Genetic Factors in Birth Defects

已从大约20个主要畸形中获得DNA，用于当前和未来的调查。 我们最近扩大了我们的调查，包括在罕见的缺陷中寻找拷贝数变异。 纽约拥有极其宝贵的研究资源，每年约有25万名新生儿，可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之外，还选择了用于拷贝数变异研究的病例。 实验室工作现已完成，在许多条件下选择的拷贝数变异检测。 拷贝数变异体已在几种感兴趣的条件下鉴定。我们已经完成了对异位相关拷贝数变异的研究，并将结果发表在《遗传学医学》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。 对Klippel Trenaunay Weber综合征的分析已经完成，手稿正在编写中。 梅干腹综合征的分析已经完成，将准备一份手稿。 对Ebstein异常的分析将很快完成，并将准备一份手稿。 我们还与进行全基因组关联研究的大型团体合作。我们对特发性肥厚性幽门狭窄（IHPS）的研究值得注意。 IHPS是一种严重的疾病，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显示出很强的家族聚集性和遗传性，但关于特定遗传风险变异的知识有限。我们之前与丹麦和瑞典的研究人员合作，进行了全基因组的候选基因搜索。我们在染色体11q23.3上发现了一个新的IHPS全基因组显著位点。 这些发现已经发表在《美国医学会杂志》上。我们正在扩大我们对幽门狭窄的研究，包括其他基因。 我们已经开始与CDC的国家出生缺陷预防研究进行新的合作。 我们将与爱荷华州大学的Paul Romitti博士合作，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。 这项研究包括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的许可，并选择了样品。 拷贝数变体检测将很快开始开始。 我们将与另一个财团合作，继续我们在去年关于颅缝早闭的报告中所描述的工作（见Justice et al. Nature Genetics）。 以前的工作集中在矢状面颅缝早闭。 未来的工作将在此基础上扩展，以寻找与其他缝线缺陷相关的遗传因素。这项工作得到了外部资助，目前正在进行中。 我们与丹麦哥本哈根的Statens血清研究所建立了合作关系，以检查先天性脑积水的遗传因素。 我们已经从他们的GWAS研究中确定了用于SNP确证性测试的样本。

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.