Clinical characteristics.

GATA1-related cytopenia is characterized by thrombocytopenia and/or anemia ranging from mild to severe. 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 lifelong; at the milder end, anemia and the risk for bleeding may decrease spontaneously with age. One or more of the following may also be present: neutropenia, splenomegaly, cryptorchidism, hypospadias, and rarely additional clinical features of Diamond-Blackfan anemia. Heterozygous females may have mild-to-moderate symptoms such as menorrhagia. Rarely, GATA1-related cytopenia can progress to myelodysplastic syndrome or aplastic anemia.

Diagnosis/testing.

The diagnosis of GATA1-related cytopenia is established in a male proband with cytopenia resulting from ineffective hematopoiesis by identification of a hemizygous pathogenic variant in GATA1 by molecular genetic testing. The diagnosis of GATA1-related cytopenia may be established in a female proband with cytopenia by identification of a heterozygous pathogenic variant in GATA1 by molecular genetic testing.

Management.

Targeted therapy: For severe disease, hematopoietic stem cell transplantation (HSCT) can be curative.

Supportive care: Platelet transfusions for moderate-to-severe epistaxis, severe gingival bleeding, or other clinically significant bleeding; DDAVP^© may be helpful for short-term management of mild-to-moderate bleeding; platelet transfusion prior to surgical or invasive dental procedures for individuals with a history of pathologic bleeding, thrombocytopenia, and/or platelet dysfunction; red blood cell transfusions for clinical manifestations of anemia (fatigue, tachycardia); iron chelation therapy as needed for chronic red blood cell transfusions; extended pre-transfusion red blood cell phenotyping and consideration of Rh and K antigen matching for those receiving frequent transfusions. Treatment for neutropenia includes counseling regarding infection risk; prophylactic antibiotics when indicated; prompt evaluation when febrile; empiric parenteral antibiotics for febrile individuals with severe neutropenia. HSCT can be curative for those with severe disease.

Surveillance: Complete blood count (CBC) with frequency based on disease severity; annual CBC in those with mild cytopenia(s) and monthly CBC in those with severe cytopenia(s) that require intervention such as red blood cell transfusion. Monitor for iron overload in those with frequent erythrocyte transfusions.

Agents/circumstances to avoid: Those with thrombocytopenia and/or platelet aggregation defects should avoid antiplatelet agents including aspirin and nonsteroidal anti-inflammatory drugs (e.g., ibuprofen) and 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.

Evaluation of relatives at risk: If a GATA1 pathogenic variant 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 CBC to evaluate for thrombocytopenia, anemia, and/or neutropenia.

Genetic counseling.

GATA1-related cytopenia is inherited in an X-linked manner. If the mother of the proband has a GATA1 pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and may have mild-to-moderate symptoms. Affected males transmit the GATA1 pathogenic variant to all of their daughters and none of their sons. Once the GATA1 pathogenic variant has been identified in an affected family member, identification of female heterozygotes and prenatal and preimplantation genetic testing are possible.

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

• Complete blood count. Thrombocytopenia and/or mild-to-severe anemia; rarely neutropenia
• Peripheral blood smear examination. Platelets may be larger and more spherical; variation in erythrocyte size and shape
• Bone marrow aspirate and biopsy
  • Hyper- or hypocellularity
  • Evidence of ineffective hematopoiesis
  • Increased or decreased numbers of megakaryocytes
  • Small, dysplastic megakaryocytes with signs of incomplete maturation
  • Dyserythropoiesis
  • Hypocellularity of granulocytic lineages
  • Mild-to-moderate reticulin fibrosis [Åström et al 2015]
• Platelet aggregation studies. Normal to abnormal platelet aggregation in response to agonists (e.g., ristocetin, adenosine diphosphate, epinephrine, collagen) in some individuals [Thompson et al 1977, Freson et al 2001, Balduini et al 2004, Hollanda et al 2006, Jurk et al 2022]
• Electron microscopy. Reduced number of platelet alpha granules in some individuals [Jurk et al 2022] and dysplastic features in megakaryocytes and platelets

Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.

Note: (1) Hematologic findings in GATA1-related cytopenia are variable and usually nonspecific and thus by themselves not indicative of a specific diagnosis. (2) Affected individuals are typically male; females often present with milder findings.

Establishing the Diagnosis

Male proband. The diagnosis of GATA1-related cytopenia is established in a male proband with cytopenia resulting from ineffective hematopoiesis by identification of a hemizygous pathogenic (or likely pathogenic) variant in GATA1 by molecular genetic testing (see Table 1). Note: GATA1 pathogenic variants have been rarely identified in individuals with CEP (see Genetically Related Disorders).

