GENETIC CONTRIBUTIONS TO LEARNING DISABILITIES SUBTYPES

本项目的总体目标是研究遗传因素 参与阅读障碍和书写困难的特定亚型， 其成员具有良好的学习特征的Kinemons 残疾人（LD）。 四条证据支持这一假设， 有一个遗传贡献LD：1）个人与诵读困难 在家庭中聚集; 2）阅读障碍的一致性更大， 单卵双生子与异卵双生子的分离分析 家庭系谱数据发现了主要基因座和 多基因传播; 4）遗传连锁分析已确定 与LD非随机相关的基因组区域。 的确切 基因在这些疾病中的作用是未知的， 基因-基因相互作用和基因-环境相互作用可能 要复杂。 分子遗传学方法的最新进展 随着统计分析方法的改进， 确定复杂疾病中的遗传因素。 LD是一组具有一系列表型的异质性疾病。 个人可以有诵读困难单独，书写困难单独或组合 两种残疾。 这些残疾可进一步细分为： 涉及的具体处理缺陷;个人可能 拼写受损、语音受损或两者兼有 这两种赤字。 此外，失读症的缺陷可能是规则- 被统治的或特定的词。 此外，计算障碍可能是也可能不是 与其他残疾相结合。 目前还不知道 这些LD亚型在遗传上是否不同， 代表着同一种基因缺陷的不同表现。 有证据表明，1号、6号和15号染色体可能含有基因， 参与LD。 导致这些定位的连锁研究 在未按LD分类的受试者人群中进行 亚型 我们建议评估阅读障碍与 和书写困难，在正字法和语音处理之间 残疾之间的具体和规则的赤字。 在 与临床和统计核心合作，项目3将（a） 接收和处理来自受试者和家庭成员的血液样本， 制备和储存DNA并建立淋巴母细胞样细胞系（B）确认 已发表的与染色体1、5和15上的标记的连锁关联， (c)研究遗传异质性和定位与LD相关的其他基因。 这将通过对DNA样品进行基因分型来实现， 多态性短串联重复序列标记。 将对谱系数据进行评价 以确定LD的可能传播模式。 为了检测 LD基因，基因型数据将使用连锁分析和非连锁分析进行分析。 参数化方法 一旦确定了区域定位， 基因的位置将被精确化以实现定位克隆。

The overall objective of this project is to investigate genetic factors involved in specific subtypes of dyslexia and dysgraphia by evaluating kindreds whose members have been well-characterized for learning disabilities (LD). Four lines of evidence support the hypothesis that there is a genetic contribution to LD: 1) individuals with dyslexia cluster in families; 2) the concordance for dyslexia is greater in monozygotic twins that in dizygotic twins; 3) segregation analysis of family pedigree data has found evidence for both major locus and polygenic transmission; 4) genetic linkage analyses have identified regions of the genome that are nonrandomly associated with LD. The exact role of genes in these disorders in unknown and patterns of inheritance, gene-gene interactions and gene-environment interactions are likely to be complex. Recent advances in molecular genetic methodology combined with improved approaches to statistical analysis make it possible to identify genetic factors in complex disorders. LD is a heterogeneous group of disorders with a spectrum of phenotypes. Individuals can have dyslexia alone, dysgraphia alone or a combination of both disabilities. These disabilities can be further subdivided by the specific processing deficit involved; individuals may be orthographically impaired, phonologically impaired or have a combination of both deficits. Furthermore, the deficit in dyslexia may be rule- governed or word-specific. In addition, dyscalculia may or may not be found in combination with the other disabilities. It is not known whether these LD subtypes are genetically distinct or whether they represent different manifestations of the same genetic defect. There is evidence that chromosomes, 1, 6 and 15 may contain genes involved in LD. Linkage studies that resulted in these localizations were performed on subject populations that were not categorized by LD subtype. We propose to evaluate the genetic distinction between dyslexia and dysgraphia, between orthographic and phonologic processing disabilities and between word-specific and rule-governed deficits. In collaboration with the Clinical and Statistical Cores, Project 3 will (a) receive and process blood samples from subjects and family members, prepare and store DNA and establish lymphoblastoid cell lines (b) confirm the published linkage associations to markers on chromosomes 1, 5 and 15, (c) investigate genetic heterogeneity and map other genes involved in LD. This will be accomplished by genotyping DNA samples for highly polymorphic short tandem repeat markers. Pedigree data will be evaluated to determine possible modes of transmission of LD. To detect sites of LD genes, genotype data will be analyzed using linkage analysis and non- parametric methods. Once regional localizations are identified, the map locations of the genes will be refined to enable positional cloning.