Genetic Bases of Developmental Language Disorders

描述(申请人提供)：语言和书面语障碍(DSWL)是儿童中最常见的一组障碍。他们中的一些人，虽然部分得到了补救，但仍然坚持到成年。我们打算调查俄罗斯北部偏远地区与世隔绝人群(以下称为OSH)中受影响儿童的DSWL的遗传基础，以及通过受影响儿童先证者亚群确定的大量扩展家系。由于其复杂性和大小，该谱系基本上代表了该分离物的大部分。职业安全与健康组织成立于10世纪和11世纪，有着相对孤立的历史.目前，它包括850个人，其中200人是18岁以下的儿童。该项目的俄罗斯合作者之前识别了先证者，在评估所有18岁及以下儿童时使用了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人(-73%)在临床上被诊断为各种DSWL。此外，尽管没有临床诊断，但许多儿童在言语和语言相关领域(如发音、阅读、写作、语音处理)方面存在缺陷。在接受评估的25名幼儿(2-6岁)中，有17名发音困难，并表现出语言迟缓和/或障碍。在60名与确诊儿童有关的接受评估的成年人中，45人表现出与DSWL有关的各种缺陷。家谱和人种学表明，OSH是由5-7个人创立的，大约80%的人有不同程度的亲属。该种群在遗传上是同质的，是近亲交配的，但其特点是整个基因组具有高度的遗传变异，使其适合进行遗传分析。我们的俄罗斯合作者一直在收集职业安全局居民的DNA样本。目前，已经建立了404个细胞系，从全血标本中提取了487个没有可用的细胞系的DMAS，从口腔拭子中提取了47个DMAS。我们建议(1)仔细分析OSH家系中传播的表型；(2)进行复杂的多变量分析以了解DSWL的传播模式；以及(3)对OSH家系中包含至少三代多个患病个体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.