Female proband. The diagnosis of GATA1-related cytopenia may be established in a female proband with cytopenia by identification of a heterozygous pathogenic variant (or likely pathogenic) in GATA1 by molecular genetic testing (see Table 1). Note: GATA1 pathogenic variants have been rarely identified in individuals with CEP (see Genetically Related Disorders).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this GeneReview is understood to include any likely pathogenic variant. (2) Identification of a hemizygous or heterozygous GATA1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with cytopenia, including GATA1-related cytopenia, are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Clinical Description

Individuals with GATA1-related cytopenia have thrombocytopenia, anemia, and/or neutropenia.

Genotype-Phenotype Correlations

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. Findings that have only been reported in association with GATA1 missense variants are hydrops fetalis, hypospadias, cryptorchidism, and chronic hemolysis.

c.2T>C, c.3G>A, c.220+2T>C. These GATA1 variants have been identified in several unrelated probands with macrocytic anemia and either thrombocytopenia or megakaryocyte dysplasia and clinical features of Diamond-Blackfan anemia without an associated pathogenic variant in a ribosomal protein-encoding gene.

c.220+1delG. This GATA1 variant has been identified in two related individuals with pure red cell aplasia and a clinical diagnosis of Diamond-Blackfan anemia without an associated pathogenic variant in a ribosomal protein-encoding gene.

To date, only limited genotype-phenotype correlations have been identified. However, the authors have compiled a comprehensive table of GATA1 variants and reported phenotypes in order to contribute to future understanding of genotype-phenotype correlations (see Table 2).

Nomenclature

Until pathogenic variants in GATA1 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 used in the current literature are:

• "Familial dyserythropoietic anemia and thrombocytopenia" [Nichols et al 2000, Del Vecchio et al 2005];
• "X-linked macrothrombocytopenia" [Freson et al 2001]; and
• "X-linked anemia with or without neutropenia and/or platelet abnormality" (XLANP) [Ogura et al 2016].

The diagnosis of "GATA1-related Diamond-Blackfan anemia" was primarily made before GATA1-related cytopenia was recognized as a distinct entity. Based on the underlying disease etiology, the appropriate diagnostic term for individuals with this phenotype is "GATA1-related cytopenia" [Author, personal observation].

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 at least 36 families.

GATA1 pathogenic variants may be more common than previously appreciated, particularly in persons with mild, unexplained thrombocytopenia present since birth [Tubman et al 2007] or individuals with congenital hypoplastic anemia and other clinical features of Diamond-Blackfan anemia with no pathogenic variants affecting ribosomal proteins identified [Sankaran et al 2012].

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/μL.
• 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

Surveillance

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.

Agents/Circumstances to Avoid

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.

Evaluation of Relatives at Risk

For early diagnosis and treatment. Both male and female relatives of an affected individual, including those who are apparently asymptomatic, should be offered molecular genetic testing for the familial GATA1 pathogenic variant. This helps identify as early as possible those who would benefit from prompt evaluation and treatment for cytopenia.

Note: Evaluation of at-risk relatives can include a CBC to evaluate for thrombocytopenia, anemia, or neutropenia. However, platelet, erythrocyte, and neutrophil counts can vary significantly in individuals with GATA1 pathogenic variants and normal results do not rule out the possibility that the relative has a GATA1 pathogenic variant and is at risk for developing complications of the disorder.

For HSCT donor evaluation. Any relative who is a potential HSCT donor should undergo molecular genetic testing to clarify genetic status; only those relatives who do not have the GATA1 pathogenic variant should be evaluated further.

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

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 [Voit et al 2022].

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.

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.

Mode of Inheritance

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

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder, nor will he be hemizygous for the GATA1 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the GATA1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (evidence of germline mosaicism has not been observed to date).
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo GATA1 pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/germline mosaicism. Because very few families with GATA1 pathogenic variants have been described to date, the frequency of de novo pathogenic variants is not known.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a GATA1 pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected.
  • Females who inherit the pathogenic variant will be heterozygous and may manifest platelet abnormalities and/or mild anemia with mild-to-moderate symptoms such as menorrhagia or easy bruising (see Clinical Description, Heterozygous Females).
• If the proband represents a simplex case and if the GATA1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males transmit the GATA1 pathogenic variant to all of their daughters, who will be heterozygotes (see Clinical Description, Heterozygous Females), and none of their sons.

Other family members. The maternal aunts and maternal cousins of a male proband may be at risk of having a GATA1 pathogenic variant.

Heterozygote Detection

Identification of female heterozygotes typically requires prior identification of the GATA1 pathogenic variant in the family so that targeted testing can be performed.

Note: Females who are heterozygotes for this X-linked disorder may develop clinical findings related to the disorder (see Clinical Description, Heterozygous Females).

