The Neuroanatomy of Autism Spectrum Disorder Symptomatology in 22q11.2 Deletion Syndrome

Abstract

22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition associated with a high prevalence of neuropsychiatric conditions that include autism spectrum disorder (ASD). While evidence suggests that clinical phenotypes represent distinct neurodevelopmental outcomes, it remains unknown whether this translates to the level of neurobiology. To fractionate the 22q11.2DS phenotype on the level of neuroanatomy, we examined differences in vertex-wise estimates of cortical volume, surface area, and cortical thickness between 1) individuals with 22q11.2DS (n = 62) and neurotypical controls (n = 57) and 2) 22q11.2DS individuals with ASD symptomatology (n = 30) and those without (n = 25). We firstly observed significant differences in surface anatomy between 22q11.2DS individuals and controls for all 3 neuroanatomical features, predominantly in parietotemporal regions, cingulate and dorsolateral prefrontal cortices. We also established that 22q11.2DS individuals with ASD symptomatology were neuroanatomically distinct from 22q11.2DS individuals without ASD symptoms, particularly in brain regions that have previously been linked to ASD (e.g., dorsolateral prefrontal cortices and the entorhinal cortex). Our findings indicate that different clinical 22q11.2DS phenotypes, including those with ASD symptomatology, may represent different neurobiological subgroups. The spatially distributed patterns of neuroanatomical differences associated with ASD symptomatology in 22q11.2DS may thus provide useful information for patient stratification and the prediction of clinical outcomes.

Neuroanatomical underpinnings of autism symptomatology in carriers and non-carriers of the 22q11.2 microdeletion

“…The results reported in the present study also extend the findings of a previous neuroimaging study by our group, which was conducted in a subset of this sample, where we compared 22q11.2DS individuals with ASD symptomatology to 22q11.2DS without, and to TD controls (16). Notably, the main effect of 22q11.2DS was associated predominantly with significant reductions in SA, which have been shown to contribute more significantly to commensurate differences in rCV than measures of CT (49), and is also in line with previous findings in 22q11.2DS (15,39,50).…”

“…Neuroanatomical differences associated with the 22q11.2 microdeletion are well documented in the literature and include spatially distributed differences in rCV, SA, and CT in parietotemporal and cingulate regions, as well as the bilateral insula, parahippocampal gyrus, and DLPFC (15,16,39).…”

“…Corrections for multiple comparisons across the whole brain were performed using 'random field theory' (RFT)-based cluster analysis for non-isotropic images using a cluster based significance threshold of p<0.05 (2-tailed) (29). An RFT-based cluster correction was chosen over a permutationbased approach given its computational efficiency particularly for complex GLMs as utilized in the present study, and to make the results comparable to previous findings by our group (16,30).…”

“…A recent study by our group also reported differences in regional cortical volume (rCV) and surface area (SA) between 22q11.2DS individuals with and without ASD symptomatology. These differences were predominantly observed in parieto-temporal regions as well as in the posterior cingulate and dorsolateral prefrontal cortices, brain regions that have previously been linked to wider autistic symptoms and traits (16).…”

“…This study aimed to examine the neuroanatomical underpinnings of ASD symptomatology across disorders using a categorical approach that allowed us to establish the extent to which 22q11.2DS modulates the neuroanatomy of ASD. Based on prior evidence (16), it was hypothesized that ASD symptomatology in 22q11.2DS is not simply due to a higher neuroanatomical 'load' or affection status (i.e. more severe behavioral impairments associated with more pronounced neuroanatomical differences), but instead significantly interacts with the microdeletion to give rise to a distinct neuroanatomical brain phenotype.…”