This helpful chart (link chart) of inherited conditions lists the gene and location, mode of inheritance and key features. The following are a summary of some of the inherited platelet disorders that are understood the best and identified through genetic testing for thrombocytopenia. Because this is an active area of growing knowledge, many new disorders and causes are still being identified and this list is not complete. It does give a general flavor for the types of platelet disorders and signs or symptoms that might be clues to an inherited platelet disorder.
If any of the terms below are not familiar to you, please browse through our genetics glossary.
Cytoskeleton Disorders
MYH9 Related Diseases
(includes May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome or Epstein’s syndrome)
These diseases are grouped together because they are all caused by variants within a gene called MYH9. MYH9 related disease is inherited in an autosomal dominant mode which means an affected parent has a 50% chance to pass the condition onto their children and is characterized by abnormally large platelets, thrombocytopenia, mild to moderate bruising, and a potential for hearing loss, early cataracts, abnormal liver enzyme testing and kidney problems.
Resources:
- https://rarediseases.info.nih.gov/diseases/180/myh9-related-thrombocytopenia
- https://globalgenes.org/disorder/myh9-related-disease/?gclid=Cj0KCQiAutyfBhCMARIsAMgcRJQ_sMS0fT7SRrvmiFjitgXPSN59mURPXMIKXBNCHk8hxIU1RRyLY5kaAjS1EALw_wcB
Wiskott-Aldrich Syndrome (WAS) & X-Linked Thrombocytopenia (XLT)
Both are X-linked disorders occurring almost exclusively in males because it is inherited on the X-chromosome and passed through the maternal line (you need only one working copy to have no symptoms, but males only inherit one copy of an X chromosome). Platelets are small with these conditions and may be accompanied by immunodeficiency and eczema. Individuals with WAS usually have more severe immune problems, starting earlier in life compared to those with XLT. They two conditions are similar because they both arise from variants in the WAS gene. Patients with either XLT or WAS need to be followed by both an immunologist and a hematologist and are at increased risk of severe infection with splenectomy, making it very important to identify this cause of low platelets.
Resources:
- Wiskott-Aldrich Foundation
- https://www.niaid.nih.gov/sites/default/files/Wiskott-Aldrich-Syndrome-Factsheet.pdf
- https://rarediseases.info.nih.gov/diseases/7895/wiskott-aldrich-syndrome
- https://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/wiskott-aldrich-syndrome
- https://rarediseases.org/rare-diseases/was-related-disorders/
Filamin-A (FLNA)-related Thrombocytopenia
Variants within the X-linked FLNA gene can cause larger than normal platelets in addition to hemorrhaging, abnormal clotting, and thrombocytopenia. They can also be associated with periventricular nodular heterotopia (FLNA-PVNH), a neurological disorder that may have other issues associated as well including lung problems and kidney issues. Because the first symptoms can be variable, it is important to consider this diagnosis in patients who have unusual combinations of symptoms. FLNA related thrombocytopenia can affect individual with two X chromosomes.
Resources:
ACTN1-related Thrombocytopenia
One of the most recently recognized genes to play a role in inherited thrombocytopenia is the ACTN1 gene. Individuals with ACTN1-related thrombocytopenia usually have larger than normal platelets with mild thrombocytopenia and mild risks for bleeding. Variants in this gene show variable expressivity, meaning it may affect family members differently. Some may be more affected that others. The variant can also cause unequal sizes of red blood cells (anisocytosis). Variants inherited within this gene are passed on in an autosomal dominant manner which means the variant can be inherited from either parent and affects males and females equally.
Resources:
At this time, there are no resources available for this condition.
DIAPH-1 related Thrombocytopenia
Individuals with DIAPH-1 related thrombocytopenia have platelets that are larger than normal. Variants within the DIAPHI-1 gene are inherited in an autosomal dominant mode. Researchers have learned that individuals with a variant in this gene are more likely to have (and often present with) early-onset and progressive hearing loss (sensorineural type) and may experience mild asymptomatic neutropenia (low white blood cell count).
Resources:
At this time, there are no resources available for this condition.
FYB-related Thrombocytopenia
The FYB gene regulates a protein called the ‘degranulation-promoting adaptor’ protein (or ADAP), involved in platelet activation and proliferation. While very rare, individuals with variants in this gene show significant bleeding tendencies. This is an autosomal recessive platelet disorder, and patients also have small platelets. To date, only two platelet disorders have characteristically small platelets (Wiskott Aldrich Syndrome and FYB-related thrombocytopenia).
Resources:
At this time, there are no resources available for this condition.
