Genetic Bases of Developmental Language Disorders

描述（由申请人提供）：口语和书面语言障碍（DSWLs）是儿童中最常见的一组障碍。其中一些虽然得到部分补救，但在成年后仍然存在。我们打算在俄罗斯北方偏远地区（以下简称奥什）的一个孤立的人群中调查受影响儿童的DSWLs的遗传基础，并通过受影响儿童先证者的一个亚组确定一个大的扩展谱系。由于其复杂性和规模，谱系基本上代表了大多数分离株。奥什建立于10世纪和11世纪，有一段相对孤立的历史。目前，它包括-850人，其中-200人是18岁以下的儿童。该项目的俄罗斯合作者先前确定了先证者，在对所有18岁及以下儿童的评估中使用俄罗斯的言语和语言障碍诊断方案。在130名接受评估的儿童和青少年（7-18岁）中，95名（-73%）被临床诊断为各种DSWL。此外，虽然没有临床诊断，但许多儿童在言语和语言相关领域有缺陷（例如，发音、阅读、写、语音处理）。在接受评估的25名幼儿（2-6岁）中，17名有发音困难，表现出语言迟缓和/或障碍。在60名与诊断儿童相关的评估成人中，45名表现出与DSWLs相关的各种缺陷。家谱和人种学资料表明，奥什是由5-7个人建立的，大约80%的人有不同程度的亲属。该种群在遗传上是同质的和近交的，但其特征是整个基因组的遗传变异程度很高，使其适合于遗传分析。我们的俄罗斯合作者一直在收集奥什居民的DNA样本。目前，已经建立了404个细胞系，487个DMA从全血标本中提取，没有可用的细胞系，47个DMA从口腔拭子中提取。我们在此建议：（1）仔细描述奥什家系中传递的表型;（2）进行复杂的多变量分析，以了解DSWL的传递模式;（3）对至少三代中包含多个受影响个体的奥什家系的选定核分支进行全基因组采样分析。

DESCRIPTION (provided by applicant): Disorders of spoken and written language (DSWLs) are the most prevalent group of disorders in children. A number of them, although partially remediated, persist in adulthood. We intend to investigate genetic bases of DSWLs in affected children in an isolated population in a remote area of Northern Russia (hereafter referred to as OSH) and a large extended pedigree ascertained through a subgroup of affected child probands. Because of its complexity and size, the pedigree essentially represents the majority of the isolate. Established in the 10th and 11 th centuries, OSH has a history of relative isolation. Currently, it includes -850 individuals, -200 of whom are children under age 18. Probands were previously identified by Russian collaborators on the project, using Russian diagnostic schemes for speech and language impairments in an evaluation of all children 18 and younger. Of 130 assessed children and adolescents (aged 7-18), 95 (-73%) were diagnosed clinically with a variety of DSWLs. In addition, although not clinically diagnosed, many children had deficits in speech and language-related domains (e.g., pronunciation, reading, writing, phonological processing). Of 25 young children (aged 2-6) assessed, 17 had difficulties in pronunciation and exhibited language delays and/or impairments. Of the 60 evaluated adults related to the diagnosed children, 45 demonstrated various deficiencies related to DSWLs. Genealogical and ethnographical suggest that OSH was founded by 5-7 individuals, and that approximately 80% of the people there are relatives of various degrees. The population is genetically homogeneous and inbred, but is characterized by a high degree of genetic variation across the genome, making it suitable for genetic analyses. Our Russian collaborators have been collecting DNA samples from OSH residents. Currently, 404 cell lines have been established, 487 DMAs extracted from whole blood specimens without an available cell line, and 47 DMAs extracted from buccal swabs. We here propose to (1) carefully characterize the phenotypes transmitted in the OSH pedigree; (2) carry out complex multivariate analyses to understand the transmission patterns of DSWL; and (3) conduct whole-genome sampling analyses on selected nuclear branches of the OSH pedigree that contain multiple affected individuals in at least three generations.