BRAIN STRUCTURE AND FUNCTION IN CHILDREN WITH ORAL CLEFTS

点击翻译按钮获取中文摘要

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. Oral clefts comprise a significant component of morbid human birth defects. Clefts of the lip and palate affect about 1/700 births with wide variability related to geographic origin and socioeconomic status. These oral clefts are developmental craniofacial abnormalities that result, at least in part, from a failure of neural crest cells to migrate properly. As a group, 70% of clefting disorders are comprised of those that are isolated to facial clefts only (non-syndromic), and 30% are those in which the facial cleft is part of a well-defined syndrome of additional anomalies. Nonsyndromic oral clefts occur in approximately 1 per 1,000 live births among Caucasians and are further divided anatomically into clefts of the lip and/or palate (CLP) and clefts of the palate only (CPO). The etiology of non-syndromic clefts of the lip and/or palate (NSCLP) is complex with both genetic and environmental factors having a role. Genetic epidemiological studies have shown that several interacting loci, including a major gene, are involved in the etiology of NSCLP, possibly accounting for approximately one-half of the familial occurrences. A number of candidate genes have been identified as being involved in NSCLP based on expression, phenotype in transgenic animal, mutations, and linkage/associations in mice or humans. Three genes that appear to have the strongest data regarding their role in NSCLP are MSC1 (a homeodomain gene), TGFA and TGFB3 (growth factor gene). This study has the following hypotheses: 1) Children with NSCLP will have abnormal brain morphology compared to age and sex matched healthy controls. 2) Children with NSCLP will show cognitive dysfunction compared to healthy controls with a pattern of overall mild depression of general IQ, and more specific deficits in expressive language and executive functions. A substantial proportion will also show significant social inhibition. 3) The abnormalities in brain morphology will correlate with abnormalities in cognitive function in the following manner: (a) There will be an inverse correlation between IQ and anterior cerebral volume and a positive correlation between IQ and posterior cerebral volume. (b) Disturbed language function will be associated with abnormalities of left temporal lobe structures. (c) In addition, morphology of the ventral aspect of the frontal lobe cortex will be related to social function. 4) Degree of brain abnormality (structure and function) will be associated with degree of oral clefting. 5) There will be a significant correlation between abnormalities in brain structure and genetic variation in TGFA, TGFB3 and MSX1. 6) Females will have the same pattern of brain abnormalities as males, but to a lesser degree. Females will also show a milder degree of language impairment and social dysfunction.