Variants in CYCS and TUBB1
CYCS and TUBB1-related thrombocytopenia can lead to mild bleeding tendency with usually only a mild low platelet count. Variants in both the CYCS and TUBB1 genes are inherited in an autosomal dominant fashion. Variants in either of these genes usually do not lead to a significant bleeding risk.
Granule Disorders
Gray Platelet Syndrome (GPS)
A syndrome is a collection on symptoms that occur together as part of the underlying genetic condition. Patients with gray platelet syndrome (GPS) can experience prolonged bleeding because their platelets lack some of the protein-carrying granules (the chips in the platelets) needed for a normal blood-clotting process. Platelets without these chips look pale gray (instead of purple) under the microscope. Except in rare cases, the bleeding tendency in GPS is usually mild to moderate. Patients often experience easy bruising, nosebleeds, and, in women, excessive menstrual bleeding. Recurrent anemia and abnormal bleeding after surgery, dental work or childbirth can occur. GPS is usually an autosomal recessive condition most commonly due to variants within the NBEAL2 gene, although other genetic conditions can cause a similar change in the platelets including variants in GATA1.
Resources:
Platelet Storage Pool Deficiency
Platelet storage pool deficiency refers to a group of conditions caused by problems with the platelet granules, the tiny storage sacs found within platelets, which release various substances to help stop bleeding. Platelet storage pool deficiencies occur when platelet granules are absent, reduced in number or unable to empty their contents into the bloodstream. Signs and symptoms include frequent nosebleeds, abnormally heavy or prolonged menstruation, easy bruising, recurrent anemia and abnormal bleeding after surgery, dental work, or childbirth. The genetics of the platelet storage pool deficiencies have not been worked out yet and many patients have storage pool deficiency without other associated medical problems. In some rare patients, rare inherited genetic disorders such as Hermansky Pudlak Syndrome (HPS), Gricelli Syndrome, or Chediak Higashi Syndrome (CHS) are associated with a platelet storage pool deficiency.
Resources:
- National Institutes of Health Genetic and Rare Disease Information Center
- American Society of Hematology (ASH)
Hermansky-Pudlak Syndrome
Hermansky-Pudlak syndrome is a disorder resulting in oculocutaneous albinism, which causes abnormally light pigmentation of the skin, hair and eyes. A syndrome is a collection on symptoms that occur together as part of the underlying genetic condition. Those affected by the disorder have fair skin and white or light-colored hair, causing them to have a higher risk of skin damage and skin cancers caused by long-term sun exposure, as well as often lighter colored eyes (rarely pink or red eyes as seen in some albino animals). Hermansky-Pudlak syndrome also causes problems with the platelet dense granules (storage pool deficiency), which leads to easy bruising and prolonged bleeding. The genes associated with the condition include HPS1 through HPS93. The condition is inherited in an autosomal recessive fashion and some patients may have significant other health problems beyond the partial albinism including lung or intestinal problems and significant visual problems because of the effects on the eyes.
Resources:
- https://www.hpsnetwork.org/
- https://medlineplus.gov/genetics/condition/hermansky-pudlak-syndrome/
- https://rarediseases.org/rare-diseases/hermansky-pudlak-syndrome/
Chediak-Higashi Syndrome
Chediak-Higashi syndrome is an autosomal recessive inherited condition that is caused by variants within the lysosomal trafficking regular gene (LYST gene). A syndrome is a collection on symptoms that occur together as part of the underlying genetic condition. In this syndrome, individuals can experience oculocutaneous (eye and skin) albinism, immune deficiencies, large platelet granules, platelet dysfunction, and thrombocytopenia.
Resources:
GFI1B-related Thrombocytopenia
The GFI1b gene codes for a protein called “Growth Factor Independent IB” which is a transcription factor meaning it controls the production of several proteins involved in the production of platelets. It is now recognized that variants in this gene can lead to mild-moderate thrombocytopenia with a variable defect in platelet function showing up at any age. It is inherited in an autosomal dominant fashion which means it can be inherited from either parent affecting males and females in the same way. GFI1B related thrombocytopenia can also be associated with large red blood cells (macrocytosis) and mild anemia (low hemoglobin).
Resources:
At this time, there are no resources available for this condition.
Surface Receptor Disorders
Bernard-Soulier Syndrome
Bernard-Soulier syndrome (BSS) is most commonly an autosomal recessive inherited disorder (both parents must carry the genetic trait) caused by a defect in platelet glycoprotein complex Ib-IX. A syndrome is a collection on symptoms that occur together as part of the underlying genetic condition. In addition to thrombocytopenia, people with Bernard-Soulier syndrome have very large platelets and platelet function defects that prompt much more bleeding at a particular platelet count than people with ITP. Genes involved include GP1BA, GP1BB, and GP9. There are a few variants in these genes that can cause low platelet counts and more mild bleeding and platelet dysfunction with only a single inherited variant (monoallelic BSS) which can look very much like chronic ITP except that these patients do not respond to therapies for ITP and do not have as variable platelet counts (rarely have very severe thrombocytopenia).
