ETV6-Related Thrombocytopenia and Predisposition to Leukemia
Synonyms: ETV6-Linked Leukemia / Familial Thrombocytopenia Syndrome, Thrombocytopenia 5 (THC5)
Bojana Pencheva, MMSc, CGC, Jorge Di Paola, MD, and Christopher C Porter, MD.
Author Information and AffiliationsInitial Posting: November 19, 2020; Last Update: June 26, 2025.
Estimated reading time: 20 minutes
Summary
Clinical characteristics.
Individuals with ETV6-related thrombocytopenia and predisposition to leukemia most often present with a lifelong history of thrombocytopenia, which is usually in the mild-to-moderate range. No syndromic features or associations are consistently shared across pedigrees. Affected individuals also have a high risk of developing a hematologic malignancy (with B-cell acute lymphoblastic leukemia [B-ALL] being the most common) and possibly other benign and malignant solid tumors.
Management.
Treatment of manifestations: For clinical bleeding, local measures with consideration of antifibrinolytic agents, desmopressin, and/or platelet transfusion if bleeding is moderate to severe. For individuals with a history of moderate or severe bleeding, antifibrinolytic agents or desmopressin may be considered prior to surgical procedures to reduce bleeding complications. Platelet transfusions should be used judiciously, particularly in women of childbearing age, to reduce the risk of alloimmunization. For neoplasm, standard neoplasm-specific therapy with extra consideration of indications for stem cell transplantation, eligibility, and available donors.
Surveillance: Complete blood count (CBC) with differential every six to 12 months and consideration of bone marrow aspirate and biopsy every one to three years. The frequency of such screening must be weighed against the burden of the screening protocol, particularly in young children. The exact frequency of CBC and bone marrow evaluations should be determined on a case-by-case basis by the physician and with consideration of patient/family preferences.
Agents/circumstances to avoid: For those with a history of bleeding, avoidance of medications that decrease platelet function (e.g., aspirin, nonsteroidal anti-inflammatory drugs) and avoidance of participation in contact sports are recommended.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of clinical surveillance for malignancy and management of potential significant thrombocytopenia.
Pregnancy management: Platelet counts should be monitored during pregnancy and prior to delivery. Platelet transfusions prior to invasive procedures (e.g., epidural analgesia or cesarean section) or at the time of delivery may be considered in those with a history of bleeding or severe thrombocytopenia on a case-by-case basis.
Genetic counseling.
ETV6-related thrombocytopenia and predisposition to leukemia is inherited in an autosomal dominant manner. To date, most individuals diagnosed with ETV6-related thrombocytopenia and predisposition to leukemia inherited a pathogenic variant from a parent either known to be heterozgyous based on molecular genetic testing or presumed to be heterozgyous based on pedigree analysis or reported history of thrombocyotpenia. The heterozygous parent may not have any known clinical findings associated with ETV6-related thrombocytopenia and predisposition to leukemia. Each child of proband has a 50% chance of inheriting the ETV6 pathogenic variant. Once the ETV6 pathogenic variant has been identified in an affected family member, predictive testing for at-risk asymptomatic family members and prenatal/preimplantation genetic testing are possible.
Diagnosis
ETV6-related thrombocytopenia and predisposition to leukemia is a nonsyndromic genetic disorder of thrombocytopenia and high risk of leukemia without any other consistent congenital anomalies. Formal clinical diagnostic criteria have not been published.
Suggestive Findings
ETV6-related thrombocytopenia and predisposition to leukemia should be considered in individuals with the following clinical and laboratory findings and family history.
