THE PREVALENCE OF GATA-2 MUTATION AMONG PEDIATRIC PATIENTS WITH MYELODYSPLASTIC SYNDROME IN CZECH REPUBLIC

Background
Germline mutation in GATA-2 transcription factor was recently identified in patients with immunodeficiency, familiar and sporadic myelodysplastic syndrome (MDS) and lymphoedema. Germline mutation in GATA-2 represents the most frequent genetic cause of MDS among children. Detailed prevalence of GATA-2 mutation among pediatric patients with MDS or aplastic anemia (AA) was not so far estimated.

Aims
Our aim was to define the prevalence of GATA-2 mutation among children with MDS or aplastic anemia in Czech Republic.

Methods
Since 1998 there were 27 Czech pediatric patients diagnosed with MDS refractory anemia with excess blasts (RAEB) or RAEB in transformation (RAEBt). The final diagnostic algorithm including histopathological investigation for discrimination of MDS subtype refractory cytopenia (RCC) and AA was introduced in 2005. Therefore only RCC/AA patients diagnosed in 2005-2014 were included: 32 RCC patients and 41 AA patients. Fanconi anemia as a cause of bone marrow failure was excluded in all patients. The coding part and the intronic enhancer region of GATA2 gene was sequenced in all patients with available material, except for 2 patients with RAEB emerging on the background of Fanconi anemia and morbus Recklinghausen (in total 22 patients with RAEB/RAEBt, 31 RCC and 38 AA were analyzed).  Immunophenotyping using flow cytometry was performed in bone marrow and peripheral blood. Levels of intronRSS-Kde recombination excision circles(KREC) were measured in peripheral blood and bone marrow with the aim to describe the level of B cell production.

Results
GATA-2 mutation was found in 9 patients with MDS: in 3 RAEB/RAEBt and in 6 RCC patients. As expected there was no AA patient with GATA-2 mutation. Patients with GATA-2 mutation frequently harbored cytogenetic abnormalities including monosomy 7 and trisomy 8. Interestingly one patient did not have any cytogenetic abnormality, however her father died of MDS harboring monosomy 7. In total 7 patients had monosomy 7, 1 patient had trisomy 8 and one patient had simultaneously monosomy 7 and trisomy 8. The prevalence of GATA-2 mutation within patients with monosomy 7 and trisomy 8 was 41% and 29%, respectively. Considering patients with monosomy 7 only, patients with GATA-2 mutation had significantly lower KRECs in peripheral blood and tend to have lower number of B cells in bone marrow. However, at the time of birth there was no major decrease in KRECs in 3 out of 4 analyzed Guthrie cards from GATA-2 mutated patients, indicating postnatal impairment of B cell production. The only one patient with low KRECs at birth developed MDS RAEB at the age of 4 and is the youngest patient in our cohort. Except for this patient, all other GATA-2 mutated patients were older than 11 years at time of diagnosis (median 17y). Two patients with GATA-2 mutation died: one of CMV pneumonitis, another one of AML with a phenotypic switch to BCP ALL.

Summary
So far published cohorts of patients were mainly identified based on clinical symptoms (i.e. immunodeficiency, familiar AML/MDS or lymphoedema). The incidence of GATA-2 mutation among pediatric MDS RCC, MDS RAEB/RAEBt and AA patients is 19%, 14% and 0%, respectively. However, the real prevalence could be higher since not all the introns are sequenced. Interestingly mutation in GATA-2 transcription factor can be identified even in patients without any cytogenetic abnormality. Diagnosis of GATA-2 mutation is important for genetic counselling and potential identification of GATA-2 mutation in a family donor before stem cell transplantation.

Supported by GAUK 802214, IGA NT/14534-3, UNCE 204012

Keyword(s): Aplastic anemia, GATA-2, Myelodysplasia, Prevalence

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