Abstract
22q11.2 Deletion Syndrome (22q11.2DS) is a genetic deletion syndrome associated with a wide range of somatic and neuropsychiatric conditions, which are highly heterogeneous both between and within individuals, and across different stages of development. In particular the prevalence of autism spectrum disorder (ASD) has been reported with high estimated prevalence ranging from 18% to 58% in 22q11.2DS (Fiksinski et al., 2017, Antshel et al., 2007, Schneider et al., 2014, Jalbrzikowski et al., 2017). The deleted region in 22q11.2DS contains between ~30–40 clearly mapped genes offering a unique opportunity to explore the biological mechanisms conferring vulnerability to ASD and other associated conditions. However, it is unclear whether the ASD phenotype observed in 22q11.2DS is associated with similar neuroanatomical aberrations to those found in other idiopathic forms of ASD. This is important to explore further, as better understanding of the neuroanatomy associated with ASD in 22q11.2DS can be used in several ways. For example, it can be used to develop specific biomarkers to predict vulnerability to develop ASD in individuals with 22q11.2DS, as well as developing treatments that target specific neuroanatomical aberrations associated with 22q11.2DS (i.e. if these differ to ASD).The overall objective of this thesis was to fractionate the highly heterogeneous neuroanatomical phenotype of 22q11.2DS, in particular with regards to autism spectrum symptomatology. The aims were three-fold; (1) to provide an updated meta-analysis of all structural MRI studies in 22q11.2DS, and to examine differences in brain structural variability; (2) to explore surface anatomy of the cerebral cortex of individuals with 22q11.2DS; and (3) to examine the neuroanatomical correlates of ASD symptomatology in 22q11.2DS.
First, the literature on neuroanatomy was reviewed and a meta-analysis was conducted across all current structural MRI studies conducted in 22q11.2DS (Chapter 3), where it was observed that 22q11.2DS is associated with volumetric decreases both globally and regionally, as well as increased variability in hippocampus. To further disentangle the neuroanatomical consequences of 22q11.2DS on neuroanatomy, this thesis then examined differences across the cerebral cortex level, using vertex-wise measures of grey matter, cortical thickness (CT), surface area (SA), and cortical volume (Chapters 3 & 4). Here, the results conveyed that measures of cerebral volume in 22q11.2DS are complex, with measures of CT and SA each contributing differently, and in some part overlap and ‘conceal’ some of the underlying volumetric differences. Finally, this thesis examined the effects of ASD symptomatology on the neuroanatomy of 22q11.2DS by firstly comparing 22q11.2DS individuals with ASD to those without (Chapter 5) and then by comparing these to idiopathic ASD (Chapters 6 & 7). Here, our findings suggest that the neuroanatomy of ASD symptomatology in 22q11.2DS, in particular surface area, does not represent a simple exacerbation of the 22q11.2DS phenotype. Instead, within some regions (i.e. dorsolateral pre-frontal Cortex (DLPFC) and poster cingulate cortex (PCC)), ASD characteristics interact with 22q11.2DS presenting neuroanatomical differences that cannot be explained by either the microdeletion or ASD symptomatology alone. Further, despite a similar clinical phenotype, the neuroanatomical correlates of ASD symptomatology in individuals with 22q11.2DS diverge from those in idiopathic ASD and as such, 22q11.2DS individuals with ASD symptomatology represent a neuroanatomically distinct subgroup that differs from both 22q11.2DS individuals without a diagnosis of ASD, and from individuals with idiopathic ASD.
The overall findings of this thesis demonstrate that individuals with 22q11.2DS have significant neuroanatomical variability, especially across measures of cortical morphometry. Despite having a somewhat similar behavioural profile to that of idiopathic ASD, individuals with 22q11.2DS and ASD symptomatology have a distinct neuroanatomy, representing a distinct group with a diverse phenotype. Future studies should consider applying dimensional approaches to ASD diagnosis in 22q11.2DS, alongside detailed genetic studies, to fully capture the strength and difficulties associated with 22q11.2DS. This can assist in developing more effective treatment strategies for individuals with 22q11.2DS, based on their most likely clinical outcome.
| Date of Award | 1 Aug 2021 |
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| Original language | English |
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| Supervisor | Michael Craig (Supervisor), Christine Ecker (Supervisor), Nick Puts (Supervisor) & Dafnis Batalle (Supervisor) |