Genetic Studies in Autism on Chromosome 7

自闭症是一种神经发育异常，其特征是显著的社交障碍， 沟通功能和行为功能。流行病学数据表明自闭症有很强的遗传成分。国际自闭症协会分子遗传学研究(IMGSAC)首次报道了7q31-35区域的标记在基因组自闭症筛查中的重要结果，最高Lod分数(MLS)为3.55。自这些初步结果以来，包括我们在内的多个小组已经报告了支持人类7号染色体长臂上的自闭症基因座的证据。我们数据中的其他支持来自一个多基因自闭症家族(杜克大学 7543)，存在与潜在连锁区域重叠的细胞遗传学异常(Inv(7)(q22q31.2))，以及7q上有细胞遗传学异常的其他个体和自闭症患者。在过去的三年里，我们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研究以及众多研究小组的努力趋于一致，但对染色体7q基因的明确鉴定仍然难以捉摸。 为了识别这个基因，我们提出了一种整合但多管齐下的方法。首先，我们将对自闭症峰值连锁信号两侧的15MB进行精细定位、单倍型和关联研究，使用391个多基因自闭症家系中的每个100kb(总共300个SNP)的SNP(约1600个个体在本项目开始时可用)。我们将使用新开发的使用混合患者DNA的引物扩展协议，结合DHPLC来进行大部分高密度SNP作图。然后，位于峰值SNP区域(p&lt；=0.05)内的候选基因将在整个数据集中进行评估，包括单生子家系。其次，我们将同时评估和开展7543家族断裂点周围基因的关联研究和分子分析。最后，我们将彻底评估其他建议的7q染色体候选基因，首先是reelin基因，我们最近获得了与联合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图谱研究、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估。使用这种系统和集成的方法将使我们能够最终确定7号染色体自闭症基因，这代表着在解决自闭症的遗传之谜方面向前迈出了基本的一步。

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.