Identification of disease gene variants that can lead to familial myelodysplasia and acute myeloid leukaemia
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Myelodysplasia (MDS) is characterised by inefficient haematopoiesis with dysplastic
features of blood and bone marrow, reduction of mature blood cells and continuous
bone marrow failure (BMF). Acute myeloid leukaemia (AML) is characterised by the
accumulation of immature myeloid blasts in the bone marrow. MDS and AML are
mostly sporadic clonal disorders affecting older patients. Familial occurrence of
MDS/AML is rare, and most of these cases occur in the setting of genetic syndromes.
However, it has also been reported to be caused by germline heterozygous mutations
in genes including RUNX1, CEBPA, TERC, TERT, GATA2, SRP72, and ANKRD26.
Our group has collected 115 families that have two or more individuals with BMF with
at least one of whom has MDS or AML. The aim of this project was to identify disease
causing gene variants that can lead to familial MDS/AML. Identification of
predisposing variants to familial MDS/AML is critical for effective management in
these families. This will also provide new insights into the biology of MDS/AML in
general.
Herein, we have characterised a subset of families with MDS/AML as well as identified
candidate disease genes using a range of genetic studies. Specifically, we have: i.
Identified new genetic variants in some of the known disease genes such as RUNX1
and GATA2. ii. Our studies have substantiated the discovery of DDX41 as a disease
gene as we have identified several families harbouring novel heterozygous loss of
function (LoF) DDX41 variants. iii. Identified germline heterozygous LoF RTEL1
variants in a subset of families with myelodysplasia and liver disease. This defines a
new disease group in this field, RTEL1 can now be added to the list of familial
MDS/AML disease genes. iv. We have identified nine new candidate disease genes
which are involved in RNA splicing, transcription factor, DNA modification, cell
signalling and intracellular transport.
Authors
Cardoso, Shirleny RomualdoCollections
- Theses [4155]