The 22q11.2 deletion syndrome (22q11DS) is a congenital anomaly disorder occurring in 1/4,000 live births. It is occurs due to a 3Mb deletion of chromosome 22 at band q11.2. Approximately 70% of children with 22q11DS have congenital heart disease of the conotruncal type (CTD), while 30% have no cardiac malformations as determined by echocardiography. It is likely that many factors such as stochastic events, environmental exposures and specific genes or gene pathways play a role in modifying the phenotype. This project proposes to explore and discover genetic factors that underlie the differences between 22q11DS patients with and those without a CTD. To identify genetic modifiers of CTDs, we have performed a genome- wide CNV and SNP association study of 650 22q11DS subjects using Affymetrix 6.0 arrays. We have found rare CNVs of biological interest. To enhance the significance of the CNV findings and SNP associations, we propose to expand the study of already identified rare and common CNVs by expanding the cohort to include a total of 1,150 22q11 DS patients. Thus, we will run 500 additional Affymetrix 6.0 microarrays. A GWAS will be performed on the entire cohort for SNP based modifier loci. We will compare our candidate loci with results from Project 2. Project 2 will perform a replication of their previous GWAS of non-syndromic CTD patients and normal controls, by adding 700 additional cases and additional controls to identify risk factors for CTDs. We will compare the two datasets to identify loci in common, requiring selected re-genotyping after imputation, as the studies used different platforms (lllumina versus Affymetrix). To confirm that the loci identified are CTD candidate genes, in situ hybridization on mouse embryos will be performed. It is possible that genes in the genetic pathway of TBX1, a gene in the deleted interval, can serve as modifiers. TBX1 encodes a T-box transcription factor, which in mouse models is responsible for many of the features of the 22q11DS. Therefore, 22q11DS mouse models will be evaluated to determine if the genes are in a shared pathway, such as the Tbxl pathway (Project 3). Genetic pathways of relevance that are identified by Project 3 will be examined in the CNVs and SNP loci identified in this Project. Targeted re-sequencing will be performed in an attempt to identify causative genes that modify the CTD phenotype in 22q11DS individuals. The overall outcome of the combined human and mouse program will enable us to systematically explore genetic risk factors for CTDs. This project will expand our understanding of the genetic basis of CTDs, and provide a first step towards the development of novel therapeutic and preventive strategies.

Public Health Relevance

Congenital heart defects of the conotruncal type occur in 70% of 22q11 DS patients while 30% have no cardiovascular anomalies. Our goal is to find genetic modifiers in our cohort of 1,150 subjects taking genome wide approaches. This work will uncover new genes that may alter risk of heart defects for 22q11 DS and non-syndromic patients. This will be tested by comparing our data to data from Project 2 derived from non-syndromic conotruncal defect subjects.

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Albert Einstein College of Medicine
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Mlynarski, Elisabeth E; Xie, Michael; Taylor, Deanne et al. (2016) Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome. Hum Genet 135:273-85
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