Mosaic: post-zygotic mutations in vascular and lymphatic developmental disorders

镶嵌：血管和淋巴发育障碍的合子后突变

• 批准号: 9217664
• 负责人: William B. Dobyns
• 金额: $ 73.33万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-08 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217664
• 关键词: Address; Affect; Algorithms; Arteriovenous malformation; Bioinformatics; Biology; Birth; Blood Vessels; Cell Count; Cell division; Cells; Clinical; Communities; DNA; DNA Sequence Alteration; Data; Data Analyses; Disease; Embryonic Development; Gastrula; Gene Mutation; Generations; Genes; Genetic; Genomics; Genotype; Germ-Line Mutation; Growth; Handedness; Hemangioma; Hereditary Disease; Heterogeneity; Human; Lesion; Leukocytes; Location; Lymphatic; Lymphatic vessel; Malignant Neoplasms; Massive Parallel Sequencing; Measures; Methods; Molecular; Mosaicism; Mutation; Nature; PIK3CA gene; Pathway interactions; Phenotype; Reporting; Research Personnel; Saliva; Sampling; Sequence Analysis; Skin; Syndrome; Technology; Time; Tissues; Variant; Vascular Diseases; Venous Malformation; Work; analytical method; base; body system; cohort; design; developmental disease; exome; experience; gastrulation; genome sequencing; genome-wide; human disease; improved; malformation; mutant; next generation sequencing; novel; public health relevance; repository; success; targeted sequencing; whole genome

 DESCRIPTION (provided by applicant) Recent experience suggests that post-zygotic or mosaic mutations are a common cause of developmental disorders that can involve any organ system, although they are most easily recognized in vascular anomalies and skin. Several genes underlying rare syndromes with vascular anomalies have been identified, but so far only two that contribute to the more common non-syndromic forms: TEK for venous malformations and PIK3CA for lymphatic malformations, the latter recent work reported by the investigators. For both of these and several syndromic forms, the mutations are found in only or primarily in affected tissue and represent mosaic mutations. We propose to identify and study the genes underlying other vascular anomalies using new genomics technologies. The genetics community has rapidly moved to whole exome (WXS) or whole genome (WGS) sequencing to investigate disorders such as these, but the success rate of such studies is only ~25% when germline inheritance is expected, and much lower for patchy or asymmetric disorders that suggest mosaicism. Our first aim is to develop new genomic and bioinformatics methods that will more reliably detect low level mosaic mutations using massively parallel (NextGen) sequencing approaches. We will next study how the level and distribution of mosaicism affects the phenotype, focusing first on disorders with known causative genes (initially PIK3CA) that can be evaluated reliably because of vascular and/or lymphatic involvement. Finally, we will use existing and new methods to search for novel genes underlying vascular anomalies, focusing first on more common and clinically important types such as such as arteriovenous malformations, the remaining unexplained lymphatic malformations (that is, not due to PIK3CA mutations) and hemangiomas. We expect this work to significantly expand our understanding of vascular anomalies specifically and the nature of mosaicism more broadly.

 描述（由申请人提供） 最近的经验表明，合子后突变或嵌合突变是涉及任何器官系统的发育障碍的常见原因，尽管它们在血管异常和皮肤中最容易识别，但已经鉴定出一些导致罕见血管异常综合征的基因。目前只有两种导致更常见的非综合征形式：用于静脉畸形的 TEK 和用于淋巴管畸形的 PIK3CA，研究人员最近报告了这两种和几种。综合征，这些突变仅或主要在受影响的组织中发现，并且代表镶嵌突变，我们建议使用新的基因组学技术来识别和研究其他血管异常的基因，遗传学界已迅速转向全外显子组（WXS）或全基因组。 (WGS) 测序来研究此类疾病，但当预期有种系遗传时，此类研究的成功率仅为 25%，对于表明嵌合体的斑片状或不对称疾病，成功率要低得多。新的基因组和生物信息学方法将使用大规模并行（NextGen）测序方法更可靠地检测低水平嵌合突变，我们接下来将研究嵌合体的水平和分布如何影响表型，首先关注具有已知致病基因（最初是 PIK3CA）的疾病。最后，我们将使用现有的和新的方法来寻找血管异常的新基因，首先关注更常见和更常见的基因。临床上重要的类型，例如动静脉畸形、其余无法解释的淋巴管畸形（即不是由于 PIK3CA 突变）和血管瘤，我们希望这项工作能够显着扩大我们对血管异常的理解，并更广泛地了解嵌合体的性质。