NICHD-California Birth Defects Study

我们扩大了与加州卫生部和斯坦福大学的合作。 第一项实验室工作--分析典型异位病例的拷贝数变异--已经完成。分析已经完成，数据已经以抽象的形式呈现出来。一个包含250万个单核苷酸多态(SNPs)的微阵列被用来对从1998-2009年间从加州活产中发现的69例经典异位症病例进行基因分型。用PennCNV软件鉴定CNV。我们确定了56个CNV，这些CNV涵盖了节点(NIPBL，TBX6)、BMP(PPP4C)和WNT(FZD3)信号通路中的基因，以前这些基因与经典的异质性没有关联。我们还发现了一个涉及FGF12的CNV，这是一个以前在典型的异位性病例中发现的基因。多例检测到含有RBFOX1和MIRNA302F的CNV。 我们的发现说明了身体模式路径对心脏发育和左右轴确定的重要性。FGF12、RBFOX1和MIRNA302F在人类异位基因中可能是重要的，因为它们在多个病例中被发现。有必要进一步研究结节、BMP和WNT体型形成途径中涉及的基因，以及FGF12、RBFOX1和MIRNA302F的剂量效应。 来自加利福尼亚州的更多样本已经被识别、选择并提取DNA，以寻找其他先天性心脏缺陷。这些样本目前正在进行拷贝数变异的实验室分析。 这项研究将在2017财年资金到位的情况下扩大到包括其他罕见的非心脏缺陷。由于加州的出生人数非常多，我们预计能够识别出非常罕见的缺陷病例进行调查。由于我们在纽约州的工作，我们也应该能够识别来自纽约的受试者，以验证我们在加利福尼亚州的调查结果。

We have expanded our collaboration with The California Department of Health and Stanford Universiy. The first laboratory work, assaying copy number variants in classic heterotaxy cases was completed. The analysis is complete and data have been presented in abstract form. A microarray containing 2.5 million single-nucleotide polymorphisms (SNPs) was used to genotype 69 cases of classic heterotaxy identified from California live births from 1998-2009. CNVs were identified using PennCNV software. We identified 56 CNVs encompassing genes in the NODAL (NIPBL, TBX6), BMP (PPP4C), and WNT (FZD3) signaling pathways, previously unlinked to classic heterotaxy. We also identified a CNV involving FGF12, a gene previously noted in a classic heterotaxy case. CNVs involving RBFOX1 and MIRNA302F were detected in multiple cases. Our findings illustrate the importance of body patterning pathways for cardiac development and left/right axis determination. FGF12, RBFOX1 and MIRNA302F could be important in human heterotaxy because they were noted in multiple cases. Further investigation into genes involved in the NODAL, BMP, and WNT body patterning pathways and into the dosage effects of FGF12, RBFOX1, and MIRNA302F is warranted. Additional samples from California have been identified, selected and the DNA extracted to look at other congenital heart defects. The samples are currently undergoing laboratory assaying for copy number variants. This study will be expanded, funding being available, in fiscal year 2017 to include other, rare, non-cardiac defects. Because of the very large number of births in California, we anticipate being able to identify cases of very rare defects for investigation. Because of our work in New York State, we also should be able to identify subjects from NY to verify findings from our investigations in California.