Familial predispositions to myeloid malignancies are well recognized. Germline mutations in genes such as RUNX1, CEBPA, GATA2, TERT, TERC, ANKRD26, SRP72, ACD, ETV6, DDX41, SAMD9L and SAMD9, reported over the last 18 years, predispose predominantly to myeloid malignancies with or without cytopenias or other phenotypes. One study reported 4 families with predisposition to myeloid malignancies including myeloproliferative neoplasms (MPN) (Saliba et al. Nat Genet 47:1131, 2015). These French West Indies families harbored an identical 700 kb duplication within chromosome 14 encompassing the genes ATG2B, GSKIP and TCL1A . In functional assays, ATG2B and GSKIP were implicated in the predisposition and phenotype of the resultant malignancies.

Here we report a 4 generational family with 6 affected individuals with myeloid malignancy (myelodysplastic syndrome (MDS), MPN and acute leukemia). Using copy number variant analyses directly from whole exome sequencing data, 3 affecteds were shown to harbor a ~700 kb germline duplication encompassing 9 genes including DICER1 and TCL1A . Only TCL1A and a long non-coding RNA (RP11-164H13.1) are located in the overlap duplicated region between this family and the West Indies families. T-cell leukemia/lymphoma 1A (TCL1A) gene is commonly over-expressed in T and B cell malignancies, sometimes due to chromosomal translocations that bring the strong TCR (A and B) and IGH enhancers adjacent to the TCL1A gene. To date, the TCL1A gene has not been implicated in predisposition to MPN.

Mutational analysis of an MDS/MPN-U (RCMD-RS/MF) patient sample revealed that the germline duplicated region was further duplicated as part of a larger 18 Mb somatic duplication that also included ATG2B and GSKIP, likely contributing to the myelofibrosis phenotype. A somatic mosaic trisomy 14 acquisition further amplifying the duplicated region was also seen in one of the West Indies affecteds providing evidence that gene dosage of the predisposing gene or genes within the local Chr 14q32.2 region may be an important factor. Such trisomy 14 cases have been reported as rare events in MPN, MDS, CMML and aCML. In a cohort of 126 sporadic primary MDS samples, we have identified 2 cases with Chr 14q copy number neutral loss of heterozygosity encompassing the two 700 kb duplicated regions. Like the MDS/MPN-U proband (Fig.1A), these cases harbored deleterious SF3B1 mutations and displayed ring sideroblasts as a common feature. In summary, we have identified a novel germline duplication that segregates with MDS/MPN.

Figure 1. MDS/MPN family and germline duplication on chromosome 14q. A. Four generation family with MDS/MPN.Myeloid phenotype (blue); age of diagnosis, dx; age of death, d; alive, a; in years. Proband (solid triangle) B. Copy number analysis of WES data from bone marrow (BM) of the RCMD-RS/MF proband. Ploidy calculation (dark blue) and z-score (light blue) for calculation of copy number variation.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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