1 mutations may be more common than previously appreciated, particularly in persons with mild, unexplained thrombocytopenia / "grey platelet syndrome" present since birth [Tubman et al 2007].

Differential Diagnosis

GATA1-related thrombocytopenia must be distinguished from other acquired and inherited thrombocytopenias and platelet function abnormalities [Balduini & Savoia 2004, Drachman 2004] (see Table 3). Algorithms exist to help differentiate among these disorders [Drachman 2004, Noris et al 2004].

Because of its X-linked mode of inheritance and association with thrombocytopenia, Wiskott-Aldrich syndrome (WAS) can be confused with GATA1-related disorders. Distinguishing features of WAS include small platelets, eczema (~80%), and immunodeficiency, although milder mutations may manifest with microthrombocytopenia only.

In GATA1-related disorders, platelets are usually large and may be hypogranular. Relatively common congenital causes of macrothrombocytopenia that could potentially be confused with GATA1-related disorders are described in Table 3.

Table 3. Etiology and Characteristics of Other Inherited Syndromes of Macrothrombocytopenia

NameGene (Chromosomal Locus)Mode of InheritanceFeaturesReference /
OMIM Number(s)
Bernard-Soulier syndromeGP1BA (17p13.2)
GP1BB (22q11.21)
GP9 (3q21.3)
AR 1
  • Severely defective ristocetin-induced platelet agglutination
  • Severe bleeding disorder
Lopez et al [1998] /
231200
MYH9-related syndromesMYH9 (22q12.3)AD
  • Neutrophil inclusions
  • Hearing loss, cataract, or renal defects variably present
Seri et al [2003] /
May-Hegglin anomaly: 155100
Sebastian syndrome: 605249
Fechtner syndrome: 153640
Epstein syndrome: 153650
Mediterranean thrombocytopeniaGP1BA ADDysmegakaryo-cytopoiesis153670
Paris-Trousseau thrombocytopeniaFLI1, ETS1 (11q24.3)Microdeletion
  • Cardiac and facial abnormalities
  • Intellectual disability
188025
Jacobsen syndromesGrossfeld et al [2004] / 147791
Velocardiofacial/ DiGeorge syndrome(del22q11.21)Microdeletion
  • Facial and cardiac abnormalities
  • Intellectual disability
  • Psychiatric disorders
Sullivan [2004] /
188400
Gray platelet disorder 2 Heterogeneous
  • Pale platelets
  • Reduced or absent α-granules
139090

1. Heterozygotes may have mild disease.

2. One person with an X-linked form of this syndrome was found to have a GATA1 mutation [Wechsler et al 2002, Tubman et al 2007]. (See Genetically Related Disorders.)

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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 and examination of the peripheral smear to assess the degree of cytopenia(s)
  • Detailed history of age at which hematologic disease was manifest
  • 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 also be useful to 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/μL.
  • Medical genetics consultation

Treatment of Manifestations

Individuals with GATA1-related cytopenia are treated supportively.

Thrombocytopenia. Individuals with moderate to severe epistaxis, gingival bleeding, or gastrointestinal bleeding should receive platelet transfusions. Transfusion requirements vary from person to person as bleeding can be related to quantitative and/or qualitative platelet defects.

For individuals with thrombocytopenia and/or platelet aggregation defects, DDAVP treatment may be helpful for short-term management of mild to moderate bleeding.

Individuals who are only mildly symptomatic (easy bruisability without mucosal or more severe bleeding) do not require specific treatment.

There is no evidence that splenectomy is beneficial in people with GATA1-related disease, although this treatment may be considered if splenomegaly is severe. Although splenectomy may improve the cytopenias, platelet dysfunction will not be improved.

Anemia. Erythrocyte transfusions are indicated when anemia is symptomatic (fatigue, tachycardia). Iron overload and the development of alloantibodies may limit chronic transfusion therapy. Extended pretransfusion red blood cell phenotyping and matching for minor erythrocyte antigens in individuals receiving frequent transfusions can reduce the risk of alloimmunization.

Neutropenia. Patients with neutropenia who present with fever should be evaluated promptly with a physical examination, complete blood count, and blood culture and should receive appropriate parenteral antibiotics.

Bone marrow transplantation (BMT). For severe cases, BMT can be curative [Phillips et al 2005, Hollanda et al 2006, Parrella et al 2014]. BMT should be considered in individuals with severe phenotypes of GATA1-related cytopenia, particularly if an HLA-matched donor is available. While BMT may offer a cure, clinical experience with BMT in this disease is limited and families must be counseled on the significant risks and morbidity associated with BMT.

Prevention of Primary Manifestations

The only definitive cure for GATA1-related disease is bone marrow transplantation (BMT).

