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。 右心发育不良综合征是一种罕见的先天性心脏病，其特征是右心结构发育不全和畸形。家族性复发提示遗传因素可能是其病因之一。我们的研究调查了HRHS病例中拷贝数变异（CNVs）的存在。我们使用Illumina HumanOmni2.5-8阵列对整个加州（2003-2010年）从活产婴儿中鉴定的42例HRHS病例进行基因分型。根据CNVs中包含的基因及其功能，我们在14例HRHS病例（33%）中确定了14个候选CNVs。在两个不相关的病例中发现了ERBB 4的重复重叠部分。ERBB 4是一种神经调节蛋白受体，在心肌细胞分化和心脏发育中起关键作用。我们还描述了在16 q11 -12的7.5 Mb重复。重复区域中的多个基因先前与心脏缺陷和心脏发育有关，包括RPGRIP 1 L，RBL 2，SALL 1和MYLK 3。在14个经验证的CNV中，我们鉴定了4个与Wnt信号通路相关基因非常接近的CNV。这项研究扩展了我们以前的工作，支持遗传学在HRHS中的作用。我们鉴定了影响右心发育的关键基因和信号通路的CNVs。ERBB 4和16 q11 -12区域的重复是未来研究的重要领域。 由于获得了额外的资金，该研究已扩展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，我们也应该能够确定来自纽约的受试者，以验证我们在加州的调查结果。这项额外的工作已获得加州州提供生物标本的许可。 我们已收到来自加州州的关于目标缺陷的样本和数据。 基因组研究正在进行中。

We have expanded our collaboration with The California Department of Health and Stanford University. Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdeveloped and malformed structures of the right heart. Familial recurrence of HRHS indicates genetic factors contribute to its etiology. Our study investigates the presence of copy number variants (CNVs) in HRHS cases. We genotyped 42 HRHS cases identified from live births throughout California (2003-2010) using the Illumina HumanOmni2.5-8 array. We identified 14 candidate CNVs in 14 HRHS cases (33%) based on the genes included in the CNVs and their functions. Duplications overlapping part of ERBB4 were identified in two unrelated cases. ERBB4 is a neuregulin receptor with a pivotal role in cardiomyocyte differentiation and heart development. We also described a 7.5 Mb duplication at 16q11-12. Multiple genes in the duplicated region have previously been linked to heart defects and cardiac development, including RPGRIP1L, RBL2, SALL1, and MYLK3. Of the 14 validated CNVs, we identified four CNVs in close proximity to genes linked to the Wnt signaling pathway. This study expands on our previous work supporting the role of genetics in HRHS. We identified CNVs affecting crucial genes and signaling pathways involved in right heart development. ERBB4 and duplication of the 16q11-12 region are important areas for future investigation. This study has been expanded since additional funding has become available 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. This additional work has received permission from the State of California to provide biospecimens. We have received samples and data regarding the target defects from the state of California. The genomic studies are underway.