Genetic Factors in Birth Defects

出生缺陷的遗传因素

基本信息

批准号：
9150120
负责人：
James Mills
金额：
$ 33.61万
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9150120
关键词：
11q23.3 Affect Birth Blood Candidate Disease Gene Child Choanal Atresia Chromosomes Collaborations Congenital Abnormality Congenital Hydrocephalus Copy Number Polymorphism Craniosynostosis DNA Defect Denmark Ebstein&apos s Anomaly Etiology Froehlich&apos s Syndrome Funding Future Gastric outlet obstruction Genes Genetic Genetic Risk Genetic screening method Genome Heritability Hypertrophic Pyloric Stenosis Hypertrophy Individual Institution Institutional Review Boards Investigation Iowa Klippel-Trenaunay-Weber Syndrome Knowledge Laboratories Link Manuscripts Medicine Muscle Nature Neonatal Screening New York Nose Paper Population Preparation Prevention Publications Publishing Pyloric Stenosis Pyloric sphincter structure Registries Reporting Research Personnel Resources Risk Factors Role Sampling Serum Situs Inversus Surgical sutures Sweden Testing Universities Urethra Work Writing case control design genetic risk factor genetic variant genome wide association study genome-wide infancy interest malformation programs risk variant

项目摘要

DNA has been obtained from approximately 20 major malformations for current and future investigations. We have recently expanded our investigations to include searching for copy number variants in rare defects. New York has an exceptionally valuable research resource in having approximately 250,000 births per year from which to identify children with rare defects. In addition to classic candidate gene approaches, cases have been selected for copy number variant studies. The laboratory work has now been completed on many of the conditions selected for copy number variant testing. Copy number variants have been identified in several conditions of interest. We have completed our investigation of heterotaxy-associated copy number variants; written up the results; and they have been published in Genetics in Medicine. Our analysis of copy number variants in posterior urethral valves has been completed and submitted for publication. The analysis for Klippel Trenaunay Weber snydrome has been completed and a manuscript is in preparation. The analysis for prune belly syndrome has been completed and a manuscript will be prepared. The analysis for Ebstein's anomaly will be completed shortly and a manuscript will be prepared. We have also collaborated with large groups doing genome wide association studies. Our work on idiopathic hypertrophic pyloric stenosis (IHPS) is noteworthy. IHPS is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited. We previously collaborated with investigators in Denmark and Sweden to conduct a genome-wide search for candidate genes. We found a new genome-wide significant locus for IHPS at chromosome 11q23.3. These findings have been published in JAMA.We are expanding our work on pyloric stenosis to include other genes. We have initiated new collaboration with the CDC's National Birth Defects Prevention Study. In conjunction with Dr. Paul Romitti at the University of Iowa, we will be searching for genetic factors associated with choanal atresia, a defect in which the nasal passages fail to develop normally. This study involves testing samples from New York State and from the collaborative group that formed the National Birth Defects Prevention Study. IRB clearances have now been obtained and samples selected. Copy number variant testing will begin shortly. We will be collaborating with another consortium following up on our work described in last year's report on craniosynostosis (see Justice et al. Nature Genetics). The previous work focused on saggital craniosynostosis. The future work will expand on this to look for genetic factors associated with defects in other sutures. This work has received external funding and is ongoing. We have established a collaboration with the Statens Serum Institut in Copenhagen, Denmark to examine genetic factors in congenital hydrocephalus. We have identified samples for confirmatory testing of SNPs from their GWAS study.

已从大约 20 种主要畸形中获取 DNA，用于当前和未来的研究。我们最近扩大了调查范围，包括搜索罕见缺陷中的拷贝数变异。纽约拥有极其宝贵的研究资源，每年约有 250,000 名新生儿可以从中识别出患有罕见缺陷的儿童。除了经典的候选基因方法外，还选择病例进行拷贝数变异研究。为拷贝数变异测试选择的许多条件的实验室工作现已完成。已在多种感兴趣的条件下鉴定了拷贝数变异。我们已经完成了异位相关拷贝数变异的研究；写出结果；他们已发表在《医学遗传学》上。我们对后尿道瓣膜拷贝数变异的分析已经完成并提交发表。 Klippel Trenaunay Weber 综合征的分析已经完成，手稿正在准备中。对李子腹综合症的分析已经完成，并将准备手稿。对埃布斯坦异常现象的分析将很快完成，并准备一份手稿。我们还与大型团体合作进行全基因组关联研究。我们在特发性肥厚性幽门狭窄（IHPS）方面的工作值得注意。 IHPS 是一种严重疾病，其中幽门括约肌层肥大导致胃出口梗阻。婴儿肥厚性幽门狭窄表现出很强的家族聚集性和遗传性，但对特定遗传风险变异的了解有限。我们之前与丹麦和瑞典的研究人员合作，对候选基因进行了全基因组搜索。我们在染色体 11q23.3 发现了一个新的全基因组重要的 IHPS 位点。这些发现已发表在《美国医学会杂志》上。我们正在扩大对幽门狭窄的研究范围，将其他基因纳入其中。我们已经与疾病预防控制中心的国家出生缺陷预防研究启动了新的合作。我们将与爱荷华大学的保罗·罗米蒂博士一起寻找与后鼻孔闭锁相关的遗传因素，后鼻孔闭锁是一种鼻道无法正常发育的缺陷。这项研究涉及测试来自纽约州和国家出生缺陷预防研究合作小组的样本。现已获得 IRB 许可并已选定样品。拷贝数变异测试将很快开始。我们将与另一个联盟合作，跟进去年的颅缝早闭报告中描述的工作（参见 Justice 等人的 Nature Genetics）。之前的工作重点是矢状颅缝早闭。未来的工作将在此基础上扩展，寻找与其他缝线缺陷相关的遗传因素。这项工作已获得外部资助并且正在进行中。我们与丹麦哥本哈根的 Statens 血清研究所建立了合作，以检查先天性脑积水的遗传因素。我们从他们的 GWAS 研究中确定了用于 SNP 验证性测试的样本。