Prevention of Secondary Complications

Individuals with thrombocytopenia and/or platelet aggregation defects should receive a platelet transfusion prior to surgical or invasive dental procedures.

Individuals with neutropenia should be counseled regarding their increased risk of infection. They should avoid crowds and contact with individuals who have communicable diseases. When febrile, patients who are severely neutropenic (absolute neutrophil count <500/µL) should seek medical attention; typically blood cultures are obtained and parenteral antibiotics are administered to avoid the possibility of life-threatening sepsis.

Surveillance

Depending on the phenotype of the disease, complete blood counts should be monitored so that supportive care can be provided as needed.

Individuals undergoing repeated erythrocyte transfusions should be monitored for iron overload and managed appropriately with iron chelation therapy.

Agents/Circumstances to Avoid

Individuals with thrombocytopenia should avoid antiplatelet agents including aspirin and nonsteroidal anti-inflammatory agents (NSAIDs) (e.g., ibuprofen).

Individuals with thrombocytopenia and/or platelet aggregation defects should be advised to avoid contact sports or activities with a high risk of trauma.

Individuals with significant splenomegaly should avoid contact sports, which involve increased risk for traumatic splenic rupture.

Individuals with significant neutropenia should avoid crowds and avoid close contact with persons who have a communicable disease to minimize risk of infection.

Evaluation of Relatives at Risk

If a GATA1 mutation has been identified in the family, molecular genetic testing of at-risk relatives can be offered.

At-risk relatives who choose not to have molecular genetic testing should have a screening complete blood count to evaluate for thrombocytopenia, anemia, or neutropenia as these conditions have implications for their medical care. However, as platelet, erythrocyte, and neutrophil counts can vary significantly in individuals with GATA1 mutations, normal results do not rule out GATA1-related disease.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

A male fetus with an identified GATA1 mutation may be at risk for prenatal anemia and/or thrombocytopenia depending on the specific mutation and clinical phenotype of related individuals. The pregnancy should be monitored by a high-risk obstetric practice, and signs of fetal anemia or bleeding can be monitored by serial specialized ultrasounds. In utero transfusion is indicated if the fetus is severely anemic.

Therapies Under Investigation

In the future, this disorder may be treatable by gene therapy approaches to restore GATA-1 activity in hematopoietic cells. However, numerous studies indicate that GATA-1 requirements during hematopoiesis are exquisitely dosage sensitive and that too much or too little GATA-1 can be deleterious. Thus, standard gene therapy approaches using heterologous promotors to drive GATA-1 expression may be ineffective or even harmful [Whyatt et al 2000].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Unlike immune-mediated platelet disorders such as immune thrombocytopenic purpura, GATA1-related thrombocytopenia does not respond to steroid or immunoglobulin therapy.

Supplemental erythropoietin therapy is unlikely to be effective because the anemia is secondary to ineffective erythropoiesis, not erythropoietin deficiency.

A recent analysis of GATA1 mutations in murine complementation systems showed that structural studies and examination of purified proteins did not always accurately elucidate the effects of mutations, and in vivo studies are required [Campbell et al 2013]. Specifically, p.Arg216Gln and p.Arg216Trp mutations that impaired DNA binding in vitro did not measurably affect in vivo target gene occupancy. Instead, diminished TAL1 complex recruitment to GATA-1 target genes was implicated.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

GATA1-related cytopenia is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

  • The father of an affected male will not have the disease nor will he be a carrier of the mutation.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  • If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation, in which case the mother is not a carrier.
    • Because very few families with GATA1 mutations have been described to date, the frequency of de novo mutations is not known.
    • Evidence of germline mosaicism has not been observed.
  • If a woman has more than one affected son and the disease-causing mutation cannot be detected in her DNA, she has germline mosaicism.
  • When an affected male is the only affected individual in the family; several possibilities regarding his mother's carrier status need to be considered:
    • He has a de novo disease-causing mutation in GATA1, in which case his mother is not a carrier.
    • His mother has a de novo disease-causing mutation in GATA1, either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only).
    • His mother has a disease-causing allelic variant that she inherited from a maternal female ancestor.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%.
    • Male sibs who inherit the disease-causing variant will be affected.
    • Female sibs who inherit the disease-causing variant will be carriers and will usually not be affected, but may have reduced hematocrits and platelet counts to a variable degree. Large platelets may also be present and carriers of the XLTT subtype may have splenomegaly and slightly decreased β-globin synthesis.
  • If the disease-causing variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because, although not yet observed, the possibility of germline mosaicism exists.

Offspring of a proband. Males will pass the disease-causing variant to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being carriers or of being affected (depending on their gender and family relationship and the carrier status of the proband's mother).

