PDF(Pubmed)
Abstract：
The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype.
摘要：
断开的（迪斯科）相互作用蛋白2（DIP2）基因首次在黑腹D中鉴定，并包含DNA甲基转移酶相关蛋白1（DMAP1）结合域，酰基辅酶A合成酶结构域和AMP结合位点。DIP2调节D.melanogaster中蘑菇体神经元的轴突分叉，并且是C.elegans神经元轴突再生所必需的。脊椎动物中的DIP2同源物，迪斯科相互作用蛋白2同源物A（DIP2A），迪斯科相互作用蛋白2同源物B（DIP2B），和Disco相互作用蛋白2同源物C（DIP2C），在中枢神经系统中高度保守并广泛表达。尽管有证据表明DIP2C在认知中起作用，这些基因中致病变异的报道很少见，其意义尚不确定。我们提供了23个具有杂合DIP2C变体的个体，都表现出发育迟缓，主要影响表达性语言和言语衔接。八名患者具有预测DIP2C基因功能丧失的从头变异，两名患者有从头错义变异，三个有父系遗传的功能丧失变异，六个有母系遗传的功能丧失变异，而四个变异的遗传未知。四名患者有心脏缺陷（肥厚型心肌病，房间隔缺损,和二叶主动脉瓣)。轻微的面部异常不一致，但包括额头长的前发际线高，宽阔的鼻尖,耳朵异常。Brainspan分析显示，受孕后10-24周，人类新皮层中的DIP2C表达升高。有了这里介绍的案例，我们提供的表型和基因型数据支持DIP2C中功能缺失变异与神经认知表型之间的关联.
