Pathogenesis and Natural History in a Longitudinal Hemangioma Syndrome Cohort

描述(由申请人提供)： 背景：Pace综合征是面部大型节段性血管瘤和先天性出生缺陷(如后颅窝畸形)的相关性。绝大多数病例是散发的，这表明从头开始或合子后的体细胞突变可能是致病机制。GAP：对于这种血管瘤综合征的发育异常的发病机制和自然病史，我们基本上缺乏了解。目的：我们的主要目标是阐明与该血管瘤综合征相关的关键发育遗传途径。我们的次要目标是将最严重的临床特征(主动脉缩窄、脑血管异常和中风)与该基因相关。目标：1)我们将使用下一代高通量测序技术、定制设计的分析管道和标准验证方法来鉴定Phace中的马赛克突变。2)我们将利用我们严格的表型临床Phace登记和定义Phace综合征临床特征的大量初步数据来确定基因-表型的相关性。意义：这项拟议研究的贡献预计将是对Phace综合征的遗传基础以及与相关发育异常的表型相关性的理解。这一知识将具有重要意义，因为它将推动预防战略，并为新的治疗剂提供关键靶点。合作者：我们的多学科研究团队包括皮肤病学(Siegel、Drolet和Frieden)、医学遗传学和儿童神经病学(Dobyns)、生物信息学(Worthee)、基因组学(Worthee、Jacob和Shendure)、统计学(Hoffman)和细胞生物学(Rafiee)方面的专业知识。

DESCRIPTION (provided by applicant): Background: PHACE syndrome is the association of large segmental facial hemangiomas and congenital birth defects, such as posterior fossa malformations. The vast majority of cases are sporadic, suggesting de novo or postzygotic somatic mutations may be the pathogenic mechanism. Gap: There is a fundamental lack of knowledge about the pathogenesis and natural history of the developmental anomalies in this hemangioma syndrome. Goal: Our primary objective is to elucidate the critical developmental genetic pathway involved in this hemangioma syndrome. Our secondary objective is to correlate the most severe clinical features (coarctation of the aorta, cerebrovascular anomalies and stroke) with the genotype. Aims: 1) We will use next generation high-throughput sequencing technology, custom designed analysis pipelines, and standard validation methods to identify mosaic mutations in PHACE. 2) We will capitalize on our rigorously phenotyped clinical PHACE registry and extensive preliminary data defining the clinical characteristics of PHACE syndrome to determine genotype-phenotype correlations. Significance: The contribution of the proposed research is expected to be an understanding of the genetic underpinnings of PHACE syndrome and phenotypic correlation with the associated developmental anomalies. This knowledge will be significant as it will drive strategies for prevention and provide critical targets for new therapeutic agents. Collaborators: Our multi-disciplinary study team includes expertise in dermatology (Siegel, Drolet and Frieden), medical genetics and child neurology (Dobyns), bioinformatics (Worthey), genomics (Worthey, Jacob and Shendure), statistics (Hoffman) and cell biology (Rafiee).