BRAIN STRUCTURE AND FUNCTION IN CHILDREN WITH ORAL CLEFTS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。口裂是人类先天缺陷的重要组成部分。唇腭裂影响约1/700的出生，与地理来源和社会经济地位有关的变异性很大。这些口裂是颅面发育异常的结果，至少部分是由于神经嵴细胞不能正常迁移。作为一个群体，70%的分裂障碍是由那些孤立的面裂只（非综合征），30%是那些面裂是一个明确的综合征的一部分，额外的异常。非综合征性唇腭裂发生在高加索人中，每1,000例活产婴儿中约有1例，在解剖学上进一步分为唇腭裂（CLP）和仅腭裂（CPO）。 非综合征性唇腭裂（NSCLP）的病因是复杂的，遗传和环境因素都起作用。遗传流行病学研究表明，几个相互作用的位点，包括一个主基因，参与了非小细胞肺癌的病因，可能占约一半的家族发生。基于表达、转基因动物中的表型、突变和小鼠或人中的连锁/关联，许多候选基因已被鉴定为参与NSCLP。关于它们在NSCLP中的作用，似乎具有最强数据的三个基因是MSC 1（同源结构域基因）、TGFA和TGFB 3（生长因子基因）。 本研究有以下假设：1）与年龄和性别匹配的健康对照组相比，NSCLP儿童的脑形态学异常。2)与健康对照组相比，患有NSCLP的儿童将表现出认知功能障碍，具有一般智商的总体轻度抑郁模式，以及表达语言和执行功能的更具体的缺陷。相当大比例的人也会表现出明显的社会抑制。3)脑形态学的异常将以下列方式与认知功能的异常相关：（a）IQ与前脑体积之间将存在负相关，而IQ与后脑体积之间将存在正相关。(b)语言功能障碍与左颞叶结构异常有关。(c)此外，额叶皮层腹侧的形态学与社会功能有关。4)大脑异常的程度（结构和功能）将与口腔裂的程度相关。5)脑结构异常与TGFA、TGFB 3和MSX 1的遗传变异之间存在显著相关性。6)女性会有与男性相同的大脑异常模式，但程度较低。女性也会表现出较轻程度的语言障碍和社会功能障碍。

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.