The focus of my research career is to identify the causes of craniofaciai anomalies, which will provide the foundation to develop strategies and therapies to prevent this common group of birth defects. The specific goals of this award are to 1) provide intensive research time in order to accomplish the goals of the research plan; 2) immerse myself in the literature to stay abreast of new discoveries and technologies such that they can be rapidly integrated into this project when warranted; and 3) broaden my expertise in human genetics as well as molecular and developmental biology to allow me to develop a set of life long skills as my career progresses from disease gene identification and molecular characterization, to the development and study of animal models to finally the development and implementation of prevention therapies. Cleft lip with or without cleft palate (CL/P) is a common birth defect. Previous studies have indicated that CL/P is a complex trait that is caused by a combination of genetic and environmental factors. This complexity has limited studies, such that disease mutations have only been identified in one unique family. It is also unlikely that all disease loci have been identified. The overall objective of this project is to identify disease genes involved in nonsyndromic CL/P by applying new multistage linkage and linkage disequilibrium (LD) strategies to affected relative pairs and extended pedigrees. This multistage approach, which has not yet been applied to CL/P, is very powerful in that no prior knowledge about the involved genetic or biological processes is needed. Hypothesis to be tested: Nonsyndromic CLIP is caused by Genetic Variants at one or more loci. To test this hypothesis, CL/P families with both multiple affected members and mother/father and affected child trios will be recruited from a variety of clinical centers. The families will be the basis for initially evaluating candidate genes to test the above hypothesis using the genetic tools of linkage and linkage disequilibrium to reject (exclude) or provide evidence for support (i.e. linkage) the hypotheses. A 10 cM genome-wide screen will also be performed to find additional loci. Positive loci will be further evaluated by a combination of multipoint, multi-locus and TDT/association analyses using more densely spaced markers. It will be through multi-center projects such as this one, in which worldwide collaborations have been established to apply a combination of complimentary genetic strategies, that disease loci for CL/P wilt be identified. Ultimately, this will further the understanding of normal and abnormal craniofacial development, such that therapies to prevent CL/P can be developed and implemented.
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