This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this study is to characterize a number of phenotypic and genetic features in a sample of multiplex CL/P families and matched, population-based controls with the aim of extending the phenotype of nonsyndromic CL/P. The population under study includes three sites: southwestern Pennsylvania, St. Louis, Missouri, and West Virginia. From 50-75 multiplex CL/P families will be ascertained through the Pittsburgh Cleft Palage-Craniofacial Center (Pitt), about 370 total individuals. In addition, 40-50 multiplex CL/P families will be ascertained through the Cleft Lip/Palate Center of St. Louis Children's Hospital (St. Louis), about 320 total individuals; and 15-20 families from the West Virginia University Cleft Palate Center (WVU), about 150 total individuals. Therefore, 110-155 families with about 840 total family members will be ascertained. In addition, controls matched on gender and age to each multiplex family member will be ascertained at each site for another approximately 840 individuals. Each participant at each site will follow the same research protocol; briefly, an ultrasound will be taken of the upper lip (orbicularis oris), handedness will be assessed dermatoglyphic patterns will be recorded, measurements of the face will be taken (for electronic measurement of the craniofacies), VPI will be assessed by perceptual methods, and blood samples will be obtained for DNA extraction. At least 12 candidate genes will be comprehensively studied during the four years of this project. Each phenotypic feature, including CL/P, will be analyzed separately and in linear combinations of one or more features. The correlational structures of the features will be explored, as will be principal components if there is significant multi-co-linearity. Segregation analysis methods will assess the inheritance patterns for each feature, and for linear combinations of features. Linkage analysis methods will be used to assess linkage with each locus versus each phenotypic feature (and combinations of features). Both parametric and nonparametric approaches will be used. In addition, variance components analyses will be utilized for the many quantitative measures, individually and in combinations. For regions or candidate markers with positive results, a combination of bioinformatic and laboratory techniques will be used to identify and/or characterize genes.
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