Mechanisms underlying the EEG biomarker in Dup15q syndrome

Joel Frohlich,Richard W Olsen,Lawrence T Reiter,Shafali S Jeste,Andrei Irimia,Joerg F Hipp,Stormy Chamberlain,Vidya Saravanapandian,Carly Hyde,Charlotte Distefano,Scott Huberty,Carrie E Bearden,Peyman Golshani

doi:10.1186/s13229-019-0280-6

Abstract

BackgroundDuplications 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.MethodsTo 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).ResultsPeak 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.ConclusionsOur 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.

Highlights

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)
Midazolam pharmaco-EEG To assess the similarity of the beta EEG phenotype in Dup15q syndrome to beta oscillations pharmacologically induced with a GABAA positive allosteric modulator (PAM), we examined 19-channel EEG from n = 12 healthy adult controls challenged with the benzodiazepine compound midazolam
We have studied the properties of a robust EEG biomarker in Dup15q syndrome, one of the most common CNVs associated with ASD and intellectual disability (ID)

Summary

Introduction

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). Dup15q syndrome is often considered the most recurrent copy number variant implicated in ASD [5] Children with maternal duplications present with a more severe clinical phenotype and greater likelihood of ASD and ID [9]. This discrepancy is likely due to paternal imprinting of UBE3A in most neurons [10, 11], a gene implicated in neurodevelopmental disorders [12, 13] that encodes a ubiquitin-protein ligase. Isodicentric duplications are extra copies of 15q11.2-q13.1 ligated end-to-end as a supernumerary chromosome, resulting in partial tetrasomy and conferring a more severe clinical phenotype [2]. In children with maternal interstitial and isodicentric duplications, upwards of 50% and 80% meet the criteria for ASD, respectively [2,3,4, 15,16,17]

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