Genetic Studies in Autism on Chromosome 7

孤独症是一种神经发育异常，其特征是社会， 沟通和行为功能。流行病学数据表明自闭症有很强的遗传因素。国际自闭症分子遗传学研究联盟（IMGSAC）首次报道了7 q31 -35区域标记的显著结果，其最大lod得分（MLS）为3.55，用于其基因组自闭症筛查。自这些初步结果以来，包括我们在内的多个研究小组已经报告了支持人类7号染色体长臂上自闭症基因座（或基因座）的证据。我们数据中的其他支持来自一个多重自闭症家庭（杜克 7543）与潜在连锁区域重叠的细胞遗传学异常（Inv（7）（q22q31.2）），以及其他在7 q和自闭症上具有细胞遗传学异常的个体。在过去的三年里，我们已经绘制并研究了位于自闭症关键区域的候选基因。尽管连锁和细胞遗传学的研究和许多团体的努力，最终确定的染色体7 q基因仍然难以捉摸。 为了确定这个基因，我们提出了一个综合而多管齐下的方法。首先，我们将在391个多重自闭症家庭（在本项目开始时约有1600个个体）中使用每100 kb的SNP（总共300个SNP）对自闭症的峰值连锁信号两侧的15 MB进行精细作图、单倍型和关联研究。我们将使用新开发的引物延伸方案，使用合并的患者DNA与DHPLC结合，进行大部分高密度SNP作图。然后在整个数据集中评估位于SNP峰值区域（p<= 0.05）内的候选基因，包括单例家族。其次，我们将同时评估和开展7543家族中断点周围基因的关联研究和分子分析。最后，我们将重新评估其他提出的染色体7 q候选基因，从reelin基因开始，我们最近获得了联合DUMC，AGRE和Boston/VUMC相关的重要证据。 数据集。所有候选基因将通过单倍型作图研究、突变分析、转录和表达以及甲基化和细胞遗传学异常进行评价。使用这种系统和综合的方法将使我们能够最终确定7号染色体自闭症基因，代表着解决自闭症遗传之谜的基本步骤。

Autism is a neurodevelopmental abnormality characterized by significant disturbances in social, communicative, and behavioral functioning. Epidemiologic data has implicated a strong genetic component in autism. The International Molecular Genetic Study of Autism Consortium (IMGSAC) first reported significant results for markers in the region 7q31-35, with a peak maximum lod score (MLS) of 3.55, for their genomic autism screen. Since these initial results, multiple groups, ours included, have reported supporting evidence for an autism locus (or loci) on the long arm of human chromosome 7. Additional support in our data comes from a multiplex autism family (Duke 7543) with a cytogenetic abnormality (Inv (7)(q22q31.2)) overlapping the region of potential linkage as well as other individuals with cytogenetic abnormalities on 7q and autism. During the past three years we have mapped and investigated candidate genes that lie in the critical autism region. Despite this convergence of linkage and cytogenetic studies and efforts by numerous groups, definitive identification of the chromosome 7q gene has remained elusive. In order to identify this gene we propose an integrated yet multiprong approach. First, we will fine map, haplotype, and carry out association studies on the 15 MB to either side of the peak linkage signal for autism using a SNP each 100kb (total 300 SNPs) in 391) multiplex autism families (approximately 1600} individuals available at the start of this project). We will do the bulk of this high-density SNP mapping using newly developed primer extension protocols using pooled patient DNA in conjunction with DHPLC. Candidate genes that lie within peak SNP regions (p<= 0.05) will then be evaluated within the entire data set including singleton families. Secondly, we will simultaneously evaluate and carry out association studies and molecular analyses of genes surrounding the breakpoints in family 7543. Lastly, we will thorougl_y evaluate other proposed chromosome 7q candidate genes, beginning with the reelin gene, for which we have recently obtained significant evidence for association in the joint DUMC, AGRE and Boston/VUMC dataset. All candidate genes will be evaluated by haplotype mapping studies, mutational analysis, transcription and expression as well as methylation and cytogenetic abnormalities. Using this systematic and integrated approach will allow us to ultimately identify the chromosome 7 autism gene, representing a fundamental step forward in solving the genetic riddles of autism.