Molecular and genetic basis of congenital conotruncal heart defects

Congenital anomalies of the heart are the leading cause of birth defect-related infant morbidity and mortality and are rooted in genetic or environmental disturbances affecting the developing heart. I have studied the development of cardiac progenitor cells present as an undifferentiated subpopulation medially and caudally to the forming heart. Our cell tracing experiments demonstrate that the avian trabeculated free wall of the right ventricle is derived from cardiac precursors that initially formed the myocardial wall of the outflow tract, and that the developmental origin of the right ventricle is evolutionarily conserved in birds and mammals. We also show that subpulmonary myocardium shares a lineage relationship with venous pole precursors and demonstrate that transcription factor Tbx1 controls venous as well as arterial pole development by regulating the segregation of a common cardiac progenitor pool into different sublineages. Using mouse genetics, we show that Tbx1, Tbx2, and Tbx3 constitute a T-box regulatory network that controls arterial pole and pharyngeal development. Our findings highlight the central roles of Tbx1/Tbx2/Tbx3 in conotruncal morphogenesis and identify TBX2 and TBX3 as candidate modifier genes of the cardiopharyngeal phenotypes in TBX1 haploinsufficient 22q11.2DS patients. Lastly, we identified novel candidate genes underlying tetralogy of Fallot (ToF) and propose that non-coding regions, known to be pivotal in the regulation of gene expression and mRNA translation, should be more frequently interrogated for variants and compared with accumulating databases on regulatory elements in order to fully unveil the multigenic etiology of ToF.