Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
Hum Mutat. 2011 Dec;32(12):1427-35. doi: 10.1002/humu.21585. Epub 2011 Sep 23.
During the past years, significant advances have been made in our understanding of the development of the human brain, and much of this knowledge comes from genetic studies of disorders associated with abnormal brain development. We employed array-comparative genomic hybridization (CGH) to investigate copy number variants (CNVs) in a cohort of 169 patients with various structural brain malformations including lissencephaly, polymicrogyria, focal cortical dysplasia, and corpus callosum agenesis. The majority of the patients had intellectual disabilities (ID) and suffered from symptomatic epilepsy. We detected at least one rare CNV in 38 patients (22.5%). All genes located within the rare CNVs were subjected to enrichment analysis for specific Gene Ontology Terms or Kyoto Encyclopedia of Genes and Genomes pathways and to protein-protein network analysis. Based on these analyses, we propose that genes involved in "axonal transport," "cation transmembrane transporter activity," and the "c-Jun N-terminal kinase (JNK) cascade" play a significant role in the etiology of brain malformations. This is to the best of our knowledge the first systematic study of CNVs in patients with structural brain malformations and our data show that CNVs play an important role in the etiology of these malformations, either as direct causes or as genetic risk factors.
在过去的几年中，我们对人类大脑发育的认识取得了重大进展，而这些知识主要来自于与异常大脑发育相关的疾病的遗传研究。我们采用阵列比较基因组杂交 (CGH) 技术，对包括无脑回畸形、多小脑回畸形、局灶性皮质发育不良和胼胝体发育不全等各种结构性脑畸形的 169 名患者的拷贝数变异 (CNVs) 进行了研究。大多数患者存在智力障碍 (ID) 和症状性癫痫。我们在 38 名患者（22.5%）中至少检测到一个罕见的 CNV。位于罕见 CNVs 内的所有基因都进行了特定基因本体论术语或京都基因与基因组百科全书途径的富集分析，以及蛋白质-蛋白质网络分析。基于这些分析，我们提出参与“轴突运输”、“阳离子跨膜转运活性”和“c-Jun N-末端激酶 (JNK) 级联”的基因在脑畸形的病因中起重要作用。这是我们所知的首个对结构性脑畸形患者的 CNVs 的系统研究，我们的数据表明，CNVs 作为直接原因或遗传风险因素，在这些畸形的病因中起着重要作用。
