The overall goal of this proposal is to contribute to the understanding of the molecular basis for the elevated risk of Atrioventricular Septal Defects (AVSDs) in Down syndrome (DS). AVSDs are a common serious form of Congenital Heart Disease (CHD) and the most common form of CHD in people with DS. AVSD incidence in people with DS is approximately 20%, representing 2000-fold increased AVSD risk compared to the euploid population. This increased risk has not been explained at either the genetic or developmental level. The specific goals of this proposal are to investigate the differentiation and gene expression differences between Down syndrome and isogenic control cardiomyocyte progenitors, differentiated from human induced Pluripotent Stem Cell (iPSC) lines. We apply recent progress in AVSD pathophysiology to nominate a directed approach for investigating the molecular basis of ASVD risk in DS. The deliverables of this proposal will be a set of candidate genes with potential roles in DS AVSD risk. Combined with our deep knowledge of the molecular genetics of AVSD causation in the non-DS population, this data will allow generation of specific and testable hypotheses concerning DS AVSD causation. The proposed discovery are essential for future efforts to identify and interrogate specific candidate genes and pathways altered in DS and responsible for increased AVSD risk. The ultimate aim of this work is improved understanding of the molecular mechanisms of AVSDs in DS, with the potential to shed mechanistic light on AVSD causation.
Down Syndrome, or trisomy 21, causes greatly increased risk for Congenital Heart Disease in humans. The molecular basis for the increased risk is unknown. We will identify Down syndrome-specific gene expression changes in human cardiomyocyte progenitors generated from iPS cells lines to investigate this phenomenon.
