MOLECULAR GENETICS OF 15Q11-Q13 DEFECTS IN AUTISM

自闭症是一种严重的神经发育障碍，其特征是社会互动和语言缺陷，以及行为异常，包括重复或刻板的动作。自闭症是常见的，影响约2-5/10000儿童，并经常看到伴随的神经功能障碍，如精神发育迟滞和癫痫发作。 自闭症有一个复杂的病因学，从系谱，双胞胎和兄弟姐妹研究的证据表明，一个强大的遗传成分。 两类研究指出Prader-Willi综合征和Angelman综合征（AS）中染色体15 q11-q13区域缺失，为自闭症的一个或多个位点。 大的重复，影响母体来源的染色体，并导致三个或四个拷贝的15 q11-q13，在自闭症人群中始终检测到;这意味着基因组印记的潜在作用，并可能表明，正常的，可能是印记，该区域的基因剂量的破坏可以赋予自闭症的易感性。 独立的研究支持多重家庭中自闭症与15 q11- q13的连锁，以及自闭症家庭中15 q11-q13母体重组热点中的重组增加。 连锁研究的DNA标记基因分型揭示了自闭症家系中15 q11-q13内几个标记的零和三个等位基因基因型，表明较小的基因组重排。 我们表征了一个5-kb的基因组缺失，其中包含一个标记作为这些结果的原因，与对照组相比，这种缺失在自闭症家庭中的频率显着较高，这表明了一种关联。 这一潜在的易感性标志物将进一步探讨与自闭症的相关性。 大重复的母体特异性可能直接指向印记的母体表达基因，其中称为UBE 3A的AS基因就是一个例子。 然而，连锁和相关数据似乎表明自闭症基因座的端粒位置略多，在一个包含多个神经和位置候选人和未解决的印记状态的区域内。 结合重复和连锁数据可能涉及一个可能的多态性易感等位基因。 该项目将把关键区域的基因组序列和重叠群与大重复和小缺陷、基因、简单序列重复标记和发展中的多态性相关联。 将分析自闭症候选区域中的基因在大脑中的表达和印记，筛选功能序列变异，并在单一和多重家庭中分析变异，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.