MOLECULAR GENETICS OF AUTISM

自闭症是一种严重的发育障碍，每10，000人中约有2-10人患有自闭症。 个体虽然双胞胎和家庭研究支持重要的基因， 参与，基因遗传的具体模式是未知的， 倍增基因作用、遗传异质性和可变表达 潜在的易感基因是可能的。鉴于未知和 自闭症遗传的复杂模式，成功定位 自闭症的潜在疾病基因将需要评估数百个 跨越基因组的遗传标记和大样本量，以获得 有足够的能力找到潜在的基因。此外，候选基因 基于职能或职位的研究是一种补充战略， 全面的方法来理解的分子遗传基础， 自闭症 该项目的目标是通过以下方法定位自闭症的疾病基因： 系统的基因组搜索和候选基因分析。在多站点中 国际合作努力，240个兄弟姐妹受影响的家庭 将收集自闭症患者对，并在高度多态性的 这些标记以规律的紧密间隔跨越人类基因组。美国 合作小组将确定和表型120个家庭与受影响的 患有自闭症的兄弟姐妹，并将血液从家庭送到英国。为 细胞系的转化。英国-欧洲合作者小组， 通过他们自己的资金来源，将收集额外的120套 亲属配对和基因分型工作将在独立的 实验室设施。通过这种国际努力， 可以在大约240对中鉴定基因。此外，候选人 将使用传递/不平衡检验研究基因， 肾上腺素能。多巴胺能GABA能和相关疾病候选者 （结核性硬化）。连锁不平衡研究，在350个 只有一个孩子患有自闭症的家庭和80个孩子患有自闭症的家庭 伯格氏症将允许确定是否有 不同的易感基因参与单纯型自闭症，多重 孤独症，或者说是自闭症。一旦自闭症的易感基因 他们在孤独症临床变异性中的作用， 自闭症中假定的较轻变异的表达，包括社会性 功能缺陷、情绪和焦虑障碍可以被识别。在 此外，确定自闭症的遗传决定因素将奠定 为制定更好的治疗干预措施奠定基础 针对自闭症的病理生理学。

Autism is a severe developmental disorder afflicting about 2-10 per 10,000 individuals. While twin and family studies support significant gene involvement, the specific mode of genetic inheritance is unknown and multiplicative gene action, genetic heterogeneity, and variable expression of underlying susceptibility genes are probable. Given the unknown and complex mode of genetic inheritance in autism, success in localizing underlying disease genes in autism will require evaluation of hundreds of genetic markers spanning the genome and large sample sizes to obtain sufficient power to find underlying genes. In addition, candidate gene studies based on function or position are complementary strategies in a comprehensive approach to understanding the molecular genetic basis of autism. The goals of this project are to localize disease genes in autism through a systematic genome search and candidate gene analysis. In a multi-site international collaborative effort, 240 families with affected sibling pairs with autism will be collected and genotyped on highly polymorphic markers spanning the human genome at regular, close intervals. The U.S. collaborative group will identify and phenotype 120 families with affected siblings with autism and send blood from the families to U.K. for transformation of cell lines. The U.K.-European group of collaborators, through their own funding resources, will collect an additional set of 120 relative pairs and genotyping efforts will be conducted in an independent laboratory facility. Through this international effort susceptibility genes can be identified in approximately 240 pairs. In addition candidate genes will be studied using the transmission/disequilibrium test for serotonergic. dopaminergic. GABAergic and associated disease candidates (tuberculous sclerosis). Linkage disequilibrium studies, conducted in 350 families with only one child with autism and 80 families with a child with Asperger's disorder will allow determination of whether there arc different susceptibility genes involved in simplex autism, multiplex autism, or Asperger's disorder. Once susceptibility genes for autism are identified, their role in the clinical variability in autism and in the expression of putative milder variants in autism, including social functioning deficits, mood, and anxiety disorders may be identified. In addition, identification of the genetic determinants in autism would lay the groundwork for development of improved treatment interventions targeting the pathophysiology of autism.