Alternative titles; symbols
ORPHA: 480851;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q11.23 | ?Thrombocytopenia 6 | 616937 | Autosomal dominant | 3 | SRC | 190090 |
A number sign (#) is used with this entry because of evidence that autosomal dominant thrombocytopenia-6 (THC6) is caused by heterozygous mutation in the SRC gene (190090) on chromosome 20q12. One such family has been reported.
Thrombocytopenia-6 is an autosomal dominant hematologic disorder characterized by increased bleeding episodes due to reduced platelet count and abnormal platelet morphology resulting from defective megakaryopoiesis. Patients may also have bone abnormalities, including osteoporosis or tooth loss, as well as an increased risk for myelofibrosis (summary by Turro et al., 2016).
For a general phenotypic description and a discussion of genetic heterogeneity of thrombocytopenia, see 313900.
Turro et al. (2016) reported 9 individuals from a 3-generation family with thrombocytopenia and increased bleeding. Detailed clinical features were reported for 4 patients; the age at onset of symptoms was not specified, but the patients ranged in age from 16 to 55 years. Bleeding was characterized as epistaxis, petechiae, small hematomas, menorrhagia, and bleeding after tooth extraction. Blood smear showed reduced numbers of platelets with about 10 to 30% having a grayish appearance due to lack of alpha-granules; some platelets were abnormally large. Five patients presented prematurely with myelofibrosis and enlarged spleens. Several patients had bone pathology, including severe osteoporosis, edentulism, and mild dysmorphic facial features such as large forehead, hypotelorism, deep-set eyes, and wide nostrils.
The transmission pattern of THC6 in the family reported by Turro et al. (2016) was consistent with autosomal dominant inheritance.
In affected members of a family with THC6, Turro et al. (2016) identified a heterozygous missense mutation in the SRC gene (E527K; 190090.0002). The mutation was found by exome sequencing and segregated with the disorder in the family. Studies of patient platelets and in vitro transfection studies indicated that the mutation resulted in constitutive activation of the SRC kinase in a dominant manner. These changes were associated with defective megakaryopoiesis and abnormal proplatelet formation, and could be rescued with an SRC inhibitor. Expression of the mutation in zebrafish embryos resulted in abnormal early primitive hematopoiesis, thrombocytopenia, and smaller bones compared to controls.
Turro, E., Greene, D., Wijgaerts, A., Thys, C., Lentaigne, C., Bariana, T. K., Westbury, S. J., Kelly, A. M., Selleslag, D., Stephens, J. C., Papadia, S., Simeoni, I., and 32 others. A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies. Sci. Transl. Med. 8: 328ra30, 2016. Note: Electronic Article. [PubMed: 26936507] [Full Text: https://doi.org/10.1126/scitranslmed.aad7666]