GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability
GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability
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DOI：
10.1038/mp.2015.75
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发表时间：
2016-03-01
影响因子：
11
通讯作者：
Laumonnier, F.
中科院分区：
文献类型：
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作者：
Bonnet-Brilhault, F.;Alirol, S.;Laumonnier, F.
自闭症谱系障碍（ASD）主要表现为表型和遗传异质性，其分子和病理生理基础尚不清楚。ASD与其他神经发育障碍之间的显著共病和遗传重叠也得到了很好的证实。然而，对于广泛的与有害突变相关的表型谱的频繁观察，甚至在多个家族中影响单个基因，人们知之甚少。我们对ASD和/或智力残疾（ID）患者中存在已知有害NLGN4X基因突变（截断或过表达）的两个家族进行了临床、神经生理（体内脑电图-听觉诱发相关电位）和遗传（全外显子组测序）随访分析。对ASD个体家系的完整表型评估显示，在健康父母和孤立性ID家庭成员中不存在共同的特定自闭症行为特征和神经生理模式（对听觉变化的异常失配消极反应）。来自每个家族的ASD患者的全外显子组测序发现了第二个罕见的遗传变异，分别影响GLRB或编码NLGN4X相互作用蛋白的ANK3基因，这些蛋白分别在抑制性突触或兴奋性突触中表达。GRLB和ANK3突变在ID亲属和对照数据库中均不存在。总之，我们的研究结果提供了双重打击遗传模型的证据，该模型专注于ASD中的兴奋性/抑制性突触，这在孤立的ID中没有发现，与预测编码相关的非典型体内神经生理模式相关。
Phenotypic and genetic heterogeneity is predominant in autism spectrum disorders (ASD), for which the molecular and pathophysiological bases are still unclear. Significant comorbidity and genetic overlap between ASD and other neurodevelopmental disorders are also well established. However, little is understood regarding the frequent observation of a wide phenotypic spectrum associated with deleterious mutations affecting a single gene even within multiplex families. We performed a clinical, neurophysiological (in vivo electroencephalography-auditory-evoked related potentials) and genetic (whole-exome sequencing) follow-up analysis of two families with known deleterious NLGN4X gene mutations (either truncating or overexpressing) present in individuals with ASD and/or with intellectual disability (ID). Complete phenotypic evaluation of the pedigrees in the ASD individuals showed common specific autistic behavioural features and neurophysiological patterns (abnormal MisMatch Negativity in response to auditory change) that were absent in healthy parents as well as in family members with isolated ID. Whole-exome sequencing in ASD patients from each family identified a second rare inherited genetic variant, affecting either the GLRB or the ANK3 genes encoding NLGN4X interacting proteins expressed in inhibitory or in excitatory synapses, respectively. The GRLB and ANK3 mutations were absent in relatives with ID as well as in control databases. In summary, our findings provide evidence of a double-hit genetic model focused on excitatory/inhibitory synapses in ASD, that is not found in isolated ID, associated with an atypical in vivo neurophysiological pattern linked to predictive coding.