The genetic basis and pathophysiology of bone marrow failure syndromes

骨髓衰竭综合征是影响儿童和成人的多种危及生命的疾病。它们的共同点是BM（血细胞产生的部位）无法产生足够数量的成熟血细胞（红细胞、白细胞和血小板），如果没有适当的治疗，患者会因感染或出血而过早死亡。脑梗死有许多不同的亚型。这包括先天性角化不良（一种严重的遗传性疾病，除血液系统外，还会影响身体的许多其他系统）、特发性再生障碍性贫血（最常见的骨髓衰竭类型，其原因尚不清楚）和骨髓发育不良（以血细胞正常成熟异常为特征，其潜在的主要原因尚不清楚）。在大约40%的先天性角化不良患者中，遗传基础未知，在再生障碍性贫血和骨髓发育不良患者中，超过80%的患者的主要原因仍然未知。本研究项目的主要目的是确定许多未表征的骨髓衰竭病例的遗传基础和主要原因。实验将涉及在过去20年中收集的具有两个或更多BM失败影响病例的家庭中进行遗传研究（包括基于最近开发的大规模基因测序技术的研究，即所谓的下一代测序）。这些研究将导致对新基因和细胞通路的识别和表征，这是至关重要的。从临床角度来看，这些研究将提供新的诊断基因测试和开发新的治疗方法的可能性，这是非常可取的，因为许多骨髓衰竭患者的预后仍然不满意。

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.