A number sign (#) is used with this entry because of evidence that thrombocytopenia-5 (THC5) is caused by heterozygous mutation in the ETV6 gene (600618) on chromosome 12p13.

Thrombocytopenia-5 is an autosomal dominant disorder characterized by a decreased number of platelets and a bleeding tendency. Affected individuals have an increased susceptibility to the development of hematologic malignancies, and possibly to solid neoplasms. Thrombocytopenia is usually apparent in early childhood, whereas the development of malignancy can occur throughout life (summary by Zhang et al., 2015).

For a discussion of genetic heterogeneity of thrombocytopenia, see 313900.

Zhang et al. (2015) reported 3 unrelated families of different ethnicities with thrombocytopenia and various hematologic and solid malignancies. In 1 family, a mother and her 3 children of German and Native American origin all had thrombocytopenia. Two patients had neutropenia and 2 had anemia. The proband was 1 of 2 daughters who presented with easy bruising in infancy and menorrhagia in the teenage years. The proband developed myelodysplastic syndrome at age 17 and underwent hematopoietic stem cell transplant (HSCT). Her sister developed B-cell acute lymphocytic leukemia (ALL) at age 7.5 years, and the mother developed colorectal adenocarcinoma at age 45 and multiple myeloma at age 51. The mother had a history of 5 miscarriages. In a second family, of Scottish descent, 8 patients had thrombocytopenia with petechiae and epistaxis; 1 of these patients developed colon cancer at age 43, and another developed chronic myelomonocytic leukemia (CMML) at age 82. Two patients with thrombocytopenia developed skin cancer, but 2 family members who did not carry the mutation also developed skin cancer. A third patient, of African American descent, had a long history of nosebleeds and menorrhagia. She was found to have thrombocytopenia unresponsive to standard therapies, and she developed T-cell/myeloid mixed-phenotype acute leukemia (MPAL) at age 50 years. She eventually underwent allogeneic HSCT.

Noetzli et al. (2015) reported 10 patients from 3 unrelated families with THC5. Patients had thrombocytopenia, increased mean corpuscular volume (MCV), and mild to moderate bleeding. Three of the 10 patients developed B-cell leukemia at ages 3, 37, and 14 years, respectively.

The transmission pattern of THC5 in the families reported by Zhang et al. (2015) was consistent with autosomal dominant inheritance.

In affected members of 3 unrelated families with autosomal dominant thrombocytopenia, Zhang et al. (2015) identified 3 different heterozygous missense mutations in the ETV6 gene (600618.0003-600618.0005). The mutation in the first family was found by whole-exome sequencing. Functional studies showed that the mutations abrogated DNA binding, altered subcellular localization of ETV6, decreased transcriptional repression in a dominant-negative fashion, and impaired hematopoiesis. These findings identified a central role for ETV6 in hematopoiesis and malignant transformation.

In affected members of 3 unrelated families with THC5, Noetzli et al. (2015) identified 2 different heterozygous mutations in the ETV6 gene (P214L, 600618.0005 and R418G, 600618.0006). The mutation in the first family was found by whole-exome sequencing; the mutations in the 2 subsequent families were found by direct sequencing of the ETV6 gene in 23 families with a similar phenotype. Functional studies showed that all mutations resulted in decreased transcriptional repression, impaired megakaryocyte maturation, and aberrant cellular localization of mutant and wildtype ETV6, consistent with a dominant-negative effect.