Common Conditions Tested for on Inherited Thrombocytopenia Panels

This helpful chart of inherited conditions lists the gene and location, mode of inheritance and key features. The following are a summary of some of the more common pathogenic variants identified through genetic testing for thrombocytopenia.

Type: Microthrombocytic (Platelets are smaller than normal)

Wiskott-Aldrich Syndrome (WAS) and X-linked Thrombocytopenia (XLT)

Both are X-linked disorder occurring almost exclusively in males, although it is also reported in females. Platelets are very small and may be accompanied by immunodeficiency and eczema. Individuals with WAS usually have severe thrombocytopenia (very low platelet count) compared to those with XLT. They two conditions are similar because they both arise from pathogenic variants in the WAS gene.

Type: Macrothrombocytic (Platelets are larger than normal)

Bernard-Soulier Syndrome

Bernard-Soulier syndrome is an autosomal recessive inherited disorder (both parents must carry the genetic trait) caused by a defect in platelet glycoprotein complex Ib-IX. 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.

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 the VWF gene and is inherited in an autosomal dominant mode.

MYH9 Related Disorders

(includes May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome or Epstein’s syndrome).

These disorders are grouped together because they are all caused by mutations of the MYH9 gene. May-Hegglin anomaly (MHA), the most familiar, is an autosomal dominant condition in which an affected parent can pass the trait to their children, with a 50 percent likelihood of each child having low platelets. MHA is characterized by abnormally large platelets (that are frequently undercounted by automated machines), mild to moderate bruising, and potential for hearing and kidney problems.

Variants in Filamin-A (FLNA)

People with variants in the X-linked (male) FLNA gene have large platelets and experience possible hemorrhaging, abnormal clotting, as well as low platelets. This can be associated with periventricular nodular heterotopia, a disorder characterized by the migration of grey matter to places outside of the cortex in the brain.

Gray Platelet Syndrome (GPS)

Patients with gray platelet syndrome (GPS) bleed longer than others 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 rather than pink, hence the name. 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 an autosomal recessive condition affecting the NBEAL2 gene.

Variants in GATA-1

The GATA1 gene 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. Platelets in males who have inherited a mutant GATA1 are typically large and have few of the granules found in 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).

Variants in ACTN1

Individuals with ACTN1- related thrombocytopenia (ACTN1-RT) have larger than normal platelets and unequal sizes of red blood cells (anisocytosis). Individuals with this condition sometimes (not always) develop thrombocytopenia. The variant shows variable expressivity which means it may affect family members different who also have the same variant. ACTN1-RT is inherited in an autosomal dominant manner.

Variants in CYCS and TUBB1

Mild bleeding tendency and mild thrombocytopenia can be observed. Variants in both CYCS and TUBB1 are inherited in an autosomal dominant fashion. At this time, there is little information known about pathogenic variants in these two genes. Information will be updated as it becomes available. Variants in CYCS may not cause an enlarged platelet size and usually does not have a significant bleeding risk.

Variants in SLFN14

Pathogenic variants in SLFN14 usually cause moderate thrombocytopenia, enlarged platelets, and are inherited in an autosomal dominant inheritance pattern. At this time, there is little information known about pathogenic variants in this gene. Information will be updated as it becomes available.

Variants in SRC

Pathogenic variants in the gene SRC can cause thrombocytopenia, myelofibrosis, bleeding, platelet dysfunction with abnormal α-granules, and bone pathologies. At this time, there is little information known about pathogenic variants in this gene. Information will be updated as it becomes available.

Glanzmann Thrombasthenia

Pathogenic variants in the ITGA2B gene and ITGB3 gene 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. The condition is inherited in an autosomal recessive mode.

Type: Normothrombocytic (Plates are normal size)

Congenital Amegakaryocytic Thrombocytopenia (CAMT)

Congenital amegakaryocytic thrombocytopenia (CAMT) is a recessive condition in which both parents are carriers of an MPL variant, 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. Because of the severity of this disorder, it is usually recognized shortly after birth. This disorder is caused by pathogenic variants that affect the major platelet growth factor receptor and usually worsens over time until no cells are made in the bone marrow (aplastic anemia).

Familial Thrombocytopenia

Thrombocytopenia cases caused by a mutation in the ANKR26 gene are more prevalent than previously thought. ANKRDF26-related thrombocytopenia is inherited in an autosomal dominant fashion, which means it can be inherited from one parent. There is a risk for hematological malignancy.

Hermansky-Pudlak Syndrome

Hermansky-Pudlak syndrome is a disorder characterized by lack of granules in multiple different tissues resulting in oculocutaneous albinism, which causes abnormally light coloring (pigmentation) of the skin, hair and eyes. Those affected by the disorder typically 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 blood clotting (coagulation), which leads to easy bruising and prolonged bleeding because of problems with the platelet granules (the chips in the platelets). The gene associated with the condition include HPS1 and HPS3. The condition is inherited in an autosomal recessive fashion.

RUNX1 Germline Variants

RUNX1 FPD/AML is a hereditary blood disorder that predisposes an individual to develop hematological malignancies (such as leukemia). RUNX1 is inherited in an autosomal dominant fashion. Those with the blood disorder typically present as having low platelets (thrombocytopenia; their platelets are also functionally impaired, causing bleeding problems such as nose bleeds, excessive bleeding during minor surgery and easy bruising. 

More RUNX1 Resources:

Familial Thrombocytopenia and Leukemia Predisposition Syndrome

Variants in ETV6 are responsible for a familial thrombocytopenia and leukemia predisposition syndrome. Thrombocytopenia is almost always present but is usually mild. Leukemia is reported in some (not all) of individuals who have a pathogenic variant in this gene. This condition is inherited in an autosomal dominant mode.

Gaucher Disease

This 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 (Ashkenazi Jewish) but can affect families from any cultural group. All types are due to recessive pathogenic variants in the GBA gene. Individuals with Gaucher disease have a very low level of an enzyme called glucocerebrosidase which can result in bone pain, thrombocytopenia, anemia, and an enlarged liver and spleen.

Variants in MECOM

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.

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