The Genetics of Specific Language Impairment

特定语言障碍的遗传学

• 批准号: 6959150
• 负责人: James Bruce Tomblin
• 金额: $ 57.73万
• 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/6959150
• 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(申请人提供)：语言学和心理学理论，加上对语言发展和语言障碍个体差异遗传力的实证研究，支持人类语言发展能力受到遗传影响的假设。这项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，这些个体尽管有正常的语言经验、感觉能力和非语言智力，但语言发展很差。SLI患者提供了一种很好的方法来识别数量性状遗传基因座，这些基因座可能有助于语言发展和使用的所有个体差异。拟议的研究将使用两种互补的策略。首先，它将利用两个患有严重发育性言语和语言障碍的个体(TB)，他们的染色体易位似乎涉及FOXP2基因。FOXP2基因被认为是一种与发育性言语和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性和陈述性学习系统以及词汇和句子的使用。因此，这一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学和认知通路。第二个策略将使用SLI年轻成年人及其兄弟姐妹的大流行病学样本，这些兄弟姐妹参与了一项为期10年的纵向研究。对这些人的语言状况以及相关条件进行了广泛的研究。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，有价值的DOTH组织和表型数据库可用于通过使用同胞对连锁方法的高密度全基因组筛选和使用传递不平衡检验(TDT)的后续精细定位方法来识别基因。此外，根据我们的实验室和其他实验室的研究结果，将对候选基因和感兴趣的区域进行持续的精细定位，同时还将进行微缺失研究。将对SLI先证者和兄弟姐妹进行额外的表型鉴定，以获得程序性和陈述性学习措施，以及与将从结核病家庭获得的数据平行的额外语言措施。学习措施将作为内生型，可能对遗传影响更加敏感和特异。然后，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查和进一步的后续精细图谱研究。