Abstract 2368

We report on a patient born with severe congenital abnormalities including macrocephaly, brain MRI abnormalities, bilateral clubfeet, and bone marrow failure with pancytopenia presenting with none but T-lymphocytes in the peripheral blood.

A 824 kb to 868 kb heterozygous deletion on chromosome 3q26.2 was identified by array-CGH on peripheral blood using an Agilent 180k oligo array (Amadid 023363). The deletion truncated the 3' part of EVI1/MECOM and extended into microRNA 551b (MIR551B). The 3' MECOM deletion was confirmed by FISH using a MECOM specific probe on uncultured peripheral blood cells in 10 investigated metaphases and 200 interphase nuclei. To assess whether the deletion was constitutional, FISH analysis was performed on buccal swaps and cultured skin fibroblasts. Loss of one MECOM signal was observed in 200 interphases, and 10 metaphases of cells derived from buccal mucosa and skin fibroblasts, respectively, demonstrating the constitutional nature of the 3' MECOM deletion. Karyotyping and FISH analysis of both parents did not reveal a structural or numerical abnormality of 3q26.2 MECOM, indicating the deletion to be de novo.

EVI1/MECOM is a transcriptional regulator essential for maintaining embryonic and adult hematopoietic stem cells by directly regulating transcription of GATA2. In mouse models, homozygous disruption of MECOM results in embryonic lethality, with hypocellular bone marrow, reduced body size, small or absent limb buds, abnormal development of the nervous system and heart and massive hemorrhaging. Furthermore, MECOM heterozygosity leads to a marked impairment of the self-renewal capacity of hematopoietic stem cells.

In our case the heterozygous deletion results in 3' terminal truncated MECOM lacking the C-terminal acidic amino acid cluster domain (AD) encoding sequences. The AD of MECOM is important for activation of GATA2 transcription in vitro. This supports the notion that haploinsufficiency of MECOM causes bone marrow failure due to loss of critical MECOM transcriptional AD encoding sequences in this case, supposedly by deregulating GATA2 mediated control of hematopoietic stem cell homeostasis.

We will discuss our data in relation to one seemingly similar case deposited recently in the DECIPHER database. In conclusion, we report on a novel 3q26 EVI1/MECOM deletion syndrome with multiple severe congenital abnormalities and bone marrow failure due to EVI1/MECOM haploinsufficiency.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.