30895
Neuroanatomical Underpinnings of Autism Symptomatology in 22q11.2 Deletion Syndrome and Idiopathic Autism Spectrum Disorder
22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition resulting from a microdeletion at the q11.2 band of chromosome 22 (Scambler et al., 1992). All individuals with 22q11.2DS display a deletion within the same locus of chromosome 22. However, the phenotypic consequences of the deletion are both complex and variable (McDonald-McGinn et al., 2015), making the neurobiology of 22q11.2DS inherently difficult to characterize. One of the neuropsychiatric phenotypes commonly present in 22q11.2DS is co-morbid autism spectrum disorder (ASD)-symptomatology. However, the neuroanatomical underpinnings of these symptoms remain poorly understood.
Objectives:
We aimed to establish (1) whether the neuroanatomical underpinnings of ASD-symptomatology in 22q11.2DS are shared with - or distinct from - the neural systems mediating autistic symptoms in idiopathic ASD, and (2) whether the neuroanatomy of ASD is significantly modulated by the 22q11.2 microdeletion.
Methods:
We examined neuroanatomical differences in 126 individuals (6-25 years; 66 males and 60 females; IQ ≥ 60) assessed at three sites: (1) the Child and Adolescent Psychiatry, Frankfurt, Germany; (2) the King’s College London, UK; and (3) the University of California, Los Angeles, US. The total sample included (1) 25 individuals with 22q11.2DS who also met diagnostic criteria for ASD (22q11.ASD), (2) 25 individuals with 22q11.2DS without a diagnosis of ASD (22q11.nonASD), (3) 25 individuals with idiopathic ASD, and (4) 51 neurotypical controls. All groups were matched for age and gender. The 22q11.2 microdeletion was confirmed by in-situ hybridization (FISH) or microarray analysis test. ASD-symptomatology was assessed using the Autism Diagnostic Interview-Revised (ADI-R; Lord et al., 1994). We employed a 2-by-2 factorial design, controlling for age, gender, site, IQ, and total brain measures to identify neuroanatomical diversity associated with (1) the 22q11.2 microdeletion (i.e. main effect of 22q11.2DS), (2) ASD-symptomatology (i.e. main effect of ASD), and (3) a 22q11.2DS-by-ASD interaction term.
Results:
We observed a significant main effect of ASD for cortical volume (CV), cortical thickness (CT), and surface area (SA) in several regions across the cortex that have previously been linked to wider autistic symptoms and traits (e.g. superior temporal lobes, entorhinal cortices, and anterior cingulate cortex). Moreover, individuals with 22q11.2DS were neuroanatomically distinct from those without the microdeletion displaying (1) decreased CV, SA, and CT in occipito-temporal and cingulate regions, and (2) increased CV and SA in frontal regions (see Fig.1). Notably, we also identified brain regions (i.e. dorsolateral prefrontal cortex, precentral gyrus, and posterior cingulate cortex) where the 22q11.2 microdeletion significantly interacted with ASD-symptomatology to elicit neuroanatomical differences that could not be predicted by either main effect alone (see Fig.1 and Fig.2). Thus, in these brain regions the neuroanatomy of ASD-symptomatology was modulated by individuals having the 22q11.2 microdeletion.
Conclusions:
Our findings indicate that even though behaviourally similar, the neuroanatomical underpinnings of ASD-symptomatology differ between individuals with the 22q11.2 microdeletion and those without. Thus, the co-existence of both conditions does not appear to represent a combination of the neuroanatomical diversity exhibited by each of the two conditions in isolation, but rather constitutes an independent subgroup with a unique neurophenotype.