The Genetics of Specific Language Impairment

描述（由申请人提供）：语言学和心理学理论结合语言发展和语言障碍个体差异遗传性的实证研究，支持人类语言发展能力受基因影响的假设。这项研究将通过研究具有特殊语言障碍（SLI）的个体来进一步了解这种基因对语言的影响，这些个体尽管有正常的语言经验、感觉能力和非语言智力，但语言发育却很差。患有特殊语言障碍的个体提供了一种极好的方法来识别数量性状基因位点，这些基因位点可能会导致语言发展和使用方面的全面个体差异。拟议的研究将使用两种互补的策略。首先，它将利用两名患有严重发育性言语和语言障碍的TB患者，他们也有染色体易位，似乎与FOXP2基因有关。FOXP2基因是一种与发育性语言障碍有关的调节基因。这一策略将把这两个人的神经解剖学、神经生理学和神经心理学特征与他们未受影响的家庭成员进行对比。这项工作将强调程序和陈述式学习系统以及词汇和句子的使用。因此，这一策略从基因转向语言表现型，以了解基因和表现型之间的神经和认知途径。第二种策略将使用大量的流行病学样本，包括患有特殊语言障碍的年轻成年人及其兄弟姐妹，他们参加了一项为期10年的纵向研究。人们对这些人的语言状况以及相关情况进行了广泛的研究。此外，已经从SLI先证者、兄弟姐妹和他们的父母那里获得了DNA样本。因此，通过使用兄弟姐妹对连锁方法的高密度全基因组筛选和使用传播不平衡测试（TDT）的后续精细定位方法，可以获得一个有价值的组织和表型数据库来识别基因。此外，根据我们实验室和其他实验室的发现，候选基因和感兴趣区域的精细定位将与微缺失研究一起进行。将对SLI先证者和兄弟姐妹进行额外的表型分析，以获得程序性和陈述性学习测量以及额外的语言测量，这些测量与从结核病家庭获得的数据平行。学习措施是作为可能对遗传影响更敏感和特异性的内生表型。来自这些个体的表型和内表型将与现有的基因分型一起用于额外的全基因组筛选和进一步的后续精细定位研究。

DESCRIPTION (provided by applicant): Linguistic and psychological theory coupled with empirical studies on the heritability of individual differences in language development and language disorders support the hypothesis that the capacity for language development in humans is genetically influenced. The proposed research will provide for further understanding of this genetic influence on language by studying individuals with specific language impairment (SLI) who have poor language development despite normal linguistic experience, sensory abilities, and nonverbal intelligence. Individuals with SLI provide an excellent means of identifying quantitative trait genetic loci that are likely to contribute to the full range of individual differences in language development and use. The proposed research will use two complementary strategies. First, it will take advantage of two individuals (TB) with severe developmental speech and language impairment, who also have a chromosomal translocation that appears to involve the FOXP2 gene. The FOXP2 gene is known to be a regulatory gene implicated in developmental speech and language disorder. This strategy will contrast the neuroanatomical, neurophysiological, and neuropsychological characteristics of these two individuals with their unaffected family members. This work will emphasize the procedural and declarative learning systems and vocabulary and sentence use. Thus, this strategy moves from gene to language phenotype to understand the neurologic and cognitive pathways between gene and phenotype. The second strategy will use a large epidemiologic sample of young adults with SLI along with their siblings who have participated in a 10-year longitudinal study. The language status, as well as associated conditions of these individuals, has been studied extensively. Furthermore, DNA samples have already been obtained from the SLI probands, siblings, and their parents. Thus, a valuable data bank of Doth tissue and phenotypes is available to identify genes by means of high density genome-wide screens using sib-pair linkage methods and follow-up fine mapping methods using transmission disequilibrium tests (TDT). Additionally, ongoing fine mapping of candidate genes and regions of interest informed by findings from our laboratories and other laboratories will be carried out along with microdeletion studies. Additional phenotyping of the SLI probands and siblings will be conducted to obtain procedural and declarative learning measures and additional language measures that parallel the data to be obtained from the TB family. The learning measures are to serve as endophyenotypes that may be more sensitive and specific to genetic influence. The phenotypes and endophenotypes from these individuals will then be used in conjunction with the existing genotyping for additional genome-wide screens and further follow-up fine mapping studies.