GPMLS-BMC Seminar will be Tuesday, 17th March at 12:00 in Room 201 in Læknagarður

Speaker: Professor Robert A. Cornell, Department of Anatomy and Cell Biology, University of Iowa.

Title: Orofacial clefting: using zebrafish to identify candidate risk loci and the connections between genetic risk and pathogenic mechanisms. 

Short abstract: Orofacial clefts are a common structural birth defect with environmental and genetic underpinnings. Approximately half of the heritable risk for orofacial clefts remains unassigned to specific loci. For instance, in Van der Woude syndrome, which includes orofacial cleft, most but not all patients harbor mutations in coding sequence of IRF6.  To identify additional cleft-risk candidate loci we analyzed the gene regulatory network operating downstream of Irf6 in zebrafish periderm and identified Grhl3 as a key effector of Irf6 in this tissue. Concurrently, colleagues identified missense variants of GRHL3 in subset of patients with Van der Woude syndrome lacking mutations in IRF6. We found these variants had dominant negative activity in zebrafish periderm development. In addition, genome-wide association studies (GWASs) have identified multiple regions strongly associated with risk for non-syndromic orofacial clefts, but causal variants are unknown. To address this, our colleagues selected 13 regions from GWASs and other studies, performed targeted sequencing in 1,409 Asian and European trios, and carried out statistical analyses to identify candidates for causal variants.  We carried out functional analyses of several such variants using assays in vitro and in zebrafish. The results implicate a de novo variant in PAX7 coding sequence, rare variants in AHRGAP29 coding sequence, and de novo and common variants in non-coding regulatory sequence near FGFR2 and FOXE1, respectively, in pathogenesis of nonsyndromic orofacial clefts. In summary, functional tests in zebrafish have helped to connect genetic risk to pathological mechanism for a common birth defect.