The Hidden Architecture of Brain Structural Variability in 22q11.2 Deletion Syndrome: A Multi-site Study

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Abstract Importance 22q11.2 deletion syndrome (22q11DS) is among the strongest genetic risk factors for neuropsychiatric disorders and has marked effects on brain structure. Yet, it remains unclear which neuroanatomical features reflect uniform effects of the deletion versus inter-individual biological processes relevant to psychiatric outcomes. Identifying these features is critical for developing targeted treatments and interventions. Objective To identify brain regions where 22q11DS exerts its most consistent and most variable impacts, and to test whether these patterns align with normative neurotransmitter receptor distributions and cortical growth trajectories. Design Multisite cross-sectional case-control study. Setting T1-weighted brain MRI data were obtained across 15 scanners. MRI data underwent standardized processing, quality control procedures and statistical site-adjustment using ComBat. Participants A total of N = 438 individuals with 22q11DS (5-54 years, 48% females) and 380 typically developing controls (6-58 years, 48% females). Main Outcomes and Measures Primary outcomes were global and regional cortical thickness and surface area. Mean and dispersion estimates were calculated using double generalized linear models, correcting for age, age 2 , sex (and intracranial volume for surface area). Quantile shift functions characterized fine-scale distributional differences. Sensitivity analyses adjustedt for co-occurring neuropsychiatric disorders, antipsychotic use and deletion subtype. Secondary outcomes included spatial correspondence between regional structural alterations and normative maps of neurotransmitter receptor density and cortical expansion. Results Compared with controls, individuals with 22q11DS showed widespread mean differences in cortical thickness and surface area. Notably, 22q11DS was associated with greater regional heterogeneity in both measures, except for reduced dispersion in the anterior cingulate. Effects were attenuated after covariate adjustment. Cortical thickness differences spatially overlapped with regions enriched for glutamatergic and GABAergic receptors. There was partial evidence linking surface area dispersion patterns to normative cortical growth trajectories. Conclusions and Relevance 22q11DS exerts broad effects on cortical structure consistent with a global developmental mechanism, reflected in widespread mean shifts. Beyond these, region-specific variability, particularly in cortical thickness, suggests individualized neurobiological processes. The anterior cingulate emerges as a region of consistent structural deviation. Overall, structural variability in 22q11DS aligns with normative patterns of excitatory-inhibitory signaling and cortical development, implicating these pathways as potential targets for intervention. Key points Question Is 22q11.2 deletion syndrome (22q11DS) associated with altered spatial heterogeneity of cortical structure, and do these patterns map onto the brain’s underlying neurochemical and developmental architecture? Findings In this multisite case-control study of 438 22q11DS and 380 controls, 22q11DS showed regionally patterned increases in cortical thickness heterogeneity and lower cortical surface area heterogeneity. Spatial patterns of cortical thickness differences were aligned with cortical gradients of glutamate and GABAergic receptor density. Meaning Although 22q11DS is generally associated with reduced brain volume and increased cortical thickness, the present findings reveal regionally patterned cortical alterations aligned with neurotransmitter-specific cortical organization, suggesting a mechanistic link between excitatory–inhibitory signaling architecture and individualized neuroanatomic effects of 22q11DS.

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