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutation has been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the GATA1 mutation has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing allelic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Platelet Disorder Support Association (PDSA)
    133 Rollins Avenue
    #5
    Rockville MD 20852
    Phone: 877-528-3538 (toll-free); 301-770-6636
    Fax: 301-770-6638
    Email: pdsa@pdsa.org
  • Medline Plus

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. GATA1-Related X-Linked Cytopenia: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
GATA1Xp11​.23Erythroid transcription factorGATA1 @ LOVDGATA1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for GATA1-Related X-Linked Cytopenia (View All in OMIM)

300367THROMBOCYTOPENIA, X-LINKED, WITH OR WITHOUT DYSERYTHROPOIETIC ANEMIA; XLTDA
305371GATA-BINDING PROTEIN 1; GATA1
314050THROMBOCYTOPENIA WITH BETA-THALASSEMIA, X-LINKED; XLTT

Gene structure. GATA1 has six exons, although the first exon is noncoding and is not counted in some of the literature. It also has two alternative untranslated regions (UTRs) (one 3’ and one 5’) [Tsai et al 1991]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Most germline GATA1 alterations associated with cytopenias are missense mutations. These mutations cluster in exon 4 amino acid residues 205, 208, 216, and 218 within the amino-terminal zinc finger domain. The mutations either affect erythroid transcription factor (GATA-1) binding to DNA or interaction of GATA-1 with its essential cofactor, friend of GATA (FOG)-1 [Nichols et al 2000, Freson et al 2001, Mehaffey et al 2001, Freson et al 2002, Yu et al 2002, Balduini et al 2004, Del Vecchio et al 2005].

A mutation in exon 2 of GATA1 that alters splicing was found in one family with anemia and neutropenia [Hollanda et al 2006]. Similar mutations have been identified in several families with Diamond-Blackfan anemia without pathogenic ribosomal protein mutations [Sankaran et al 2012, Parrella et al 2014] and unpublished studies by several groups. These mutations result in the exclusive production of an amino-truncated isoform of GATA-1, termed GATA-1s (for GATA-1 short; also discussed in Genetically Related Disorders). In the context of Down syndrome (DS, trisomy 21), somatic mutations resulting in the production of only GATA-1s are associated with leukemia and transient myeloproliferative disorder (TMD) [Wechsler et al 2002]; however, the same GATA1 mutations present in the germline of persons who do not have DS cause cytopenia but not leukemia [Hollanda et al 2006]. In mice, analogous mutations increase the proliferative capacity of embryonic megakaryocyte precursors but produce a minimal hematopoietic phenotype in adults [Li et al 2005].

Cis element mutations affecting GATA-1 binding to target genes have also been implicated in red cell production or function. For example, Africans frequently carry a mutation in the Duffy antigen/chemokine receptor (DARC) gene promoter that disrupts GATA-1 binding [Tournamille et al 1995]. This leads to the common African Duffy negative red cell phenotype, which confers resistance to Plasmodium vivax malaria.

CEP can also be caused by mutations in the promoter region of the gene encoding the heme synthetic enzyme uroporphyrinogen III synthase, where GATA-1 normally binds [Solis et al 2001].

X-linked sideroblastic anemia (XLSA) typically results from partial loss-of-function missense mutations in the erythroid-specific heme biosynthesis protein 5-aminolevulinate synthase 2 (ALAS2). Mutations in the GATA binding site located in a transcriptional enhancer element in ALAS2 have been identified in several pedigrees with XLSA [Campagna et al 2014, Kaneko et al 2014].

Importantly, mutations in gene regulatory regions are not likely to be detected by exome sequencing. The authors predict that such mutations will be increasingly recognized over time, as whole-genome sequencing is increasingly used for clinical diagnostics and as DNA regulatory regions are mapped and characterized through ongoing multi-investigator studies, including those performed by the Encyclopedia of DNA Elements (ENCODE) Consortium.

Table 4. Selected GATA1 Pathogenic Allelic Variants

DNA Nucleotide Change (Alias 1)Protein Amino Acid Change Reference Sequences
c.2T>Cp.Met1_Cys83del 2NM_002049​.3
NP_002040​.1
c.220G>C 3p.Val74Leu
c.220+1delG 4
c.613G>Ap.Val205Met
c.622_623delGGinsTC
(622_623GG>TC)
p.Gly208Ser
c.622G>Cp.Gly208Arg
c.647G>Ap.Arg216Gln 5
c.646C>Tp.Arg216Trp
c.653A>Gp.Asp218Gly
c.652G>Tp.Asp218Tyr
c.994G>Tp.Gly332Cys
c.1240T>Cp.Ter414ArgextTer42 6

