Discovery of the 6p.21.3 Reading Disability Gene

6p.21.3 阅读障碍基因的发现

• 批准号: 7061713
• 负责人: JEFFREY R GRUEN
• 金额: $ 56.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061713
• 关键词: behavioral /social science research tag; chromosomes; clinical research; functional magnetic resonance imaging; genetic polymorphism; genetic susceptibility; genotype; human subject; linkage disequilibriums; matrix assisted laser desorption ionization; neural information processing; neuropsychological tests; nucleic acid sequence; phenotype; quantitative trait loci; reading; reading disorder; statistics /biometry

DESCRIPTION (provided by applicant): Reading disability (RD) is a multifactorial heritable disorder defined as difficulty in learning to read despite adequate intelligence and opportunity. It is the most common neurobehavioral disorder affecting children, with a prevalence rate of 10 to 20% accounting for more than 80% of all learning disabilities. While acquisition of skilled reading is to a great extent influenced by important environmental factors such as exposure to print media, story reading, and early childhood education, our group and others have shown that approximately 50% or more of the deficits in RD children can be attributed to inherited factors. Specific risk factors that make a child susceptible to RD are variant alleles of a small number of genes at loci yet to be precisely identified on human chromosome 18, 25, 6, 3, 2, and 2. Clues to the function of these genes may be found in the converging data from functional magnetic resonance imaging (fMRI) studies, which consistently and convincingly show that the normal neural circuitry activated in reading is disrupted in children and adults with RD. We recently confined the location of the strongest-acting of the RD susceptibility loci to a 4 million base region on chromosome 6p through high-resolution studies of linkage disequilibrium in families whose children have RD. Thus, we hypothesize that the 6pRD gene can be identified by an intense genetic analysis of this region using a high-density marker panel in well-characterized cohorts. To address this hypothesis we will: A) Define three RD cohorts for analysis, B) Map the peak of linkage disequilibrium to localize the 6pRD gene, and C) Identify sequence variants in gene-candidates. These studies will take advantage of our experience in gene mapping of the 6p region and our experience in characterizing RD. We anticipate that these studies will lead to the identification of a gene that plays a role in the pathogenesis of RD.

描述（由申请人提供）：阅读障碍（RD）是一种多因素遗传性疾病，定义为尽管有足够的智力和机会，但仍难以学习阅读。它是影响儿童的最常见的神经行为障碍，患病率为 10% 至 20%，占所有学习障碍的 80% 以上。虽然熟练阅读的获得在很大程度上受到重要环境因素的影响，例如接触印刷媒体、故事阅读和幼儿教育，但我们的小组和其他人已经表明，RD 儿童中大约 50% 或更多的缺陷可以通过归因于遗传因素。使儿童易患 RD 的具体危险因素是人类 18、25、6、3、2 和 2 号染色体上尚未精确鉴定的少数基因的变异等位基因。这些基因功能的线索可能是我们可以从功能性磁共振成像 (fMRI) 研究的汇总数据中发现这一点，这些研究一致且令人信服地表明，患有 RD 的儿童和成人在阅读时激活的正常神经回路受到了干扰。我们最近通过对儿童患有 RD 的家庭中连锁不平衡的高分辨率研究，将 RD 易感性位点的最强作用位置限制在 6p 染色体上的 400 万个碱基区域。因此，我们假设 6pRD 基因可以通过在特征明确的群体中使用高密度标记物组对该区域进行深入的遗传分析来鉴定。为了解决这一假设，我们将：A) 定义三个 RD 队列进行分析，B) 绘制连锁不平衡峰图以定位 6pRD 基因，以及 C) 识别候选基因中的序列变异。这些研究将利用我们在 6p 区域基因图谱方面的经验以及我们在表征 RD 方面的经验。我们预计这些研究将鉴定出在 RD 发病机制中发挥作用的基因。