Clinical findings
Absent-to-moderate bleeding tendencies (e.g., menorrhagia, epistaxis, easy bruising, gum bleeding)
Hematologic malignancies, including:
B-cell acute lymphoblastic leukemia (B-ALL), which is the most common
Acute myeloid leukemia (AML)
Myelodysplastic syndrome (MDS)
Myeloproliferative neoplasms (MPN)
Multiple myeloma
Possibly, benign and malignant solid tumors
Laboratory findings
Persistent and unexplained mild-to-moderate thrombocytopenia (platelet counts are often >75 × 109/L) with typically normal platelet size and occasionally accompanied by a high mean platelet volume
Normal white blood cell count
Normal hemoglobin concentration, sometimes with a high mean erythrocyte corpuscular volume (MCV)
Variably, abnormal bone marrow histology with small hyperchromatic megakaryocytes, disseminated toxic granulations, and dysplastic eosinophils in the absence of frank myelodysplasia
Family history. One or more relatives with thrombocytopenia, acute leukemia, AND/OR solid tumors (particularly colorectal cancer) consistent with an autosomal dominant inheritance pattern. Note: Absence of a known family history of thrombocytopenia, acute leukemia, or solid tumors does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of ETV6-related thrombocytopenia and predisposition to leukemia is established in a proband by identification of a heterozygous germline pathogenic (or likely pathogenic) variant in ETV6 by molecular genetic testing (see Table 1).
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 variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous ETV6 variant of uncertain significance does not establish or rule out the diagnosis.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive
genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).
Option 1
When the clinical and laboratory findings suggest the diagnosis of ETV6-related thrombocytopenia and predisposition to leukemia, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
Single-gene testing. Sequence analysis of
ETV6 detects
missense,
nonsense, and
splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-
exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted
deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
A multigene panel that includes
ETV6 and other genes of interest (see
Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of
uncertain significance in genes that do not explain the underlying
phenotype. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Option 2
When the diagnosis of ETV6-related thrombocytopenia and predisposition to leukemia is not considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Note: A diagnosis of ETV6-related thrombocytopenia and predisposition to leukemia should not be confused with individuals who have malignancies with somatic pathogenic variants or chromosome rearrangements involving ETV6 (see Genetically Related Disorders).
Table 1.
Molecular Genetic Testing Used in ETV6-Related Thrombocytopenia and Predisposition to Leukemia
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| Gene 1 | Method | Proportion of Pathogenic Variants 2 Identified by Method |
|---|
|
ETV6
| Sequence analysis 3 | ~90% 4 |
| Gene-targeted deletion/duplication analysis 5 | 5%-10% 6 |
| Karyotype | <5% 7 |
- 1.
- 2.
- 3.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
- 6.
- 7.
Järviaho et al [2019] described a pedigree in which two second-degree relatives developed B-ALL and had a constitutional balanced translocation involving ETV6 (t(12;14)(p13.2;q23.1). An additional seven family members had the same translocation but did not have a history of leukemia. No family members had thrombocytopenia.
Clinical Characteristics
Clinical Description
Individuals with ETV6-related thrombocytopenia and predisposition to leukemia most often present with a lifelong history of thrombocytopenia, which is usually in the mild-to-moderate range. No syndromic features or associations are consistently shared across pedigrees. Affected individuals also have a moderate risk of developing a hematologic malignancy (with B-cell acute lymphoblastic leukemia [B-ALL] being the most common) and possibly other malignant solid tumors, particularly colorectal cancer. To date, more than 150 individuals from about 30 families have been identified with a germline pathogenic variant in ETV6 [Paulsson et al 2010, Di Paola & Porter 2019, Rampersaud et al 2019, Ross et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.
Thrombocytopenia
Thrombocytopenia is found in more than 90% of affected individuals at the time of diagnosis. However, most affected individuals have normal hemostasis or only a mild bleeding tendency.
Bleeding history
Complete blood counts
Most reported platelet counts are between 100 and 150 × 109/L.
Some affected individuals have platelet counts as low as 32 × 109/L, but severe thrombocytopenia (<20 × 109/L) is rarely seen without concurrent myelodysplastic syndrome.
Platelet size is usually normal by automated method (mean platelet volume) or microscopic analysis, although some affected individuals exhibit increased platelet volume.
Platelet structure and function studies. While abnormal platelet aggregation studies have been observed in a few individuals, no abnormal pattern on platelet membrane receptor distribution has been observed to date. Platelets have also shown abnormal clot retraction and spreading on fibrinogen surfaces [Poggi et al 2017, Di Paola & Porter 2019].
Bone Marrow Biopsy
Bone marrow aspirates in those without concurrent leukemias have variably revealed dyserythropoiesis, megakaryocyte hyperplasia, and small hypolobulated megakaryocytes [Di Paola & Porter 2019].