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Obliterates initiation codon and alternative initiation Met84 residue is used resulting in lack of full length cDNA [Parrella et al 2014]

3. Mutation affects the last nucleotide of exon 2 and is predicted to affect splicing [Sankaran et al 2012].

4. Exon skipping and frameshift predicted because the deletion affects the canonic splice donor site. [Sankaran et al 2012]

5. Also reported in one family with “grey platelet syndrome” (see Genetically Related Disorders)

6. Mutation in stop codon 414 results in addition of 41 amino acids and use of new stop codon at residue 42 [Singleton et al 2013]

Normal gene product. GATA1 encodes a nuclear protein of 413 amino acid residues that contains two zinc fingers and an acidic amino terminal domain that can function as a transcriptional activator [Ferreira et al 2005, Lowry & Mackay 2006]. The C-terminal zinc finger is responsible for DNA binding activity for most or all target genes and the N-terminal zinc finger plays a role in stabilization of GATA-1 binding to DNA at a subset of target sites containing duplicated or palindromic GATA-1 motifs [Ohneda & Yamamoto 2002]. The N-f is also critical for binding of GATA-1 to numerous partner proteins, including FOG1, an essential factor required for many GATA-1 functions [Tsang et al 1997, Fox et al 1999]. GATA-1 is expressed in hematopoietic lineages and in Sertoli cells of testis. Gene targeting studies in mice indicate that GATA-1 is essential for the development of erythrocyte, megakaryocyte, mast cell, and eosinophil lineages. It is not known whether individuals with inherited GATA1 mutations have defects in the latter two cell lineages.

Abnormal gene product. All disease-causing mutations are missense mutations, indels, or splice site substitutions resulting in the production of an abnormal protein. Missense mutations in N-f affect its ability to bind either GATA1 sites in DNA, the cofactor FOG1, or both. Splice site mutation results in a short form of the protein, GATA-1s. Mice genetically engineered to express GATA-1s show prenatal anemia and megakaryocyte proliferation, but newborn and adult mice display no hematopoietic abnormalities [Li et al 2005]. The functions of these abnormal proteins and their relationship to disease phenotypes are discussed in Genotype-Phenotype Correlations and in Table 2.

References

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Suggested Reading

  1. Balduini CL, De Candia E, Savoia A. Why the disorder induced by GATA1 Arg216Gln mutation should be called "X-linked thrombocytopenia with thalassemia" rather than "X-linked gray platelet syndrome". Blood. 2007;110:2770–1. [PMC free article: PMC1988927] [PubMed: 17881640]
  2. Ciovacco WA, Raskind WH, Kacena MA. Human phenotypes associated with GATA-1 mutations. Gene. 2008;427:1–6. [PMC free article: PMC2601579] [PubMed: 18930124]
  3. de Waele L, Freson K, Louwette S, Thys C, Wittevrongel C, de Vos R, Debeer A, van Geet C. Severe gastrointestinal bleeding and thrombocytopenia in a child with an anti-GATA1 autoantibody. Pediatr Res. 2010;67:314–9. [PubMed: 19924028]
  4. Hamlett I, Draper J, Strouboulis J, Iborra F, Porcher C, Vyas P. Characterization of megakaryocyte GATA1-interacting proteins: the corepressor ETO2 and GATA1 interact to regulate terminal megakaryocyte maturation. Blood. 2008;112:2738–49. [PMC free article: PMC2556610] [PubMed: 18625887]
  5. Millikan PD, Balamohan SM, Raskind WH, Kacena MA. Inherited thrombocytopenia due to GATA1 mutations. Semin Thromb Hemost. 2011;37:682–9. [PubMed: 22102271]

Chapter Notes

Author History

Stella T Chou, MD (2006-present)
Melissa A Kacena, PhD (2006-present)
Jessica Kirk, BS; Yale University School of Medicine (2006-2011)
Wendy H Raskind, MD, PhD (2006-present)
Mitchell J Weiss, MD, PhD (2006-present)

Acknowledgments

This work was supported in part by NIH grants NCRR RR025760 and RR025761 (MAK), NIH K08 HL093290 (STC), NIH P30 DK090969 (MJW, STC), P30 DK0724429 (MAK), NIAMS R03 AR055269 (MAK), NIAMS R01 AR060332 (MAK), NIA R01 AG046246 (MAK) and by the American Society of Hematology Scholar Award (STC).

Revision History

  • 17 April 2014 (me) Comprehensive update posted live
  • 22 March 2011 (me) Comprehensive update posted live
  • 30 March 2007 (cd) Revision: prenatal testing clinically available
  • 21 February 2007 (cd) Revision: clinical testing available
  • 22 November 2006 (me) Review posted to live Web site
  • 10 August 2006 (whr) Original submission
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