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Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

机译：连接 CNTNAP2 网络与神经发育障碍

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Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.
机译：基于基因组重排和拷贝数变异，与接触素相关的蛋白样2基因（CNTNAP2）已牵涉到神经发育障碍，例如吉尔斯·德·图雷特综合症，智障，强迫症，皮质发育异常-局灶性癫痫综合症，自闭症，精神分裂症，皮特-霍普金斯综合征和注意缺陷多动障碍。为了解释CNTNAP2改变的表型多效性，提出了一些假设。这些包括基因破坏，由于杂合缺失而导致的基因拷贝丢失，由于转录因子结合和DNA甲基化位点的丧失而引起的基因表达调控的改变以及编码蛋白氨基酸序列中的突变，这些突变可能引起蛋白质相互作用的改变。 CNTNAP2编码的蛋白质Caspr2，以及其他蛋白质。同样，外显子组测序覆盖了CNTNAP2基因组DNA的<0.2％，在健康个体和神经发育障碍患者中发现了许多单核苷酸变异体。在其中一些疾病中，CNTNAP2的破坏可能被解释为易感因素，而不是直接的致病突变。除了与语言发育障碍有关，CNTNAP2可能成为控制神经发育的分子网络中的中心节点。这篇综述讨论了CNTNAP2突变对其控制大脑发育的多个组合遗传网络功能的影响。此外，针对神经发育障碍患者及其家属的临床遗传管理，提出了基因组检测的建议。

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