Oral clefts are complex and heterogenous birth defects, and genetic factors are clearly important in their etiology. It has proven difficult, however, to map susceptibility genes through linkage studies. We have been involved in family studies of oral clefts for some time, and have accumulated a number of multiplex families (i.e., those ascertained through two or more probands with an oral cleft) suitable for linkage analysis. As part of the Comprehensive Center for Oral Health Research, we propose to use multiplex families ascertained from four collaborating centers (Mid-Atlantic region of the U.S., Mexico City, Buenos Aries and Prague) to conduct a genome wide search for susceptibility genes. Recent advances in technical methods now make it possible to genotype large numbers of markers on individuals in multiplex families and recent statistical advances make it easier to test for linkage heterogeneity when mapping a complex disorder such as oral clefts.
The specific aims of this study are: 1) To conduct a genome wide search for susceptibility loci using multiplex families ascertained from our collaborating centers: Mid-Atlantic, Mexico City, Buenos Aires, and Prague. This mapping effort will focus on efforts to detect linkage and test for linkage heterogeneity, both among families drawn from different populations and within samples of families from a single population. Admixture tests for linkage heterogeneity and conditional approaches for identifying linkage from multiple markers will be employed. 2) To fine map chromosomal region suggesting linkage using these same individuals to identify variant alleles that could be responsible for oral clefting. Results of this study should yield a better understanding of the gene or genes contributing to risk of oral clefts and may suggest strategies for either preventing these birth defects or for identifying individuals at highest risk.
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