Resources:
- National Institutes of Health U.S. National Library of Medicine
- https://rarediseases.org/rare-diseases/bernard-soulier-syndrome/
- https://glhf.org/glanzmanns-thrombasthenia-and-bernard-soulier-syndrome/
Von Willebrand Disease Type 2B
Von Willebrand factor is a protein in the blood needed for normal clotting. Von Willebrand disorder is caused by a defect in that protein, leading to abnormal bleeding. In the Type 2b variety of this condition, platelets stick to the abnormal von Willebrand factor rather than to each other. This action forms platelet clumps and causes thrombocytopenia. This condition involves variants in the VWF gene and can be inherited (autosomal dominant) from either parent affecting both males and females.
Resources:
Glanzmann Thrombasthenia
Pathogenic variants in the ITGA2B gene and ITGB3 genes cause hereditary Glanzmann Thrombasthenia. Symptoms in affected individuals mimic ITP including spontaneous petechiae and bruising, bleeding from gums, heavy menstrual bleeding in women, and prolonged bleeding following surgery, but patients have normal platelet counts. The condition is inherited in an autosomal recessive mode.
Resources:
Intracellular Signaling Disorders
Aspirin-like Platelet Defect (ADP)
APD is a condition caused by inherited autosomal recessive variants in PTGS1 that predisposes an individual to platelet defects that lead to mild-moderate bleeding symptoms and impaired platelet function. In fact, the disorder causes a similar effect on platelets as when a person takes aspirin. When prolonged bleeding occurs following minimal impact, hereditary platelet function defects are important to consider. This condition can mimic the bleeding symptoms seen in ITP but does not cause thrombocytopenia.
Resources:
At this time, there are no resources available for this condition.
FLI1-related Thrombocytopenia
Variants within FLI1 can lead to two different types of platelets disorders: Paris-Trousseau syndrome (when the defect is due to a variant in the gene alone) and Jacobson Syndrome (a multisystem disorder due to loss of chromosome 11q including FLI1 causing both Paris Trousseau AND other systemic defects). The platelet disorder consists of platelet granule abnormalities, and thrombocytopenia that is usually worse in the first year of life and improves over time (but may not completely normalize). The bleeding is variable but can be associated with increased bleeding risk with procedures, especially dental procedures.
Resources:
At this time, there are no resources available for this condition.
P2Y12-related Platelet Disorder
P2Y12 variants are rare and can lead to mild to moderate bleeding with easy bruising, mucosal bleeding, and excessive post-surgical bleeding due to abnormalities within the platelet P2Y12 receptor causing a selective impairment of platelet responses to a molecule called adenosine diphosphate (ADP). This is like being treated with medications that block this receptor (such as clopidogrel: Plavix or thienopyridines). These patients have bleeding like ITP but have a normal platelet count.
Resources:
At this time, there are no resources available for this condition.
Transcription Factor Disorders
ANKRD26-related Thrombocytopenia
Thrombocytopenia cases caused by variants in ANKR26 are more prevalent than previously thought. ANKRDF26-related thrombocytopenia is inherited in an autosomal dominant fashion. There is a risk for hematological malignancy, such as leukemia that has not been well characterized but is between 20-30%. This condition was previously referred to as familial thrombocytopenia syndrome.
Resources:
At this time, there are no resources available for this condition.
RUNX1-related Thrombocytopenia
RUNX1 variants predisposes an individual to develop thrombocytopenia (often) and hematological malignancies, such as leukemia. RUNX1 is inherited in an autosomal dominant fashion. Individuals with this condition may present with a low platelet count or abnormal platelet function causing excessive bleeding following minor trauma or surgery, or family or personal history of leukemia. The degree of bleeding and low platelet count and the risk of leukemia/ myelodysplastic syndrome (pre-leukemia bone marrow changes) is very variable from family to family and even within the family so once the disorder is identified, all at risk family members should be counselled and offered testing as checking a platelet count is not sufficient to rule out the presence of the genetic variant.
Resources:
- RUNX1 Research Program: The online community for individuals with RUNX1 FPD/AML
- Video showcasing the Anderson Family
- A Spotlight on RUNX1 and Inspiring Family Story
- National Human Genome Research Institute: RUNX1
ETV6-related Thrombocytopenia
Individuals with ETV6-related thrombocytopenia often present with multiple family members with thrombocytopenia, as well as a predisposition to leukemia. Some people who have a variant in this gene may only develop a low platelet count, others may not have any symptoms, and approximately 30% will develop leukemia, usually B-cell acute lymphoblastic leukemia type. Families with variants with ETV6 variants identified in one family members should have counselling and testing offered to other at-risk family members.
