The Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Birth Defects Res. 2017 Mar 1;109(4):271-295. doi: 10.1002/bdra.23609. Epub 2017 Feb 13.
Previous studies using different cardiac phenotypes, technologies and designs suggest a burden of large, rare or de novo copy number variants (CNVs) in subjects with congenital heart defects. We sought to identify disease-related CNVs, candidate genes, and functional pathways in a large number of cases with conotruncal and related defects that carried no known genetic syndrome.
Cases and control samples were divided into two cohorts and genotyped to assess each subject's CNV content. Analyses were performed to ascertain differences in overall CNV prevalence and to identify enrichment of specific genes and functional pathways in conotruncal cases relative to healthy controls.
Only findings present in both cohorts are presented. From 973 total conotruncal cases, a burden of rare CNVs was detected in both cohorts. Candidate genes from rare CNVs found in both cohorts were identified based on their association with cardiac development or disease, and/or their reported disruption in published studies. Functional and pathway analyses revealed significant enrichment of terms involved in either heart or early embryonic development.
Our study tested one of the largest cohorts specifically with cardiac conotruncal and related defects. These results confirm and extend previous findings that CNVs contribute to disease risk for congenital heart defects in general and conotruncal defects in particular. As disease heterogeneity renders identification of single recurrent genes or loci difficult, functional pathway and gene regulation network analyses appear to be more informative. Birth Defects Research 109:271-295, 2017. © 2017 Wiley Periodicals, Inc.
先前的研究使用不同的心脏表型、技术和设计，表明在患有先天性心脏缺陷的患者中存在大量、罕见或新生的拷贝数变异（CNVs）负担。我们试图在没有已知遗传综合征的大量法洛四联症和相关畸形患者中识别与疾病相关的 CNVs、候选基因和功能途径。
病例和对照样本分为两个队列进行基因分型，以评估每个受试者的 CNV 含量。进行分析以确定总体 CNV 患病率的差异，并确定相对于健康对照，法洛四联症病例中特定基因和功能途径的富集。
仅呈现两个队列中均存在的发现。从 973 例总法洛四联症病例中，两个队列均检测到罕见 CNVs 的负担。基于与心脏发育或疾病的关联，以及/或在已发表的研究中报道的其破坏作用，从两个队列中发现的罕见 CNVs 中鉴定出候选基因。功能和途径分析显示，与心脏或早期胚胎发育相关的术语显著富集。
我们的研究测试了一个专门针对心脏法洛四联症和相关畸形的最大队列之一。这些结果证实并扩展了先前的发现，即 CNVs 导致先天性心脏缺陷的疾病风险增加，特别是法洛四联症。由于疾病异质性使得识别单个反复出现的基因或基因座变得困难，因此功能途径和基因调控网络分析似乎更具信息量。出生缺陷研究 109:271-295, 2017。© 2017 Wiley Periodicals, Inc.