Lymphoid and Myeloid Malignancies
About 20%-30% of individuals with ETV6-related thrombocytopenia and predisposition to leukemia develop a hematologic malignancy.
Children with ETV6-related thrombocytopenia and predisposition to leukemia may be more likely to have hyperdiploid leukemia and be older at the time of diagnosis of leukemia than sporadic cases of leukemia [Moriyama et al 2015]. There is currently no evidence that the presence of a heterozygous germline ETV6 pathogenic variant influences response to therapy, nor are there any recommendations to alter standard therapy based on the presence of a heterozygous germline ETV6 pathogenic variant.
Solid Tumors
There may be an increased risk for the development of solid tumors in those with ETV6-related thrombocytopenia and predisposition to leukemia. While the exact risk has not been defined, at least seven molecularly confirmed individuals have a reported history of solid tumors diagnosed before age 50 years, including two with colorectal cancer [Di Paola & Porter 2019].
Penetrance
The penetrance of thrombocytopenia in this disorder is thought to exceed 90%.
The penetrance of malignancy, specifically lymphoid and myeloid, is estimated at 20%-30%.
Differential Diagnosis
Hereditary platelet disorders with increased leukemia risk to consider in the differential diangosis of ETV6-related thrombocytopenia and predisposition to leukemia are listed in Table 2.
Table 2.
Genes of Interest in the Differential Diagnosis of ETV6-Related Thrombocytopenia and Predisposition to Leukemia
View in own window
| Gene | Disorder | MOI | Associated Malignancies | Hematologic Findings |
|---|
|
ANKRD26
|
ANKRD26-related thrombocytopenia
| AD | Myeloid malignancies (incl myelodysplastic syndrome, acute myelogenous leukemia, & chronic myelogenous leukemia) | Mild-to-moderate thrombocytopenia w/normal platelet size |
|
RUNX1
|
RUNX1 familial platelet disorder / acute myeloid leukemia
| AD | Myeloid malignancies are most common, incl acute myelogenous leukemia & myelodysplastic syndrome. T- & B-cell acute lymphoblastic leukemias & lymphomas have also been reported.
| Quantitative &/or qualitative platelet defect |
Management
Expert and consensus clinical guidelines for the management of inherited thrombocytopenia and leukemia predisposition syndromes, including those with germline ETV6 pathogenic variants, have been proposed [Dupuis & Gachet 2018, Maese et al 2024].
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with ETV6-related thrombocytopenia and predisposition to leukemia, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).
Surveillance
Individuals with ETV6-related thrombocytopenia and predisposition to leukemia should adhere to published population-based cancer screening guidelines, including for breast and colon cancers. In addition to education regarding the signs and symptoms of hematologic malignancies, the following surveillance should be considered.
Agents/Circumstances to Avoid
For individuals with ETV6-related thrombocytopenia and predisposition to leukemia and a history of bleeding, medications that decrease platelet function (e.g., aspirin, nonsteroidal anti-inflammatory drugs) should be avoided. Similarly, participation in contact sports is not recommended.
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of clinical surveillance for malignancy and management of thrombocytopenia.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Platelet counts should be monitored during pregnancy and prior to delivery, in collaboration with a hematologist. Platelet transfusions prior to invasive procedures (e.g., epidural analgesia or cesarean section) or at the time of delivery may be considered in those with a history of bleeding or severe thrombocytopenia on a case-by-case basis.
Therapies Under Investigation
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.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
ETV6-related thrombocytopenia and predisposition to leukemia is inherited in an autosomal dominant manner.
Risk to Family Members
Parents of a proband
To date, most individuals diagnosed with
ETV6-related thrombocytopenia and predisposition to leukemia inherited an
ETV6 pathogenic variant from a parent either known to be heterozgyous based on
molecular genetic testing or presumed to be heterozgyous based on
pedigree analysis or reported history of thrombocyotpenia. The
heterozygous parent may not have any known clinical findings associated with
ETV6-related thrombocytopenia and predisposition to leukemia. Note: Famiy history and
familial molecular genetic test results were not reported for some probands in cohort studies of leukemia or thrombocytopenia.
An individual with
ETV6-related thrombocytopenia and predisposition to leukemia may have the disorder as the result of a
de novo ETV6 pathogenic variant. The proportion of probands with a
de novo
ETV6 pathogenic variant is unknown.
