Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. A genome-wide survey of 114 TOF patients and their unaffected parents identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. A second, independent TOF cohort (n = 398) was then examined for additional CNVs at these loci. In 1% (5/512, p = 0.0002, OR = 22.3) of non-syndromic sporadic TOF cases we identified CNVs at chromosome 1q21.1. Recurrent CNVs were also identified at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single TOF case occurred at six loci, two that encode known (NOTCH1, JAG1) disease genes. Our data predicts that at least 10% (4.5–15.5, 95% CI) of sporadic, non-syndromic TOF reflects de novo CNVs and implicates mutations within these loci as etiologic in other cases of TOF.

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Congenital heart disease (CHD) occurs in ∼1% of newborns. CHD arises from many distinct etiologies, ranging from genetic or genomic variation to exposure to teratogens, which elicit diverse cell and molecular responses during cardiac development. To systematically explore the relationships between CHD risk factors and responses, we compiled and integrated comprehensive datasets from studies of CHD in humans and model organisms. We examined two alternative models of potential functional relationships between genes in these datasets: direct convergence, in which CHD risk factors significantly and directly impact the same genes and molecules and functional convergence, in which risk factors significantly impact different molecules that participate in a discrete heart development network. We observed no evidence for direct convergence. In contrast, we show that CHD risk factors functionally converge in protein networks driving the development of specific anatomical structures (e.g., outflow tract, ventricular septum, and atrial septum) that are malformed by CHD. This integrative analysis of CHD risk factors and responses suggests a complex pattern of functional interactions between genomic variation and environmental exposures that modulate critical biological systems during heart development.genetics | transcriptional profiles | systems biology | developmental biology C ongenital heart disease (CHD) is a prevalent birth defect that can occur from genetic variations, environmental exposures, and other factors. Genetic risk factors for CHD include Mendelian mutations, copy number variants (CNVs), translocations, and single nucleotide polymorphisms (SNPs) (1-3). The cardiac responses to some genetic risks have been identified through transcriptional analyses of model organisms engineered to carry human CHD mutations (4). There are many environmental risk factors for CHD, including pesticides and therapeutic agents (5), and some of these are known to target particular genes. Although the cardiac molecular responses to environmental teratogens remain largely unexplored, transcriptional profiles of zebrafish exposed to retinoic acid have been characterized (6). As CHD risk factors and responses rarely incriminate the same genes nor directly impact a limited set of biological pathways, whether these converge on discrete molecular programs involved in heart development is unknown.We used systems biology analyses to integrate the heterogeneous risk factors and response involved in CHD. Given the extraordinary conservation of genes and processes involved in heart development across species (7-10), it is possible to integrate data from humans and model organisms in a straight forward manner. Moreover, our analyses capitalize on a series of previously published and validated functional molecular networks, which direct the development of distinct anatomical structures of the human heart (11). These networks provided a developmental scaffold onto which risk and responder datasets of CHD were assessed. The hypothesis underlying o...

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