Congenital heart defects (CHD) are the leading cause of morbidity and mortality in infants, affecting nearly 1% of live births. The genetic architecture that underlies CHD is only beginning to be understood, but most approaches are limited by grouping a large variety of etiological forms of CHD. Further, these studies exclude those with Down syndrome (DS), although DS forms one of the largest identifable groups among those with CHD. We have taken a different strategy to discover CHD susceptibility genes: 1) we focus on DS (or trisomy 21), a population highly sensitized to CHD and 2) we focus on atrioventricular septal defects (AVSD), a severe septal defect that occurs in 20% of those with DS compared with 1/10,000 among those with euploid chromosome constitution. While increased dosage of chromosome 21 genes clearly contributes to this risk, trisomy 21 is not sufficient by itself to cause CHD; close to 50% of infants with DS have structurally normal hearts. Thus, additional modifying genetic and environmental factors must exist. We hypothesize that fewer modifying variants are necessary to exceed the liability threshold compared with that for euploids; that is, trisomy 21 essentially takes the place of multiple modifiers, so that fewer predisposing mutations are required to result in AVSD. With NIH resources, whole genome sequences (WGS) will be available on approximately 600 DS+AVSD, 600 DS with other CHDs (DS+oCHD) and 900 individuals with DS and structurally normal hearts (DS+NH) by the end of June 2020, all linked to cardiac and extra-cardiac phenotypes. The goal of this R03 is to analyze these first-of-their-kind data from individuals with DS to achieve the following aims: 1) characterize the genetic architecture of high-frequency DS-associated AVSD, 2) identify potential shared genetic risk among DS-associated CHD subtypes, and 3) explore pleiotropic effects of CHD-susceptibility genes. The results from this study will generate new hypotheses about biological pathways associated with abnormal heart development due to trisomy 21. This proposal completely aligns with the goals of the trans-NIH INCLUDE project and will be done in parallel to their effort to build a new cohort that can be used for replication and testing of new hypotheses generated through this proposed. Our goals and that of NIH?s INCLUDE and TOPMed projects, are to identify potential prevention and treatment targets to move towards precision medicine for individuals DS and to translate these successes to those without DS.

Public Health Relevance

Children with Down syndrome (DS), which occurs due to trisomy 21, have a 2000-fold increased risk of atrioventricular septal defects and a 50-fold increased risk of congenital heart defects overall, but why this increased vulnerability exists in unknown. The aim of this study is to identify genetic variants underlying this increased risk in children with DS. Insights into the genes and perturbed pathways that drive this risk for abnormal heart development will have implications for improved genetic counseling, surveillance, clinical management, and treatment strategies for both children with and without DS.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1)
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Li, Huiqing
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Emory University
Schools of Medicine
United States
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