Clefts of the lip and/or palate are common human birth defects that require substantial surgical, dental, speech, and behavioral interventions and impose economic and societal burdens.

While there are many rare causes of clefting disorders, approximately 70% are considered nonsyndromic and the result of the complex interplay of gene-gene and gene-environment interactions. After more than a decade of investigation and relatively modest advances, the last two years has seen the field become excitingly dynamic. We have recently demonstrated significant contributions by the MSX1 and IRF6 genes to cases of nonsyndromic clefting and have just completed the first stage of the largest genome-wide search undertaken to identify genes for clefts. Our genome-wide search has found one novel high probability locus (8p21) in the first 106 families with data analysis almost complete on an additional 164 families. Coupling these successes to a realistic capacity for high throughput genotyping with powerful new statistical approaches affords the opportunity to characterize genetic and gene-environmental causes of clefting with unprecedented power and resolution. In this proposal we will use a large collection of families (over 270) and case parent triads (over 850) from the Philippines with a complimentary set from the United States to carry out gene identification and to provide resources for long term investigations. We will investigate admixture mapping using an African-American cleft population and make use of very powerful gene expression analysis to select candidate genes. The specific aims of this proposal will result in a new understanding of the genetics of nonsyndromic clefts by using gene identification after fine mapping and gene mutation screening. We will characterize gene-gene and gene-environment interactions, and provide a resource for long-term studies in mouse models. Genetic findings will inform developing projects on micronutrient intervention trials to prevent cleft lip and palate. The outcome of this project will be immediate and direct contributions to genetic counseling and prevention and a far better understanding of the basic biology of craniofacial development. It will confirm proof of principle that complex human birth defects can be understood, and diagnosis and prevention improved.