Defining Oligogenic Mechanisms Involved in CHD
It has been long thought that CHD has oligogenic origins given that monogenic causes are rarely identified. However, the field does not currently have sufficient cases to bioinformatically derive oligogenic mechanisms or polygenic risk scores. Similarly, until recently it was also difficult to pursue multigenic hypotheses experimentally due to technical limitations. In our lab, we perform high-throughput CRISPR screens in human induced pluripotent stem cell-derived populations to identify genetic interactions necessary for faithful differentiation of cell types found in the heart. We then perform genetic association studies using essential genetic interaction networks to identify the combinations of genes whose collective mutation is associated with CHD. This approach is currently being pursued to identify causes of defects such as hypoplastic left heart syndrome and left ventricular noncompaction.
Exploring the Link Between CHD and Neurodevelopmental Delay
The incidence of neurodevelopmental delay disorders (NDD), such as autism, is higher in CHD patients compared to control cohorts. While there are multiple hypotheses regarding this connection, there is a shared genetic association; patients that suffer from both CHD and NDD show enrichment of variants in genes that encode chromatin modifiers. However, there is limited experimental evidence that these variants negatively impact the development of afflicted cell types. We are using hiPSC differentiation to study the molecular perturbations that result from these mutations and to understand which mutations are sufficient to produce the specific phenotypes observed in patients. An additional hypothesis we are pursuing is that a subset of previously identified mutations acts as modifiers and that the causative mutation(s) remains unidentified.
Identifying Cellular Interactions Involved in Cardiovascular Development
The coincident development of multiple cell types is crucial for faithful heart development. There is increasing evidence that congenital heart disease can arise when endothelial cell specification is disrupted. Signals emanating from the endocardium in particular provide instruction to cardiomyocytes regarding their organization and maturation. Cardiac neural crest and pharyngeal endoderm additionally contribute in both direct and indirect ways to cardiovascular development. One of the goals in our lab is to develop the tools required to study the interactions between these cell types using hiPSC differentiation. These tools could then be used to disentangle cell autonomous and non-autonomous relationships that contribute to human heart development.