Conotruncal defects (CTDs) comprise 36% of all congenital heart defects and carry significant morbidity. Although their etiology is poorly defined, data suggest that complex genetic mechanisms contribute to their etiology. This Program will define the genetic basis of CTDs. Molecular evaluation of genetic syndromes with CTDs have provided valuable insight into their genetic basis. In particular, studies on the 22q11.2 deletion syndrome defined a large CTD population, identified genes (e.g. TBX1) and developmental pathways contributing to cardiac development and disease. To continue this work, Project 1 will identify genetic modifiers of CTDs in an exceptional, large 22q11.2 deleted patient cohort using genome wide approaches. In Project 2, genome wide studies in a unique, large non-syndromic patient CTD cohort will be completed to identify both case (inherited) and maternal genetic effects. Discoveries made in one patient cohort will be examined for significance in the other. Mouse models based on 22q11 DS will be used to elucidate developmental pathways critical to conotruncal morphogenesis. Genes and developmental pathways described in the mouse models will be examined for disease associated genetic variants in each of the two patient cohorts, and discoveries in Projects 1 and 2 will in turn be examined in the mouse for expression pattern and placement in key developmental pathways. Candidate genes from these studies will be subject to deep sequencing to identify the full range of disease related genetic variants. The proposed studies are highly interactive, leverage unique patient cohorts and mouse models, build upon long standing collaborations, and test the hypotheses that: (1) the 22q11.2 deleted cohort will serve to unmask genetic risk factors for the characteristic cardiac defects, (2) these risk factors apply to the non-syndromic cardiac cohort, and (3) critical developmental pathways can be elucidated in the mouse whose gene members are disease- related in humans. These studies wilt greatly expand our understanding of the genetic basis of CTDs, and will promote the development of novel therapeutic and preventive strategies.
The goal of this project is to understand the genetic causes of congenital heart defects. Project 1 is to find genetic modifiers of heart defects in 22q11 DS. Project 2 is to find genetic risk factors for non-syndromic conotruncal heart defects and Project 3 will use mouse models to help determine which of the candidates identified in Projects 1 and 2 function in cardiac development.
|Jackson, Abigail; Kasah, Sahrunizam; Mansour, Suzanne L et al. (2014) Endoderm-specific deletion of Tbx1 reveals an FGF-independent role for Tbx1 in pharyngeal apparatus morphogenesis. Dev Dyn 243:1143-51|
|Agopian, A J; Mitchell, Laura E; Glessner, Joseph et al. (2014) Genome-wide association study of maternal and inherited loci for conotruncal heart defects. PLoS One 9:e96057|
|Wang, Tao; Zhou, Baiyu; Guo, Tingwei et al. (2014) A robust method for genome-wide association meta-analysis with the application to circulating insulin-like growth factor I concentrations. Genet Epidemiol 38:162-71|
|Castellanos, Raquel; Xie, Qing; Zheng, Deyou et al. (2014) Mammalian TBX1 preferentially binds and regulates downstream targets via a tandem T-site repeat. PLoS One 9:e95151|
|Yi, James J; Tang, Sunny X; McDonald-McGinn, Donna M et al. (2014) Contribution of congenital heart disease to neuropsychiatric outcome in school-age children with 22q11.2 deletion syndrome. Am J Med Genet B Neuropsychiatr Genet 165B:137-47|
|Schneider, Maude; Debbané, Martin; Bassett, Anne S et al. (2014) Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry 171:627-39|
|Kong, Ping; Racedo, Silvia E; Macchiarulo, Stephania et al. (2014) Tbx1 is required autonomously for cell survival and fate in the pharyngeal core mesoderm to form the muscles of mastication. Hum Mol Genet 23:4215-31|
|Widdershoven, Josine C C; Bowser, Mark; Sheridan, Molly B et al. (2013) A candidate gene approach to identify modifiers of the palatal phenotype in 22q11.2 deletion syndrome patients. Int J Pediatr Otorhinolaryngol 77:123-7|
|Delio, Maria; Guo, Tingwei; McDonald-McGinn, Donna M et al. (2013) Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes. Am J Hum Genet 92:439-47|
|McDonald-McGinn, Donna M; Fahiminiya, Somayyeh; Revil, Timothee et al. (2013) Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS. J Med Genet 50:80-90|