Initial Phenotypic Characterization across Three Developmental Synaptopathies

Background: Pathways involved in synaptic function play a critical role in conditions associated with intellectual disability and autism spectrum disorder (ASD) such as Tuberous Sclerosis Complex (TSC), PTEN hamartoma tumor syndrome (PHTS), and Phelan-McDermid Syndrome (PMS). Defining observable phenotypes within and across related developmental synaptopathies is a fundamental level of analysis to understanding the relationship between underlying genetic causes and behavioral/cognitive expressions in these syndromic conditions.

Objectives: We analyzed baseline data from DSC to characterize and compare patterns of intellectual disability (ID), autism, and behavioral/psychiatric symptoms in TSC, PHTS, and PMS.

Methods: A comprehensive battery was collected at baseline for children ages 3-18 with TSC (n=98), PHTS (n=67), and PMS (n=98). This battery included measures of IQ, adaptive behavior, problem behaviors, mood and psychiatric symptoms, and ASD symptoms. Adaptations to this assessment battery were necessary to facilitate the evaluation of ID, ASD, and behavioral symptoms in these samples and will be detailed in the presentation. Initial results are presented from one-way ANOVAs with Bonferroni’s corrections were conducted to analyze group differences on IQ, Vineland Adaptive Behavior Scale-II (VABS-II) Adaptive Behavior Composite (ABC) and domain standard scores standard scores , the ADOS2 Calibrated Severity Score (CSS), Repetitive Behavior Scale-Revised (RBS-R) Total Score, and Child Behavior Checklist 6-18 (CBCL/6-18) Internalizing and Externalizing T-scores.

Results: Mean chronological age of 8.74 years (SD=4.74) did not differ across the samples. Intellectual disability (ID) appeared as a characteristic phenotype in all three developmental synaptopathies. In the context of wide within-group variability, significant group differences were found on FSIQ (F_{(2, 237)}=93.9, p<.0001) and VABS-II ABC (F_{(2, 207)}=14.4, p<.001), such that PHTS>TSC>PMS, corresponding to the following levels of ID: PHTS (Borderline), TSC (Mild to Moderate), and PMS (Severe to Profound). Initial analyses suggesting group differences on ADOS2 CSS require correction for IQ and cohort effects. RBS-R total scores did not differ across groups (F_{(2, 211)}=1.9, p=.156). Across groups, mean CBCL scores were in the non-clinical range or cusp of the borderline clinical range. Post-hoc analyses pointed to significantly lower CBCL/6-18 internalizing symptoms in PMS vs. TSC (p=.013) (omnibus F_{(2, 112)}=4.8, p=.010) though no differences were found on VABS-II internalizing scale. Higher externalizing problem behavior levels were reported in TSC vs. PHTS on both the CBCL/6-18 (p=.001) (omnibus F_{(2, 211)}=6.9, p=.001) and VABS-II (p=.031) (omnibus F_{(2, 199)}=4.4, p=.014).

Conclusions: Initial results suggest diverse ID, ASD, and behavioral phenotypes across PTEN, PMS, & TSC, as well as considerable within syndrome variability. Interpretation of findings requires further study given that many of measures were not validated on individuals with moderate to severe ID (e.g., CBCL/6-18). Additional analyses related to within-disorder variability and genotype-phenotype correlations will be presented. In addition, the effect of IQ/ID on autism and behavior profiles and potential age-cohort effects are of interest given evidence that individuals now diagnosed with genetic conditions associated with ASD and ID may not be as severe as those previously identified.