Genetic Correlates of Electrophysiological Responses to Repeated Auditory Stimuli in Phelan-Mcdermid Syndrome

Poster Presentation
Saturday, May 4, 2019: 11:30 AM-1:30 PM
Room: 710 (Palais des congres de Montreal)
E. Isenstein1,2, H. Grosman2, Y. Zhang2, M. Mulhern2, C. McLaughlin2, A. R. Durkin2, E. Wilkinson2, P. M. Siper2, S. De Rubeis3, J. Buxbaum4, L. E. Ethridge5, A. Kolevzon2 and J. Foss-Feig2, (1)University of Rochester, Rochester, NY, (2)Seaver Autism Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, (3)Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, (4)Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, (5)Pediatrics, University of Oklahoma Health Science Center, Norman, OK

Phelan-McDermid Syndrome (PMS) is a rare disorder caused by a loss-of-function point mutation in the SHANK3 site or a deletion at site 22q13.3, which includes the SHANK3 site, that alters synaptic and glutamatergic function. PMS is characterized by global developmental delay, hypotonia, and generalized sensory hyporesponsiveness. The presence of PMS confers approximately a 75% likelihood of a comorbid Autism Spectrum Disorder (ASD) diagnosis. Sensory differences including both hyporesponsiveness and hyperresponsiveness are a common feature of ASD.


We investigated whether the hyporesponsiveness observed behaviorally in individuals with PMS can be recorded in electrophysiological (EEG) responses to repeated auditory stimuli. Additionally, we examined whether deletion size at the 22q13.3 locus in individuals with PMS correlated with degree of neural hyporesponsiveness and habituation to repeated auditory stimuli, as compared to typically developing (TD) controls.

Methods: EEG was recorded from 19 participants with PMS and 21 with TD, all 9-30 years of age, while a series of four consecutive 1000Hz tones was repeatedly presented. Within trials, each 50ms tone was separated by 616ms; inter-trial interval was 4000ms. Amplitudes of N1, P2, and N2 event-related potentials (ERPs) were extracted and compared between groups. Genetic reports for all PMS participants were assessed for base pair deletion length at the 22q13 gene. Individuals with a loss of function mutation at SHANK3 were assigned a deletion size of 58571 base pairs, the size of the entire SHANK3 gene.

Results: The PMS group showed a significantly lower mean P2 amplitude to the first tone relative to controls (p=.045). Habituation of the mean P2 amplitude was significantly larger in the TD group than the PMS group between tones 1 and 2, tones 1 and 3, and tones 1 and 4 (p=.038, p=.003, p=.018, respectively). Larger deletion size was associated with smaller mean P2 amplitude (r=-.43, p=.06) to the initial tone. Increased deletion size also correlated significantly with lesser habituation of mean P2 amplitude between tone 1 and 2 (r=-.51, p=.023), and approached significance for habituation between tones 1 and 3 as well as tones 1 and 4 (r=-.36, p=.12; r=-.38, p=.10; respectively).


Our results indicate relative electrophysiological hyporesponsiveness to auditory stimuli in the PMS group as compared to the TD group, consistent with global behavioral observations of under-reactivity in this group. Results also suggest lower levels of habituation of the P2 ERP component in the PMS group, with a robust negative relationship to base pair deletion size at the 22q13.3 locus. Results also demonstrate a strong relationship between degree of neural hyporesponsiveness and base pair deletion size; further investigation in necessary to parse the relationship between these variables.