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22q11.2 deletion syndrome (22q11.2DS) is a genetic condition accompanied by a range of psychiatric manifestations, including autism spectrum disorder (ASD). It remains unknown, however, whether these symptoms are mediated by the same or distinct neural mechanisms as in idiopathic ASD. Here, we examined differences in lGI associated with ASD in 50 individuals with 22q11.2DS (n = 25 with ASD, n = 25 without ASD) and 81 individuals without 22q11.2DS (n = 40 with ASD, n = 41 typically developing controls). We initially utilized a factorial design to identify the set of brain regions where lGI is associated with the main effect of 22q11.2DS, ASD, and with the 22q11.2DS-by-ASD interaction term. Subsequently, we employed canonical correlation analysis (CCA) to compare the multivariate association between variability in lGI and the complex clinical phenotype of ASD between 22q11.2DS carriers and noncarriers. Across approaches, we established that even though there is a high degree of clinical similarity across groups, the associated patterns of lGI significantly differed between carriers and noncarriers of the 22q11.2 microdeletion. Our results suggest that ASD symptomatology recruits different neuroanatomical underpinnings across disorders and that 22q11.2DS individuals with ASD represent a neuroanatomically distinct subgroup that differs from 22q11.2DS individuals without ASD and from individuals with idiopathic ASD.

Background A crucial step to understanding the mechanistic underpinnings of autism spectrum disorder (ASD), is to examine if the biological underpinnings of ASD in genetic high-risk conditions, like 22q11.2 deletion syndrome (22q11.2DS), are similar to those in idiopathic illness. This study aimed to examine if ASD symptomatology in 22q11.2DS is underpinned by the same—or distinct—neural systems that mediate these symptoms in non-deletion carriers. Methods We examined vertex-wise estimates of cortical volume (CV), surface area (SA), and cortical thickness across 131 individuals between 6 and 25 years of age including (1) 50 individuals with 22q11.2DS, out of which n = 25 had a diagnosis of ASD, (2) 40 non-carriers of the microdeletion with a diagnosis of ASD (i.e., idiopathic ASD), and (3) 41 typically developing (TD) controls. We employed a 2-by-2 factorial design to identify neuroanatomical variability associated with the main effects of 22q11.2DS and ASD, as well as their interaction. Further, using canonical correlation analysis (CCA), we compared neuroanatomical variability associated with the complex (i.e., multivariate) clinical phenotype of ASD between 22q11.2 deletion carriers and non-carriers. Results The set of brain regions associated with the main effect of 22q11.2DS was distinct from the neuroanatomical underpinnings of the main effect of ASD. Moreover, significant 22q11.2DS-by-ASD interactions were observed for CV and SA in the dorsolateral prefrontal cortex, precentral gyrus, and posterior cingulate cortex, suggesting that the neuroanatomy of ASD is significantly modulated by 22q11.2DS (p < 0.01). We further established that the multivariate patterns of neuroanatomical variability associated with differences in symptom profiles significantly differed between 22q11.2 deletion carriers and non-carriers. Limitations We employed a multicenter design to overcome single-site recruitment limitations; however, FreeSurfer-derived measures of surface anatomy have been shown to be highly reliable across scanner platforms and field strengths. Further, we controlled for gender to address the differing distribution between idiopathic ASD individuals and the other groups. Nonetheless, the gender distribution in our sample reflects that of the respective populations, adding to the generalizability of our results. Last, we included individuals with a relatively wide age range (i.e., 6–25 years). Conclusions Our findings indicate that neuroanatomical correlates of ASD symptomatology in carriers of the 22q11.2 microdeletion diverge from those in idiopathic ASD.

The 22q11.2 deletion syndrome (22q11.2DS) is a neurodevelopmental disorder associated with a number of volumetric brain abnormalities. The syndrome is also associated with an increased risk for neuropsychiatric disorders including schizophrenia and autism spectrum disorder. An earlier meta-analysis showed reduced grey and white matter volumes in individuals with 22q11.2DS. Since this analysis was conducted, the number of studies has increased markedly, permitting more precise estimates of effects and more regions to be examined. Although 22q11.2DS is clinically heterogeneous, it is not known to what extent this heterogeneity is mirrored in neuroanatomy. The aim of this study was thus to investigate differences in mean brain volume and structural variability within regions, between 22q11.2DS and typically developing controls. We examined studies that reported measures of brain volume using MRI in PubMed, Web of Science, Scopus and PsycINFO from inception to 1 May 2019. Data were extracted from studies in order to calculate effect sizes representing case–control difference in mean volume, and in the variability of volume (as measured using the log variability ratio (lnVR) and coefficient of variation ratio (CVR)). We found significant overall decreases in mean volume in 22q11.2DS compared with control for: total brain (g = −0.96;p g = −0.81,p g = −0.81;p g = −0.47;p g = −0.84;p g = −0.73;p = 0.053), cerebellum (g = −1.25;p g = −0.90;p p = 0.036; CVR, 1.30;p p = 0.004). The results support the notion that structural abnormalities in 22q11.2DS and schizophrenia are convergent, and also to some degree with findings in autism spectrum disorder. Finally, the increased variability seen in the hippocampus in 22q11.2DS may underlie some of the heterogeneity observed in the neuropsychiatric phenotype.

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.