Resources:
At this time, there are no resources available for this condition.
Thrombocytopenia-Absent-Radius (TAR) Syndrome
TAR is a congenital thrombocytopenia syndrome which means it’s present at birth. A syndrome is a collection of symptoms that occur together because of the underlying genetic condition. TAR syndrome is caused by variants in the RBM8A gene and leads to an individual developing a low platelet count in addition to being born without a bone (called the radium) the one or both forearms. The thrombocytopenia may be variable, meaning some with this condition may have normal platelet count levels. Skeletal problems, cardiac defects, and other birth defects may also be seen as part of this condition. Almost half of all individuals with TAR syndrome have an allergy to cow’s milk, and this allergy may worsen the thrombocytopenia associated with the condition and result in GI or pulmonary (lung) bleeding. TAR syndrome is inherited as an autosomal recessive condition however, there are some unique nuances that would need to be reviewed with a genetic counselor. TAR syndrome has complex genetics and requires co-inheritance of a low functioning version of the RBM8A gene and a deletion of part of the RBM8A gene at chromosome 1q21.1.
Resources:
https://www.disabilityscot.org.uk/organisation/t-a-r-syndrome-support-group/
GATA1-related Thrombocytopenia
GATA1 on the X-chromosome regulates red cell and platelet development, causing those with variants in GATA1 to sometimes have both low red cells and low platelets. Because GATA1 is on the X-chromosome, males who only have a single X-chromosome are affected more often than females, a pattern referred to as X-linked inheritance. In males who have inherited a pathogenic variant in GATA1, their platelets are typically large and have less granules than normal platelets. The hemoglobin is variably mildly to severely low with small red blood cells and call look like iron deficiency or thalassemia (but iron levels are normal).
Resources:
- https://rarediseases.info.nih.gov/diseases/6274/diamond-blackfan-anemia
- https://dbafoundation.org/
- https://rarediseases.org/rare-diseases/anemia-blackfan-diamond/
Stem Cell Differentiation Related Disorders
Congenital Amegakaryocytic Thrombocytopenia (CAMT)
Congenital amegakaryocytic thrombocytopenia (CAMT) is a recessive condition in which both parents are carriers of an MPL variant (which is the gene that codes for the TPO receptor), but neither has low platelets. One fourth of their children (on average) will be affected with severe thrombocytopenia and absence of megakaryocytes in the bone marrow. Due to the severity of this disorder, it is usually recognized shortly after birth because of severely low platelet counts and bleeding symptoms. This disorder is caused by pathogenic variants that affect the major platelet growth factor receptors and, in many patients, worsens over time until no cells are made in the bone marrow (bone marrow failure).
Resources:
- https://rarediseases.info.nih.gov/diseases/640/congenital-amegakaryocytic-thrombocytopenia
- https://globalgenes.org/disorder/congenital-amegakaryocytic-thrombocytopenia/
THPO-related Thrombocytopenia
Individuals with variants in the THPO gene often have variable platelet size with large platelets and mild bleeding risk, and no malignancy risk. It can mimic other conditions in terms of a larger platelet size and may be mistaken for chronic ITP. Variants in this gene are inherited in an autosomal dominant fashion. Patients with variants in THPO may respond well to TPO-receptor agonists.
Resources:
At this time, there are no resources available for this condition.
MECOM-related Thrombocytopenia
Pathogenic variants in MECOM lead to bone marrow failure and skeletal abnormalities (such as radioulnar synostosis) and is inherited in an autosomal dominant fashion. At this time, there is little information known about pathogenic variants in this gene. Information will be updated as it becomes available.
Resources:
At this time, there are no resources available for this condition.
Other Inherited Disorders That Could Cause a Low Platelet Count
Gaucher Disease
Gaucher disease is an inherited metabolic disease. There are three different types of Gaucher disease. Type one is identified more in individuals who are of Jewish descent (specifically, Ashkenazi Jewish descent) but can affect families from any cultural group. All types are due to recessive variants in GBA. Individuals with Gaucher disease have a very low level of an enzyme called glucocerebrosidase which can accumulate in various organs result in bone pain, thrombocytopenia, anemia, liver disease, and an enlarged liver and spleen. The low platelet count and anemia can be due to the large spleen or due to infiltration of the bone marrow by abnormal deposits of the glucocerebrosidase in the marrow and spleen.
Resources:
- https://rarediseases.org/organizations/gaucher-community-alliance-gca/
- https://www.gaucherdisease.org/about-gaucher-disease/resources/connect/