GENETIC CONTRIBUTIONS TO LEARNING DISABILITIES SUBTYPES

这个项目的总体目标是研究遗传因素。 通过评估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点的家族 残疾(LD)。有四条证据支持这一假设 阅读障碍与遗传因素有关：1)阅读障碍患者 家庭聚集性；2)阅读障碍的符合率较高 同卵双胞胎；3)分离分析 家系数据已经找到了主要基因座和 多基因传播；4)遗传连锁分析已确定 基因组中与LD非随机相关的区域。完全相同的 基因在这些疾病中的作用未知和遗传模式， 基因-基因相互作用和基因-环境相互作用可能会 要复杂一点。联合分子遗传学方法学的最新进展 随着统计分析方法的改进，使得有可能 确定复杂疾病的遗传因素。 LD是一组具有不同表型的异质性疾病。 个人可能有单独的阅读困难，单独的书写困难或两者的组合 两种残疾都有。这些残疾可以进一步细分为 涉及的特定加工缺陷；个体可能是 正字法障碍、语音障碍或有混合体 这两个赤字。此外，阅读障碍的缺陷可能是规则- 受统治的或特定于词的。此外，计算障碍可能是也可能不是 与其他残疾合并发现。目前尚不清楚 这些LD亚型是否在遗传上是不同的，或者他们是否 代表同一基因缺陷的不同表现。 有证据表明，1、6和15号染色体可能含有基因 参与了身份认证。导致这些本地化的连锁研究 对没有按LD分类的受试者人群进行了测试 子类型。我们建议评估阅读障碍之间的遗传差异。 和书写困难，介于拼写和语音加工之间 残疾之间的差距以及特定词语的赤字和规则管辖的赤字之间的差距。在……里面 与临床和统计核心的协作，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并建立淋巴母细胞系(B)确认 已发表的与第1、5和15号染色体上的标记的连锁关系， (C)调查遗传异质性并定位与LD有关的其他基因。 这将通过对高度敏感的DNA样本进行基因分型来实现 多态短串联重复序列标记。将对谱系数据进行评估 以确定LD可能的传播方式。要检测以下位置，请执行以下操作 将使用连锁分析和非连锁分析来分析LD基因、基因型数据 参数方法。一旦确定了区域定位，地图 基因的位置将被改进，以实现位置克隆。

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.