Forward genetic analysis of congenital craniofacial malformations

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Craniofacial anomalies are among the most common congenital birth defects (>1 in 700 live births) with a large, but poorly understood, genetic component. The overall objective of this application is to take a human genetic approach to identify the genetic causes of congenital craniofacial malformations with complementary animal model studies. Our central hypothesis is that careful selection (based on pedigree analysis, phenotypic presentation, etc.) and genomic sequencing of pedigrees will allow us to identify novel causes of craniofacial malformations and facilitate experiments to uncover the underlying mechanisms. The rationale of this proposed research is that identification of variants causing craniofacial malformations will improve our understanding of the underlying pathogenic mechanisms, inform patient counseling, and ultimately lead to improved diagnosis, treatment, and patient care. We plan to test this central hypothesis and accomplish the goals of this application by pursuing the following specific aims: 1) use whole genome sequencing to identify variants leading to human syndromic cleft lip and palate, 2) determine the mechanism of Fzd2 truncation pathogenesis in skeletal development, and 3) perform functional analysis of candidate variants in novel human craniofacial malformations. Aim 1 will be accomplished by whole genome sequencing of selected patients from our CCHMC cohort. In Aim 2, we will further study a novel mouse model of FZD2 omodysplasia to evaluate the role on non-canonical Wnt signaling in this disorder. In Aim 3, we will apply our expertise in creation and study of mouse models to understand the molecular mechanism of variants identified in affected human probands. The results from this proposal will further identify genes essential for human craniofacial development and have direct and persistent relevance for craniofacial developmental biology, human genetics and genetic counseling. By identifying novel roles for single genes, entire gene regulatory networks can often be implicated which can dramatically increase the range of potential therapeutic targets. Moreover, the novel animal models generated as part of these studies can be further utilized as tools for understanding basic mechanism(s) of disease and potentially as platforms for testing therapeutic interventions in future studies. For clinicians, increased understanding of the specific genes involved in craniofacial development and connectivity leads to more effective diagnosis, treatment, risk-assessment, and family planning.