Profiles of Autistic Symptoms in Individuals with 22q11.2 Duplication or Deletion Syndromes, Regardless of Autism Diagnosis

Background: Genetic syndromes associated with Autism Spectrum Disorder (ASD) may hold promise for understanding its underlying biology, but such insights depend on a solid understanding of human phenotypes. Our groups recently reported increased prevalence of ASD among individuals with 22q11.2 Deletion (DS; Ousley et al., 2017) and Duplication Syndromes (DupS; Wenger et al, 2016). Many studies note pervasive autism-like symptoms in individuals with 22q11.2DS/DupS, regardless of ASD diagnosis, highlighting social communication impairments (SCI) such as reduced facial expression and difficulty initiating in 22q11.2DS, and high rates of restricted or repetitive behaviors and interests (RRBI) in 22q11.2DupS. Thus, possessing either one or three copies of the 22q11.2 region appears to yield at least some SCI or RRBI symptoms in most individuals. It remains unknown how or why autistic symptom profiles differ between deletions and duplications, which could inform clinical practice at 22q11.2 clinics as well as 22q11.2 animal models of ASD.

Objectives: To compare and describe the profile of autistic symptoms between individuals with 22q11.2 duplication and deletion.

Methods: We recruited participants with 22q11.2DupS (n=20; ages 4-14; 80% male) or DS (n=61; ages 4-29, 50.8% male) confirmed by SNP, MLPA, or FISH testing. We examined differences in RRBI and SCI between and within groups on the subsets that completed the ADI-R, ADOS, and DSM5 checklist. We computed the proportion of possible algorithm points (or possible symptom count for DSM5 checklist) endorsed in each domain to facilitate comparisons across domains and measures. We used MANOVA followed by Bonferroni-corrected (adjusted-p=0.004) nonparametric posthoc Wilcoxon within- and between-group tests to account for small, non-normal distributions and ordinal data. We report effect sizes to aid interpretation given our small sample.

Results: Results showed no significant differences in levels of SCI or RRBI between deletions or duplications of 22q11.2. Posthoc tests revealed small effect sizes for most comparisons (r’s 0.006-0.23), and negligible effect sizes for the most powered between-group analysis, the ADI-R (SCI r=0.006, RRBI r=0.015; see figure). Preliminary ADOS results showed two large, non-significant effects driven by low RRBI scores for deletions (ADOS SCI vs. RRBI within deletions: r=0.72, p=0.042; ADOS RRBI between groups: r=0.58, p=0.35). Future analyses available by May 2018 will include clinically useful descriptions of item endorsement rates for each group.

Conclusions: Individuals with duplication or deletion of 22q11.2 appear to show similar ADI-R profiles of SCI and RRBI symptoms in the full sample. These surprising results open questions about ‘dosage’ effects of genes in the region, as both too many and too few copies yield similar autistic profiles. Animal models might be particularly suited to probe these questions; recent work with 22q11.2DS mouse models reported partial relief of schizophrenia phenotypes, and similar advances may be possible with ASD. Furthermore, Auerbach and colleagues (2012) studied such ‘dosage’ effects and relieved autistic phenotypes by cross-breeding two mouse models (TSC and FragX) with excessive or insufficient synaptic protein synthesis. Our study will provide nuanced information about the autistic phenotypes that can be expected in individuals with 22q11.2DS and DupS.