If the
proband appears to be the only affected family member (i.e., a
simplex case),
molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform
recurrence risk assessment, and determine their need for clinical surveillance for malignancy and management of thrombocytopenia. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced
penetrance of malignancies, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
de novo occurrence of an
ETV6 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is
heterozygous for the
ETV6 pathogenic variant.
If the
pathogenic variant identified in the
proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The
proband inherited a
pathogenic variant from a parent with gonadal (or somatic and gonadal)
mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of
somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:
If a parent of the
proband is affected and/or is known to have the
ETV6 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. A sib who inherits the
ETV6 pathogenic variant is expected to exhibit mild thrombocytopenia but may or may not develop leukemia due to the reduced
penetrance of the hematologic malignancies in
ETV6-related thrombocytopenia and predisposition to leukemia.
If the parents have not been tested for the
ETV6 pathogenic variant but have no clinical findings of
ETV6-related thrombocytopenia and predisposition to leukemia, the risk to the sibs of a
proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for the disorder because of the possibility of reduced
penetrance in a
heterozygous parent and the possibility of parental
gonadal mosaicism.
Offspring of a proband. Each child of an individual with ETV6-related thrombocytopenia and predisposition to leukemia has a 50% chance of inheriting the ETV6 pathogenic variant.
Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the ETV6 pathogenic variant, the parent's family members are at risk.
Prenatal Testing and Preimplantation Genetic Testing
Once the ETV6 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
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.
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.
ETV6-Related Thrombocytopenia and Predisposition to Leukemia: Genes and Databases
View in own window
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Molecular Pathogenesis
ETV6 has two start codons, one located at exon 1 and one located upstream of exon 3. Although two isoforms have been demonstrated to be expressed at the protein level, the function of the isoforms has not been evaluated. ETV6 encodes transcription factor ETV6. There are three main domains:
DNA-binding
domain located at the C terminus
Linker region
ETV6 is a repressor of transcription, with critical roles in embryonic development and hematopoietic regulation [Hock et al 2004]. ETV6 is highly expressed in hematopoietic progenitor cells and is essential for hematopoiesis in the bone marrow [Di Paola & Porter 2019].
Mechanism of disease causation. Loss of function. The majority of pathogenic germline variants described to date have been located within the DNA-binding domain at the C terminus. These are mostly loss-of-function missense variants, but nonsense and frameshift variants have also been identified. Single- and multiexon deletions have also been described and are thought to affect splice sites, resulting in truncation of the protein [Di Paola & Porter 2019].
Cancer predisposition. The molecular basis for predisposition to hematologic malignancy, specifically leukemias, in individuals with ETV6-related thrombocytopenia and predisposition to leukemia is not fully understood. Individuals with germline pathogenic ETV6 variants and leukemias were not found to have a somatic hit on the second ETV6 allele, though two individuals have been reported with biallelic loss of ETV6 [Topka et al 2015]. Laboratory studies suggest that loss of ETV6 transcriptional repression leads to aberrant expression of genes involved in inflammatory responses [Fisher et al 2020, Zhou et al 2022, Bloom et al 2023], which may promote leukemogenesis.
Chapter Notes
Author Notes
Bojana Pencheva is a certified genetic counselor who serves children and their families for germline genetic evaluation of suspected cancer predispositions, including bone marrow failure syndromes.
Dr Di Paola is a pediatric hematologist whose research focuses on the genetics of bleeding and thrombotic disorders and mechanisms of platelet activation. Web page: dipaolalab.wustl.edu
Dr Porter is a pediatric hematologist-oncologist with a clinical and research interest in childhood cancer predispositions. His laboratory studies mechanisms of hematopoiesis and leukemogenesis. He is a founding co-Chair of the Consortium for Childhood Cancer Predisposition. Web page: childhoodcancerpredisposition.org
Acknowledgments
The authors are grateful for the work of the contributors to this field cited in this chapter, as well as the many more who are not cited due to space constraints. We would like to thank the GeneReviews Editors and Reviewers for their suggestions and contributions to the development of this GeneReview chapter.
Revision History
26 June 2025 (sw) Comprehensive update posted live
19 November 2020 (ma) Review posted live
31 January 2020 (bbp) Original submission
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