Background Duplications of 15q11.2-q13.1 (Dup15q syndrome), including the paternally imprinted gene UBE3A and three nonimprinted gamma-aminobutyric acid type-A (GABAA) receptor genes, are highly penetrant for neurodevelopmental disorders such as autism spectrum disorder (ASD). To guide targeted treatments of Dup15q syndrome and other forms of ASD, biomarkers are needed that reflect molecular mechanisms of pathology. We recently described a beta EEG phenotype of Dup15q syndrome, but it remains unknown which specific genes drive this phenotype. Methods To test the hypothesis that UBE3A overexpression is not necessary for the beta EEG phenotype, we compared EEG from a reference cohort of children with Dup15q syndrome (n = 27) to (1) the pharmacological effects of the GABAA modulator midazolam (n = 12) on EEG from healthy adults, (2) EEG from typically developing (TD) children (n = 14), and (3) EEG from two children with duplications of paternal 15q (i.e., the UBE3A-silenced allele). Results Peak beta power was significantly increased in the reference cohort relative to TD controls. Midazolam administration recapitulated the beta EEG phenotype in healthy adults with a similar peak frequency in central channels (f = 23.0 Hz) as Dup15q syndrome (f = 23.1 Hz). Both paternal Dup15q syndrome cases displayed beta power comparable to the reference cohort. Conclusions Our results suggest a critical role for GABAergic transmission in the Dup15q syndrome beta EEG phenotype, which cannot be explained by UBE3A dysfunction alone. If this mechanism is confirmed, the phenotype may be used as a marker of GABAergic pathology in clinical trials for Dup15q syndrome.

中文翻译：

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Dup15q综合征中脑电生物标志物的潜在机制。

15q11.2-q13.1（Dup15q综合征）的背景重复，包括父系印迹基因UBE3A和三个非印迹γ-氨基丁酸A型（GABAA）受体基因，对于神经发育障碍（例如自闭症谱系障碍（ASD））具有很高的渗透性）。为了指导Dup15q综合征和其他形式的ASD的靶向治疗，需要生物标志物来反映病理学的分子机制。我们最近描述了Dup15q综合征的βEEG表型，但仍不清楚哪个特定基因驱动该表型。方法为了验证βEEG表型不需要UBE3A过表达的假设，我们将来自Dup15q综合征患儿（n = 27）的参考队列中的EEG与（1）GABAA调节剂咪达唑仑（n = 12）的药理作用进行了比较）健康成年人的脑电图，（2）来自典型发育中的（TD）儿童（n = 14）的EEG，以及（3）来自两个父系15q重复的儿童（即，UBE3A沉默的等位基因）的EEG。结果相对于TD对照，参考队列中的峰值β功效显着增加。咪达唑仑给药在健康成人中概括了βEEG表型，其中央通道的峰值频率（f = 23.0 Hz）与Dup15q综合征（f = 23.1 Hz）相似。父本的Dup15q综合征病例均显示出与参考队列相当的beta功效。结论我们的结果表明，Dup15q综合征βEEG表型中GABA能传递的关键作用，这不能仅通过UBE3A功能障碍来解释。如果确认了这种机制，则该表型可以在Dup15q综合征的临床试验中用作GABA能病理学的标志物。