Delineation of molecular basis of autism using array CGH

自闭症是一种复杂的发育障碍，通常出现在生命的头三年，是一种影响大脑正常功能的神经系统疾病的结果，影响了社会交往和沟通技能领域的发展。据推测，遗传背景会导致自闭症。然而，只有10%的患者表现出明确的基因异常。我们设计了一个带有60000个探针的定制阵列。探针被密集地分配在X染色体上的基因上，这些基因的突变已知会导致发育迟缓的多种畸形综合征（如发育迟缓）。e. Cornelia de Lange综合征、Rubinstein-Taybi综合征)，以及已知与自闭症相关的基因（NLGN3、NGLN4、NRXN1、SHANK3、CNTNAP2、PCDH10、CNTN3、NHE9、NHE6、DIA1、A2BP1）及其同源/上下游基因。我们已经确定了两例危重病例：一名患者在6q14, 2-15处存在5.4MB的重复，包括GABA受体GABRB3；另一名患者在2p16.3处缺失6.6MB，包括NRXN1。NRXN与NLGN在突触后膜上形成复合物，在GABA受体和谷氨酰胺受体介导的神经传递中起关键作用。我们认为GABRB3的重复和NRXN1的缺失与自闭症有关。

Autism is a complex developmental disability that typically appears during the first three years of life and is the result of a neurological disorder that affects the normal functioning of the brain, impacting development in the areas of social interaction and communication skills. Presumably, genetic background contributes to autism. Yet, only 10% of patients exhibit definitive genetic abnormalities. We designed a custom array with 60000 probes. Probes were densely allocated at genes on X chromosome, genes of which mutations are known to cause multiple malformation syndromes with developmental delay(i. e. Cornelia de Lange syndrome, Rubinstein-Taybi syndrome), and genes already known to be related with autism(NLGN3, NGLN4, NRXN1, SHANK3, CNTNAP2, PCDH10, CNTN3, NHE9, NHE6, DIA1, and A2BP1) and their homologous/upstream/downstream genes.We have identified two critical cases : One patient who had a duplication of 5.4MB at 6q14, 2-15 including the GABA receptor GABRB3 ; the other patient had a deletion of 6.6MB at 2p16.3 including NRXN1. NRXN forms a complex with NLGN on the post synaptic membrane and plays a critical role on neural transmission mediated through GABA receptors and glutamine receptors. We suggest that duplication of GABRB3 and deletion of NRXN1 contributes to autism.