The Genetics of Specific Language Impairment

特定语言障碍的遗传学

• 批准号: 7113770
• 负责人: James Bruce Tomblin
• 金额: $ 62.66万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113770
• 关键词: behavioral /social science research tag; behavioral genetics; clinical research; family genetics; genetic screening; human subject; language development; language disorders; patient oriented research; phenotype; quantitative trait loci; regulatory gene

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.

描述（由申请人提供）：语言和心理学理论以及对语言发育和语言障碍中个体差异遗传性的实证研究支持人类语言发育能力受遗传影响的假设。拟议的研究将通过研究具有特定语言障碍（SLI）的个体来进一步了解这种遗传对语言的影响，这些个体尽管具有正常的语言经验，感官能力和非语言智力，但语言发育不良。SLI个体提供了一个很好的方法来识别数量性状遗传位点，这些基因位点可能有助于语言发育和使用的全面个体差异。拟议的研究将采用两种互补的战略。首先，它将利用两个患有严重发育性言语和语言障碍的个体（TB），他们也有一个似乎涉及FOXP2基因的染色体易位。FOXP2基因被认为是一种与发育性言语和语言障碍有关的调控基因。该策略将对比这两个个体与其未受影响的家庭成员的神经解剖学、神经生理学和神经心理学特征。这项工作将强调程序和陈述式学习系统和词汇和句子的使用。因此，这种策略从基因转移到语言表型，以了解基因和表型之间的神经和认知途径。第二个策略将使用一个大的流行病学样本的年轻成人与SLI沿着他们的兄弟姐妹谁参加了10年的纵向研究。这些人的语言状况以及相关条件已被广泛研究。此外，已经从SLI先证者、兄弟姐妹及其父母那里获得了DNA样本。因此，一个有价值的数据库的Doth组织和表型是可用于识别基因的高密度全基因组筛选使用同胞对连锁方法和后续的精细定位方法，使用传输不平衡测试（TDT）。此外，正在进行的候选基因和感兴趣的区域的精细定位将与微缺失研究一起沿着进行，这些基因和区域是由我们实验室和其他实验室的发现提供信息的。将对SLI先证者和兄弟姐妹进行额外的表型分析，以获得与从TB家族获得的数据平行的程序性和陈述性学习测量以及额外的语言测量。学习措施是作为内生型，可能是更敏感和具体的遗传影响。这些个体的表型和内表型将与现有的基因分型结合使用，用于额外的全基因组筛选和进一步的后续精细定位研究。