Predicting and preventing leukaemia in children with Down syndrome.

The aim of the study is to better understand the relationship between GATA-1 gene mutations and development of transient myeloproliferative disorder (TMD) and myeloid leukaemia in children with Down syndrome (ML-DS), particularly acute megakaryoblastic leukaemia (AMKL). GATA-1 gene mutation analysis will be performed on genetic material extracted from blood. A small sample of blood (about a teaspoon full) will be collected for GATA-1 gene mutation analysis. Another small sample of blood will be collected for a full blood count (FBC) for haematological assessment. Methods and testing Patients enroled on this protocol will be followed up by their primary clinician and study team to ensure that required blood collections are performed. The study will follow-up participants from birth or time of consent until the age of 4 years (48 months). Blood collection timepoints are designed to coincide as much as possible with routine testing procedures required for children with Down syndrome. Study samples and a full blood count (FBC) sample will be collected at the time of consent. Ideally this would be within the first few weeks after birth. All children with Down syndrome are eligible to participate in the study, regardless of any health issues they may have. Participants who do not develop TMD will have blood collected at 3,6,12,18,24,36 and 48 months. Participants who develop TMD will have additional blood collections to those stated above at 9, 30 and 42 months. These extra blood collections are required for monitoring the TMD. Participants who develop AMKL will have blood collected for the study at diagnosis. After this they will no longer be required to have blood collected for study purposes. Haematological evaluation of FBC will help clinicians monitor levels of red and white blood cells in participants. Study samples for GATA-1 gene mutation analysis will be sent to a specialised lab for testing. Results of these tests will establish methods for GATA-1 gene mutation testing in future children with Down syndrome. Primary Objectives -to assess levels of GATA-1 gene mutations detected in children with Down syndrome found to have TMD/ML-DS. -to identify factors that promote regression of TMD or subsequent progression to ML-DS in children with Down syndrome. -to evaluate the true incidence of subclinical TMD and explore its relationship to the subsequent formation of AMKL. Secondary Objectives -to develop novel techniques that will assess GATA-1 gene mutations in non-TMD or non-AMKL populations in the future. -to determine how the GATA-1 loss of function mutation contributes to the pre-leukaemic state. -to assess feasibility of monitoring children with documented TMD or AMKL for minimal residual disease using GATA-1 mutation testing. -to determine whether children with Down syndrome progressing to ML-DS can be indentified before frank leukaemia develops.