MOLECULAR GENETICS OF AUTISM

这是一个项目的竞争性续订申请，以确定 儿童自闭症的易感基因座。自闭症是一种严重的 神经发育障碍，通常在前三个月起病 生命中的岁月。它的特点是明显的社会缺陷、拖延 在语言发展方面，以及有限范围内的刻板印象 重复的行为。自闭症的患病率约为每2500人中就有1人 受影响的男孩和女孩的比例约为3：1。 虽然自闭症的确切原因在大多数情况下是未知的，但家庭 双胞胎研究有力地支持了遗传病因学。 尽管家庭研究强烈支持遗传病因学 MZ与DZ(或SIB)的符合率非常高，这是非常具有指示性的 具有交互效果的多个位置。然而，考虑到 兄弟姐妹复发与人口患病率的总体比率很高 (大约75倍)，有相当大的检测能力 即使有许多易感基因座也是如此。因此，我们是 采用受影响的同胞配对策略和整个基因组筛选 为了寻找尽可能多的致病易感基因 已确认身份。在此过程中，我们将生成一张排除地图，以 定义不包含此类基因座的所有区域。 在这个项目的初始阶段，我们已经收集了 来自80个受影响同胞对家庭的永生化细胞系，包括 父母。我们现在建议完成这个家庭 招募/评估共获得200个家庭，在 至少两个受影响的同胞，包括永生化的细胞系。我们 意欲对其中100个具有330个高度多态的家庭进行基因分型 覆盖整个基因组的标记(PIC=0.70)间隔10 cM 并使用多点同胞对分析构建排除图。 未排除的区域将被额外的多态饱和 标记并对这100个家系和第二组100个家系进行了基因分型。 因此，我们将排除以前未被排除的区域以及 识别可能包含易感基因的一个或多个区域 或者是精神错乱。对于后者，将定义95%的置信度区域以 包含一个易感基因。在这些地区，使用标记 间隔大约1厘米，我们将搜索链接 不平衡以进一步定位任何易感基因座，并设置 这是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障碍，它会导致 受影响的人以及他们的家人遭受痛苦。通过 识别易感基因，我们希望最终能理解 这种疾病背后的病理生理途径，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.