Social-Communication and Restricted and Repetitive Behavior (RRB) Profiles in Children with Phelan-Mcdermid Syndrome Compared to Non-Syndromic Autism Spectrum Disorder (ASD)

Background: Phelan-McDermid syndrome (PMS) is a genetic syndrome caused by mostly de novo chromosomal abnormalities in the terminal end of 22q that  includes the SHANK3 gene. Loss of SHANK3, either through deletion or mutation, results in a phenotype characterized by significant intellectual disability, severe speech delay, hypotonia, minor dysmorphic features, and autistic-like behaviors. PMS is described as a common genetic form of ASD, accounting for up to 1% of ASD cases, with features including poor eye contact, self-stimulation, and repetitive mannerisms. However, the specificity, type, and degree of ASD symptoms in PMS remain unclear.

Objectives: The purpose of this investigation is to examine overlap and differences in ASD phenotype between PMS and non-syndromic ASD and to inform measurement targets for intervention research in PMS and  ASD. 

Methods: We analyzed ASD symptom profiles in a prospectively recruited sample of (n=24) of children with PMS (age 1.7 to 8.4 years) and a convenience sample of non-syndromic children with ASD, intellectual disability (ID), and language delay (n=38, age 2.1-8.2 years). The comparison group was a subsample of a larger community-based study of autism, selected on chronological age and developmental quotient scores <45. Measures included the ADOSG/ADOS2, ADI-R, and developmental/behavioral assessments. Non-parametric tests (Mann-Whitney U) were conducted on demographic and domain scores on the ADOS and ADI-R. 

Results: Mean ADOS2 and ADI-R domain scores were in the ASD range for the PMS sample. Children with PMS did not differ on mean social-communication (or social affect) domain scores on the ADOS2 or ADI-R. However, subdomain analyses showed more severe communication impairments in PMS relative to non-syndromic ASD (ADOSG, communication domain).  Peer relationships were less impaired in PMS relative to non-syndromic ASD (ADI-R, A2). The RRB domain also differed significantly between groups with lower scores in PMS relative to non-syndromic ASD on the ADOS2. Domain analysis of ADI-R scores indicate the PMS group had significantly fewer lower-order repetitive behaviors (ADI-R, C3 & C4) and higher scores on encompassing preoccupations/circumscribed interests (ADI-R, C1).  

Conclusions: Results from our study are the first to characterize ASD features in PMS relative to non-syndromic ASD.  Findings are consistent with a growing body of literature indicating the overlap between ASD and the clinical features of PMS. Our findings suggest potential for a distinct RRB profile in PMS relative to non-syndromic ASD with ID.  Investigations of neurobehavioral profiles in PMS are needed to understand the unique behavioral phenotype associated with SHANK3 deficiency.