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 and discussion of the availability of prenatal/preimplantation genetic 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 heterozygous, or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the GATA1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for GATA1-related cytopenia are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

GATA1 belongs to the GATA-binding family of transcription factors that is highly expressed in hematopoietic lineages, including erythrocyte, megakaryocyte, mast cell, and eosinophil lineages. Erythroid transcription factor (GATA-1) recognizes and binds to a target site conforming to the consensus nucleotide motif WGATAR present in noncoding regulatory regions of many hematopoietic genes. The modular protein contains two zinc finger domains and an acidic N-terminal domain that can promote transcriptional activation [Ferreira et al 2005, Lowry & Mackay 2006]. The C-terminal zinc finger (C-f) domain is required for DNA binding activity at most or all target sites, and the N-terminal zinc finger (N-f) domain stabilizes GATA-1 binding to DNA at a subset of sites containing duplicated or palindromic GATA-1 motifs [Ohneda & Yamamoto 2002]. The N-f domain also binds numerous partner proteins, including friend of GATA (FOG)-1, an essential factor required for many GATA-1 functions [Tsang et al 1997, Fox et al 1999]. Many germline GATA1 variants associated with cytopenias occur in exons 4 or 5, resulting in missense variants within or near the N-f or C-f domains and resulting in altered DNA binding or impaired interaction with 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]. Germline pathogenic variants in exon 2 of GATA1 can also cause GATA1-related cytopenias, including macrothrombocytopenia, dysplastic megakaryocytes, anemia, and neutropenia [Hollanda et al 2006, Sankaran et al 2012, Klar et al 2014, Zucker et al 2016, Abdulhay et al 2019, Hasle et al 2022, Kobayashi et al 2022, van Dooijeweert et al 2022]. Notably, similar variants have been identified in several families with clinical findings suggestive of Diamond-Blackfan anemia who did not have pathogenic variants in ribosomal protein-encoding genes [Sankaran et al 2012, Ludwig et al 2014, Klar et al 2014, Parrella et al 2014, Zucker et al 2016, Chen et al 2022, van Dooijeweert et al 2022]. These variants usually result in the exclusive production of an amino-truncated isoform of GATA-1, termed GATA-1 short (GATA-1s) that is missing the first 83 amino acids of the 143-amino acid protein.

Mechanism of disease causation. Loss of function

Cancer and Benign Tumors

In children with Down syndrome (DS, trisomy 21), somatic variants resulting in the production of GATA-1s exclusively are associated with transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (M7 subtype, DS-AMKL) [Roberts et al 2013, Garnett et al 2020, McNulty & Crispino 2020]. TMD, found in up to 10% of infants with DS, usually resolves spontaneously; however, TMD confers a markedly increased risk for DS-AMKL [Garnett et al 2020, McNulty & Crispino 2020]. The acquired exon 2 variants lead to premature arrest of translation and reinitiation of protein synthesis at the downstream methionine codon at position 83, and result in the production of GATA-1s, which lacks the amino-terminal activation domain. Some splice site variants also result in generation of GATA-1s. The mechanisms by which GATA1 variants in conjunction with trisomy 21 promote DS-AMKL pathogenesis are currently unknown.

Further, similar germline protein-truncating GATA1 variants usually cause cytopenia without leukemia in individuals who do not have DS. However, these individuals, including heterozygous females, can develop myeloproliferative disorder, myelodysplastic syndrome (MDS), and/or myeloid leukemia associated with acquired trisomy 21 and other chromosomal abnormalities [Camargo et al 2022, Hasle et al 2022].

One individual with severe anemia and thrombocytopenia caused by the GATA1 pathogenic missense variant c.613G>A (p.Val205Met) developed MDS 18 years after a failed bone marrow transplantation. It is not clear whether the MDS with a clonal deletion of 20q was due to the underlying disease caused by the pathogenic variant of GATA1, bone marrow transplant-associated toxicity, or both [Authors, unpublished data].

Author Notes

Drs Kaoru Takasaki (ude.pohc@kikasakat), Mitchell Weiss, (gro.edujts@ssiew.hctim), and Stella Chou (ude.pohc@suohc) are actively involved in research regarding individuals with GATA1-related cytopenias. They would be happy to communicate with persons who have any questions regarding diagnosis of GATA1-related cytopenias or other considerations.

Contact Drs Takasaki, Weiss, or Chou to inquire about review of GATA1 variants of uncertain significance.

Acknowledgments

This work was supported in part by NIH grants R01 HL151260 (STC), R01HL165798 (MJW), R01 AG082275 (MAK), R01 AG060621 (MAK), T32 HL007150 (KT), and the American Society of Hematology Research Training Award for Fellows (KT).

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)

Kaoru Takasaki, MD (2023-present)

Mitchell J Weiss, MD, PhD (2006-present)

Revision History

• 16 February 2023 (sw) Comprehensive update posted live
• 11 May 2017 (ha) Comprehensive update posted live
• 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 live
• 10 August 2006 (whr) Original submission

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