Behavioral and Electrophysiological Characterization of Children with 15q11.2-q13.3 Duplications

Background: The surge in genetic testing for chidlren with Autism Spectrum Disorder (ASD) has facilitated the identification of causative rare genetic variants and, with the ascertainment of subgroups of individuals with shared variants, the identification of clinically meaningful genetic syndromes (Jeste and Geschwind, 2014).  Detailed developmental and behavioral characterization has lagged behind the genetic diagnoses, leaving considerable uncertainty regarding prognosis and recommended treatments. Duplication of 15q11.2-q13.3, or Dup15q syndrome, represents one of the most common copy number variants associated with ASD, and its clinical features, particularly in relation to ASD and intellectual disability, are being elucidated through collaborative efforts facilitated by a national Dup15q alliance.

Objectives: The first objective was to identify patterns of social communication, adaptive, and cognitive skills in children with Dup15q syndrome compared to those with nonsyndromic ASD. The second objective was to compare resting state EEG patterns in Dup15q syndrome with nonsyndromic ASD, as case reports have described excessive beta band power in clinical EEGs of these children.

Methods: The Dup15q Alliance has been collecting a registry of patients, with 425 patients in the registry and 212 with complete clinical records. From the registry, 142 children have isodicentric 15q duplications, 30 have interstitial duplications, 14 have mosaic isodicentric duplications, and 26 have “edge” duplications either at q11.2 or q13.3. We recruited 13 children from the UCLA Dup15q clinic and compared them to a 13 IQ and age matched cohort of children with ASD. Participants were assessed for verbal and non-verbal cognition, ASD characteristics [Autism Diagnostic Observation Schedule] and adaptive function [Vineland Adaptive Behavior Scales].  High density EEG was recorded while children watched an abstract video, with an additional TD comparison group also tested. Relative power in delta (1 – 4 Hz), theta (4 – 8 Hz), alpha (8 – 12 Hz), low beta (12 – 20 Hz), high beta (20 – 30 Hz), and gamma (30 – 48 Hz) was calculated. Group comparisons were performed between diagnostic groups: Dup15q and ASD, and within the Dup15q group based on duplication type and epilepsy status.

Results: All children with Dup15q syndrome met criteria for ASD, but severity scores were lower in children with Dup15q syndrome. Children with Dup15q syndrome demonstrated significantly more impairment in motor (Gross motor DQ: Dup15q M=35.38, ASD M=70.21; t=5.9, p<.001; Fine motor DQ: Dup15q M=30.03, ASD M=66.5; t=5.2, p<.001) and daily living skills (Dup15q M=53.18, ASD M=63.82; t=2.41, p=.03). Within the Dup15q group, children with epilpesy demonstrated significantly lower cognitive and adaptive function than those without epilepsy (p<0.01 for all measures). Relative beta power was significantly higher in Dup15q syndrome than in the TD (p < 1.0 ´ 10^-4, FDR corrected) and ASD (p < 1.0 ´ 10^-4, FDR corrected) groups.

Conclusions: We have identified behavioral and neurophysiological features that distinguish a genetically defined subgroup within the autism spectrum. Ongoing translational studies will link electrophysiological and behavioral phenotypes in mouse models to patients to facilitate the identification of the specific genetic mechanisms underlying the neurodevelopmental symptom profile in children with Dup15q syndrome.