The focus of my research is craniofacial developmental genetics. Specifically, our goal is to identify the genetic causes of craniofacial birth defects, specifically orofacial clefting which occur in 1/500-1/1000 births. Here in the U.S. most patients are treated in a clinical team setting to coordinate treatment based upon each individual's needs. Rehabilitative care, which extends from birth until at least age 18, includes multiple surgeries, procedures and other interventions. More importantly, the social and psychological ramifications from appearing abnormal can have a very adverse effect on the person and their family.
Since nonsyndromic clefting is a genetically complex trait, we use a variety of strategies to identify disease genes. We have established collaborations to recruit families from unique populations whose ethnicity or genetic heritage increase the likelihood for gene identification. Ongoing collaborations include Dr. Anna Marie Lopez & Mauricio Arcos-Burgos in Medellin, Colombia; Dr. Mary Marazita in Pittsburgh and Dr. Anne Hing in Seattle.
These collaborations have been fruitful leading to the discovery of FOXE1 as a novel gene attributing to 25% of orofacial clefts. The paucity of coding mutations, suggest common causal mutations occur in nearby regulatory elements that control FOXE1 expression. To identify variants that are associated with CL/P and alter the regulation of FOXE1 expression we are implementing 2 parallel approaches. First we are resequencing potential regulatory elements within the FOXE1 critical region to identify DNA variants in patients with CL/P. Second, since the regulatory elements that control FOXE1 expression during craniofacial development have not been characterized, we, in collaboration with Dr. Rob Cornell (Anatomy), have successfully implemented a screening technique using zebrafish. Potential regulatory elements, chosen based on conservation, are cloned into a GFP reporter vector that has a weak promoter such that expression will occur only if the cloned element has regulatory function. In situ hybridization reveals expression of FOXE1 in the ceratobranchial arches (CBA), ceratohyal arch (CTA) and oral epithelium (OE) (Figure 1). Preliminary data indicates a conserved element reproduces endogenous expression (Figure 2).