MOLECULAR GENETICS OF 15Q11-Q13 DEFECTS IN AUTISM

自闭症是一种严重的神经发育障碍，其特征是社会交往和语言缺陷，以及行为异常，包括重复或刻板的行为。自闭症很常见，影响大约2 / 5的儿童，通常伴有神经系统特征，如智力迟钝和癫痫发作。自闭症有一个复杂的病因，来自系谱、双胞胎和兄弟姐妹的研究表明有很强的遗传成分。两类研究指出，Prader-Willi综合征和Angelman综合征（AS）中缺失的染色体15q11-q13区域包含一个或多个自闭症位点。在自闭症人群中，持续检测到影响母系染色体并导致3或4个15q11-q13拷贝的大量重复；这暗示了基因组印记的潜在作用，并可能表明该区域正常（可能是印记）基因剂量的破坏可能导致自闭症的易感性。独立研究支持多重家族中的自闭症与15q11-q13的关联，以及自闭症家族中15q11-q13的母系重组热点的重组升高。连锁研究的DNA标记基因分型显示，在自闭症家庭中，15q11-q13内的几个标记上存在零等位基因型和三个等位基因型，这表明基因组重排较小。我们描述了一个包含一个标记的5kb基因组缺失是导致这些结果的原因，与对照组相比，这种缺失在自闭症家庭中出现的频率要高得多，这表明存在关联。这一潜在的易感性标志将进一步探讨其与自闭症的相关性。大量重复的母体特异性可能直接指向印迹的、母体表达的基因，其中被称为UBE3A的AS基因就是一个例子。然而，这种联系和相关数据似乎表明，自闭症基因座的端粒位置稍微多一点，在一个包含多个神经学和位置候选和未解决的印迹状态的区域内。将重复和连锁数据结合起来可能涉及一个可能的超态易感等位基因。该项目将把关键区域的基因组序列和contigs与大的重复和小的缺陷、基因、简单序列重复标记以及发展中的多态性联系起来。将分析自闭症候选区域的基因在大脑中的表达和印记，筛选功能序列变异，并分析单纯性和多重性家族的变异，以测试自闭症的参与。

Autism is a severe neurodevelopmental disorder characterized by social interaction and language deficits, and behavior abnormalities, including repetitive or stereotyped actions. Autism is common, affects approximately 2-5/10000 children, and is often seen with accompanying neurological features such as mental retardation and seizures. Autism has a complex etiology, with evidence from pedigree, twin and sibling studies indicating a strong genetic component. Two categories of investigation point to the chromosome 15q11-q13 region deleted in Prader-Willi syndrome and Angelman syndrome (AS) as harboring a locus or loci for autism. Large duplications, affecting maternally-derived chromosomes and resulting in three or four copies of 15q11-q13, are consistently detected in the autistic population; this implies a potential role of genomic imprinting and may indicate that disruption of normal, possibly imprinted , gene dosage of this region can confer susceptibility to autism. Independent studies support linkage of autism in multiplex families to 15q11- q13 and elevated recombination in a 15q11-q13 maternal recombination hotspot, in autism families. DNA marker genotyping for linkage studies reveals null and three allele genotypes at several markers within 15q11-q13, in autism families, suggesting smaller genomic rearrangements. We characterize a 5-kb genomic deletion encompassing one marker as a cause for these results, and this deletion is present at a significantly higher frequency in autism families compared to controls, suggesting an association. This potential susceptibility marker will be explored further for relevance to autism. Maternal-specificity of large duplications may point directly to imprinted, maternally-expressed genes, of which the AS gene termed UBE3A, is an example. The linkage and related data, however, appear to indicate a slightly more telomeric location for an autism locus, within a region containing multiple neurological and positional candidates and unresolved imprinting status. Uniting the duplication and linkage data could involve a possible hypermorphic susceptibility allele. The project will correlate genomic sequence and contigs for the key region, with large duplications and smaller defects, genes, simple-sequence repeat markers, and developing polymorphisms. Genes in the autism candidate region will be analyzed for expression and imprinting in the brain, screened for functional sequence variation, and variants analyzed in simplex and multiplex families to test for involvement in autism.