The genetic basis and pathophysiology of bone marrow failure syndromes

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The bone marrow (BM) failure syndromes are a diverse group of life threatening disorders affecting children and adults. They are unified by the inability of the BM (the site of blood cell production) to make an adequate number of mature blood cells (red cells, white cells and platelets) and patients die prematurely from infection or bleeding if adequate treatment is not available. There are many different subtypes of BM failure. This includes the categories of dyskeratosis congenita (a severe inherited disorder in which many other systems of the body can be affected in addition to the blood system), idiopathic aplastic anaemia (the commonest type of BM failure whose cause remains unknown) and myelodysplasia (characterized by abnormalities in normal maturation of blood cells and where the underlying primary cause remains unknown). In approximately 40% of dyskeratosis congenita patients the genetic basis is unknown and in aplastic anaemia and myelodysplasia the primary cause remains unknown in over 80% of patients. The main aim of this research project is to determine the genetic basis and primary causes in the many uncharacterized cases of bone marrow failure. The experiments will involve undertaking genetic studies (including those based on the recently developed techniques of large scale gene sequencing so called next generation sequencing) in families with two or more affected cases with BM failure we have collected over the last 20 years. These studies will lead to the identification and characterization of new genes and cell pathways that are of fundamental importance. From the clinical perspective these studies will provide new diagnostic genetic tests and the possibility of developing new treatments that are highly desirable since prognosis remains unsatisfactory for many patients with bone marrow failure.