Recent advances in clinical genetics, epidemiology, developmental biology and molecular genetics have provided greatly expanded opportunities to identify the specific etiology underlying inherited forms of craniofacial anomalies. Clinical and population genetic studies suggest there may be in excess of 200 individual inherited causes of cleft lip and palate alone. While this extensive heterogeneity creates complexities, it also provides considerable opportunity for identification of specific genes that may play a role in these conditions. We have identified one specific gene, transforming growth factor alpha (TGF-alpha) as associated with non- syndromic cleft lip and palate in Caucasian populations. This has recently been validated in studies from three other centers, as well. We have also been able to identify the linkage relationships of the Van der Woude syndrome (VWS), an autosomal dominant form of clefting, and have shown that it is linked to markers at 1q32. To extend these studies and to look for etiologic genes in a broader spectrum, it is essential that we gain access to well characterized clinical material from as many areas as possible. Dr. Antonio Richieri-Costa has such material in a Brazilian population, including not only non-syndromic cleft lip and palate, but several syndromic forms of clefting, many of which have been explicitly defined, or had their definitions improved by him. In this proposal, we would like to establish a formal collaboration that would allow Dr. Richieri-Costa's group to carry out preliminary analysis on biological material in Brazil which can then be characterized in more detail by our own laboratory in Iowa. The goal of the project would be to study three populations: 1) non-syndromic cleft lip and palate, 2) VWS, and 3) new forms of clefting. We will look for continued association, linkage or evidence of gene rearrangements respectively using the variety of candidate genes we've already identified. This project would allow expansion of current studies to a broader base of racial and ethnic groups and also make use of a very well characterized clinical population currently under study. It provides the opportunity for identification of both new genes and new alleles of existing genes as being etiologic in craniofacial anomalies and will greatly extend the molecular biologic approach to this series of disorders.