Molecular Genetic Investigation of Pediatric Myelodysplastic Syndrome

描述（由申请人提供）：小儿骨髓增生异常综合征（MDS）是一组异质性克隆性干细胞疾病，其特征为不同程度的血细胞减少、无效和发育不良的造血。MDS可分为无明显潜在病因的原发性MDS和先天性或获得性骨髓衰竭（BMF）疾病或细胞毒性治疗后的继发性MDS。关于导致儿童MDS的起始事件知之甚少。因此，不存在靶向治疗，造血干细胞移植仍然是唯一的治疗选择。 异质性的临床和实验室表现和有限的可用性临床注释良好的患者样本和体内模型已经构成了重大障碍，研究疾病，并确定遗传改变独特的儿科MDS。因此，小儿MDS仍主要通过形态学和细胞遗传学标准进行分类，这些标准提供的分子基础线索很少。在过去的18个月里，我们已经开发了第一个全国性的综合性儿科MDS和BMF疾病患者登记和组织库，目前涉及3个机构，并继续增长。除了来自3种独特的儿童MDS患者的生物材料外，该登记处还收集了来自> 60名个体患者的样品。这些样本构成了我们第一次基因组测序分析的基础，为未来的实验收集初步数据，并代表了该登记研究阐明MDS相关致病突变的能力。 我们独特的研究者团队将利用该注册并促进我们的努力，以确定儿科MDS的基本基础。该团队包括大卫威廉姆斯（临床/转化血液学），马克弗莱明（儿科血液病理学/血液遗传学），本杰明艾伯特（高通量基因组技术在成人MDS）和Kyriacos Markinanos（遗传连锁分析）。我们将进行初步研究，以证明可行性，并生成基因组数据，为未来国家层面的假设驱动的转化和临床研究提供基础。 公共卫生相关性：对儿童MDS的潜在遗传学和病理生理学了解甚少。通过利用几个具有良好特征的遗传性MDS家族，我们的目标是确定这种疾病的遗传基础。 所获得的结果不仅有望为儿科患者的生物学提供重要的见解，而且可能会增加对成人MDS遗传学的认识。

DESCRIPTION (provided by applicant): Pediatric Myelodysplastic Syndrome (MDS) is a heterogeneous group of clonal stem cell disorders characterized by varying degrees of cytopenias, and ineffective and dysplastic hematopoiesis. MDS can be classified as primary de novo MDS with no apparent underlying cause and secondary MDS following congenital or acquired bone marrow failure (BMF) disorders or cytotoxic therapies. Little is known about initiating events leading to pediatric MDS. As a result, no targeted therapies exist and hematopoietic stem cell transplantation remains the only therapeutic option. The heterogeneous clinical and laboratory presentation and limited availability of clinically well-annotated patient samples and in vivo models have posed significant obstacles to study the disease and to identify genetic alterations unique to pediatric MDS. Therefore pediatric MDS remains largely classified by morphologic and cytogenetic criteria that provide few clues as to the molecular basis. Over the last 18 months, we have developed the first nationwide comprehensive Pediatric MDS and BMF Disorder Patient Registry and Tissue Repository now involving 3 institutions and continuing to grow. The registry has collected samples from > 60 individual patients in addition to biological material from 3 unique kindreds with pediatric MDS. These samples form the basis for our first genomic sequencing analysis to gather preliminary data for future experiments and represent the power of this registry to elucidate pathogenic mutations associated with MDS. Our unique team of investigators will exploit the registry and catalyze our efforts to determine the fundamental underpinnings of pediatric MDS. The team includes David Williams (clinical/translational hematology), Mark Fleming (pediatric hematopathology /hematological genetics), Benjamin Ebert (high throughput genomic technologies in adult MDS) and Kyriacos Markinanos (genetic linkage analysis). We will undertake preliminary studies to demonstrate feasibility, and generate genomic data that will provide the basis for future hypothesis-driven translational and clinical research studies on a national level. PUBLIC HEALTH RELEVANCE: The underlying genetics and pathophysiology of pediatric MDS is poorly understood. By exploiting several well-characterized families with inherited MDS, we will aim to identify the genetic basis for this disorder. Results obtained not only promise to provide critical insights into the biology of pediatric patients, but will likely increase knowledg into the genetics of adult MDS.