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.

Keywords: 22q11.2 Deletion Syndrome; autism spectrum disorder; brain anatomy; neurodevelopment; surface based morphometry.

Figure 1.

Significant differences in cortical volume (A), surface area (B), and cortical thickness (C) in individuals with 22q11.2DS compared with neurotypical controls. The left panel shows the unthresholded t-maps where increases in 22q11.2DS relative to controls are indicated in yellow-red (i.e., 22q11.2DS > controls), and decreases in cyan-blue (i.e., 22q11.2DS < controls). The right panel shows the random-field-theory (RFT)-based cluster-corrected (P < 0.05, 2-tailed) difference maps indicating significant increases (marked in red) and decreases (marked in blue) following correction for multiple comparisons.

Figure 2.

Significant differences in cortical volume (A), surface area (B), and cortical thickness (C) in 22q11.ASD compared with 22q11.nonASD. The left panel shows the unthresholded t-maps where increases in 22q11.ASD relative to 22q11.nonASD are indicated in yellow-red (i.e., 22q11.ASD > 22q11.nonASD), and decreases in cyan-blue (i.e., 22q11.ASD < 22q11.nonASD). The right panel shows the random-field-theory (RFT)-based cluster-corrected (P < 0.05, 2-tailed) difference maps indicating significant increases (marked in red) and decreases (marked in blue) following correction for multiple comparisons.

Figure 3.

Correlations between measures of ASD symptomatology and clusters with a significant difference in surface area between 22q11.ASD and 22q11.nonASD. Significant correlations (P < 0.05, uncorrected) are highlighted in blue.