MOLECULAR GENETICS OF AUTISM

这是一个项目的竞争性续期申请，以确定 婴儿自闭症的易感基因自闭症是一种严重的 神经发育障碍，通常在前三个月发病 多年的生活。它的特点是明显的社会赤字， 在语言发展方面， 重复的行为。 自闭症的患病率约为2500分之一 受影响的男孩与女孩的比例约为3：1。 虽然自闭症的确切原因在大多数情况下是未知的， 双胞胎研究强烈支持遗传病因。 尽管家族研究强烈支持遗传病因学， 非常高的MZ与DZ（或同胞）一致性比率非常具有指示性 具有交互效果的多个位置。然而，鉴于 同胞复发与人群患病率总体比率较高 （约75倍），有相当大的力量来检测 易感基因座，即使它们有很多。因此，我们 采用受影响的同胞对策略和全基因组筛选 寻找尽可能多的易感基因， 鉴定在此过程中，我们将生成一个排除图， 定义所有不含此类基因座的区域。 在这个项目的初始阶段，我们已经收集了， 来自80个受影响的同胞对家族的永生化细胞系，包括 父母 我们现在提议让这个家族完整起来 招募/评估，以获得总共200个家庭， 至少两个受影响的同胞，包括细胞系的永生化。 我们 打算对其中100个具有330个高度多态性家庭进行基因分型 标记（PIC = 0.70），间隔10 cm，覆盖整个基因组 并使用多点同胞对分析构建排除图。 未排除的区域将充满额外的多态性 标记并对这100个和第二组100个家庭进行基因分型。 因此，我们将排除以前未排除的区域，以及 鉴定可能含有易感性基因座一个或多个区域 或位点。对于后者，将定义95%置信区域， 含有易感基因座在这些区域，使用标记 间隔约1厘米，我们将寻找 不平衡，以进一步定位任何易感基因座，并设置 定位克隆这些基因的阶段。 自闭症是一种毁灭性的神经精神紊乱， 为受影响的人及其家人带来痛苦。 通过 识别易感基因，我们希望最终了解 这种疾病的病理生理途径，导致 有效的预防和/或治疗。

This is a competitive renewal application of a project to identify susceptibility loci for infantile autism. Autism is a severe neurodevelopmental disorder with onset usually in the first three years of life. It is characterized by marked social deficits, delay in language development, and a restricted range of stereotyped repetitive behaviors. The prevalence of autism is about 1 in 2,500 births, and the ratio of affected boys to girls is around 3:1. Although the exact causes of autism are unknown in most cases, family and twin studies strongly support a genetic etiology. Although the family studies strongly support a genetic etiology the very high ratio of MZ to DZ (or sib) concordance is very indicative of multiple Loci with interactive effects. However, given the very high overall ratio of sib recurrence to population prevalence (approximately 75-fold), there is considerable power to detect susceptibility loci even if there are many of them. Thus, we are employing an affected sib pair strategy and an entire genome screen to search for as many contributing susceptibility loci as can be identified. In the process, we will produce an exclusion map to define all regions that contain no such loci. In the initial phase of this project we have already collected and immortalized cell lines from 80 affected sib-pair families including parents. We now propose to complete the family recruitment/assessment to obtain a total of 200 families with at least two affected sibs, including immortalization of cell lines. We intend to genotype 100 of these families with 330 highly polymorphic markers (PIC = 0.70) spaced 10 cm apart covering the entire genome and construct an exclusion map using multipoint sib-pair analysis. Regions not excluded will be saturated with additional polymorphic markers and genotyped these 100 and the second set of 100 families. Thus, we will exclude previously unexcluded regions, as well as identify a region or regions likely to contain a susceptibility locus or loci. For the latter, will define 95% confidence regions to contain a susceptibility locus. In these regions, using markers spaced approximately 1 Cm apart, we will search for linkage disequilibrium to further localize any susceptibility loci, and set the stage for positionally cloning these genes. Autism is a devastating neuro-psychiatric disorder that creates suffering for those affected as well as their family members. By identifying susceptibility genes, we hope to eventually understand the pathophysiological pathways underlying this disease, leading to effective prevention and/or treatments.