Iourov Ivan Y, Zelenova Maria A, Vorsanova Svetlana G, Voinova Victoria V, Yurov Yuri B
Mental Health Research Center, Moscow, Russian Federation.
Separated Structural Unit "Clinical Research Institute of Pediatrics named after Y.E Veltishev", Pirogov Russian National Research Medical University, Ministry of Health, Moscow, Russian Federation.
Curr Genomics. 2018 Apr;19(3):173-178. doi: 10.2174/1389202918666170717161426.
During the last decades, a large amount of newly described microduplications and microdeletions associated with intellectual disability (ID) and related neuropsychiatric diseases have been discovered. However, due to natural limitations, a significant part of them has not been the focus of multidisciplinary approaches. Here, we address previously undescribed chromosome 4q21.2q21.3 microduplication for gene prioritization, evaluation of cognitive abilities and estimation of genomic mechanisms for brain dysfunction by molecular cytogenetic (cytogenomic) and gene expression (meta-) analyses as well as for neuropsychological assessment. We showed that duplication at 4q21.2q21.3 is associated with moderate ID, cognitive deficits, developmental delay, language impairment, memory and attention problems, facial dysmorphisms, congenital heart defect and dentinogenesis imperfecta. Gene-expression meta-analysis prioritized the following genes: ENOPH1, AFF1, DSPP, SPARCL1, and SPP1. Furthermore, genotype/phenotype correlations allowed the attribution of each gene gain to each phenotypic feature. Neuropsychological testing showed visual-perceptual and fine motor skill deficits, reduced attention span, deficits of the nominative function and problems in processing both visual and aural information. Finally, emerging approaches including molecular cytogenetic, bioinformatic (genome/epigenome meta-analysis) and neuropsychological methods are concluded to be required for comprehensive neurological, genetic and neuropsychological descriptions of new genomic rearrangements/diseases associated with ID.
在过去几十年中，人们发现了大量新描述的与智力残疾（ID）及相关神经精神疾病相关的微重复和微缺失。然而，由于自然限制，其中很大一部分尚未成为多学科研究的重点。在此，我们针对先前未描述的4号染色体4q21.2q21.3微重复进行基因优先级排序、认知能力评估以及通过分子细胞遗传学（细胞基因组学）和基因表达（元）分析以及神经心理学评估来估计脑功能障碍的基因组机制。我们发现，4q21.2q21.3处的重复与中度ID、认知缺陷、发育迟缓、语言障碍、记忆和注意力问题、面部畸形、先天性心脏缺陷和牙本质发育不全有关。基因表达元分析确定了以下基因的优先级：ENOPH1、AFF1、DSPP、SPARCL1和SPP1。此外，基因型/表型相关性使我们能够将每个基因增益与每个表型特征联系起来。神经心理学测试显示出视觉感知和精细运动技能缺陷、注意力持续时间缩短、命名功能缺陷以及处理视觉和听觉信息方面的问题。最后，得出结论认为，对于与ID相关的新基因组重排/疾病进行全面的神经学、遗传学和神经心理学描述，需要包括分子细胞遗传学、生物信息学（基因组/表观基因组元分析）和神经心理学方法在内的新兴方法。
