This is a competitive renewal application for the grant "Brain Structure, Function, and Growth in Children with Oral Clefts" (5RO1 DEO14399-05). The study is designed to evaluate brain structure / function, and growth in subjects with non-syndromic or `isolated clefts of the lip and/or palate'(ICLP). In addition, the study will evaluate the relationship between measures of brain structure/function and genes associated with oral clefts. Clefts of the lip/palate are an aberration in development. In addition to the facial defect, subjects with ICLP also suffer from significant problems in speech, behavior, and cognition. The etiology of these deficits have typically been considered as `secondary'to factors such as hearing deficits during development from chronic otitis media (which is ubiquitous in children with clefts) or even the psychological factors of living with a cleft. However our lab has been the first to consider the notion that the deficits in speech, behavior, and cognition of subjects with ICLP may well be due to a primary problem in brain structure / function. The development of the face and the development of the brain are intimately related, thus it follows logically that an abnormality in facial development may also be accompanied by an abnormality in brain development. However, the study of the neurobiology of ICLP has been virtually non-existent. The initial phase of the proposal has shown that children with ICLP have significantly abnormal brain structure and function. Moreover, these abnormalities are directly related to speech, cognitive function, and behavioral abnormalities. However, the pattern of the brain abnormalities seen in children with ICLP are strikingly different from the pattern of brain abnormalities seen in adults with ICLP. The brain takes an exceedingly long time to develop with late maturational processes of synaptic pruning and myelination taking place through the second decade of life. Therefore, the current proposal is a combination cross-sectional and longitudinal study evaluating the developmental trajectories of brain growth and development from child to adult, ages 7-30 years. Subjects with ICLP will be matched by age and sex to healthy controls. The determinants of brain structure are highly genetic. In addition, several genes have been associated with non-syndromic oral clefting and may play a key role in its pathoetiology (e.g., MSX1, IRF6). It is likely that the genetic determinants of isolated clefting are related to the accompanying abnormalities in brain structure and function. Evaluating the relationship between brain structure/function and genes known to be associated with isolated clefts may shed light on possible etiologic mechanisms at the molecular level. PUBLIC HEALTH RELEVANCE: The study is designed to evaluate brain structure / function, and growth in subjects with non-syndromic or `isolated clefts of the lip and/or palate'(ICLP). In addition, the study will evaluate the relationship between measures of brain structure/function and genes associated with oral clefts.
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