Chromosome 14q32 Duplication Syndrome, 700-Kb

A number sign (#) is used with this entry because of evidence that susceptibility to familial myeloproliferative neoplasms can be conferred by a heterozygous germline 700-kb duplication on chromosome 14q32 involving the ATG2B (616226), GSKIP (616605), TCL1A (186960), BDKRB1 (600337), BDKRB2 (113503), and AK7 (615364) genes.

Clinical Features

Saliba et al. (2015) reported 4 unrelated families in which multiple members had various manifestations of adult-onset myeloproliferative neoplasms, including essential thrombocythemia, acute myeloid leukemia, chronic myelomonocytic leukemia, and primary myelofibrosis. All families originated from the French West Indies. The patients had an earlier average age at onset (41 years) compared to patients with sporadic disease (greater than 60 years).

Inheritance

The transmission pattern of familial myeloproliferative neoplasms in the families reported by Saliba et al. (2015) was consistent with autosomal dominant inheritance and incomplete penetrance (about 70%).

Mapping

By linkage analysis of 2 large families from the French West Indies with variable familial myeloproliferative disorders, Saliba et al. (2015) found significant linkage to a 1.86-Mb interval on chromosome 14q32 (lod score of 3.7).

Cytogenetics

In affected members of 4 families with familial myeloproliferative disorders, Saliba et al. (2015) identified a germline heterozygous 700-kb duplication within an identified linkage region on chromosome 14q32. PCR analysis showed that the copy number variant (CNV) was a 700-kb head-to-tail tandem duplication including multiple genes: TCL1A, GSKIP, ATG2B, BDKRB1, BRKRB2, and the first exon of AK7. Penetrance was incomplete but high: 24 of 34 carriers developed disease. This CNV was not identified in 199 control DNA samples from individuals with the same geographic origin or in 98 unrelated European cases with familial myeloproliferative neoplasms. Patient cells also showed somatic mutation profiles observed in sporadic cases, including the JAK2 V617F (147796.0001) mutation (in 68% of patients), mutations in the MPL (159530) gene (in 9% of patients), and mutations in the CALR (109091) gene (in 18% of patients). One patient with the CNV was triple-negative for mutations in those 3 genes. Additional sequencing of patient cells showed the acquisition of secondary events in other genes, including TET2 (612839) (in 38%), IDH1 (147700) (in 10%), IDH2 (147650) (in 19%), and ASXL1 (612990) (in 5%). These changes were associated with disease evolution to myelofibrosis and leukemia. Several patients (14%) exhibited biallelic mutation of TET2 or a combination of epigenetic mutations (in TET2 and IDH2 or IDH1 and IDH2); no TP53 (191170) mutations were detected.

Molecular Genetics

In microarray analysis of EBV-transformed cells and megakaryocytes derived from patients with the 700-kb duplication of 14q32, Saliba et al. (2015) found significantly higher levels of ATG2B and GSKIP transcripts compared to controls; the expression of other genes within the duplication were not significantly different. Studies in induced pluripotent stem cells (iPSCs) derived from the patients and controls showed that the 700-Kb duplication contributed to increased generation of hematopoietic progenitor cells and the overproduction of erythroblasts, megakaryocytes, and monocytes; this effect was reinforced by additional mutations in JAK2 and/or TET2. Megakaryocytes showed increased sensitivity to THPO (600044) and erythrocytes showed increased sensitivity to EPO (133170). Silencing of the ATG2B and GSKIP genes in CD34+ progenitor cells from patients and controls resulted in a reduction in megakaryocyte progenitors. Overall, the report suggested that overexpression of ATG2B and GSKIP resulting from the 700-kb duplication causes increased fitness of cells with somatic mutations involved in hematopoietic signaling pathways, resulting in increased probability of developing myeloid malignancies.