UCLA

Clinically defined neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) are behaviorally and etiologically heterogeneous, limiting the ability of diagnosis-first approaches to identify their underlying neurobiological mechanisms. Copy number variants (CNVs) at the 22q11.2 locus offer a genetics-first model for identifying convergent and divergent neurobiological pathways contributing to risk. Reciprocal deletions (22qDel) and duplications (22qDup) of the same 22q11.2 genomic segment provide a genetics-first model of gene-dosage effects, with 22qDel conferring markedly elevated schizophrenia risk, while 22qDup is associated with substantially lower risk, potentially protective relative to the general population. Both CNVs, however, converge in conferring elevated risk for ASD and intellectual disability. Although cortical and subcortical systems have been relatively well studied in 22q11.2 CNVs, the cerebellum, long regarded as a purely motor structure but now understood to also support cognition, social processing, and affect, has remained comparatively unexplored. This dissertation asks whether the cerebellum represents an important and gene-dosage-sensitive substrate of neuropsychiatric and neurodevelopmental risk, and whether cerebellar vulnerability converges across distinct high-risk CNVs. The first manuscript establishes the cerebellar structural phenotype in reciprocal 22q11.2 CNVs, identifying widespread volume reductions in 22qDel but comparatively preserved and regionally selective alterations in 22qDup, with Vermis VII representing a shared site of vulnerability. The second manuscript extends this work to cerebellar white matter microstructure and resting-state functional connectivity, revealing a striking dissociation across imaging modalities. Whereas cerebellar volume abnormalities were most pronounced in 22qDel, white matter microstructural alterations were unexpectedly more widespread in 22qDup, affecting all three cerebellar peduncles; 22qDel showed more selective, opposite-direction effects concentrated in the superior cerebellar peduncle. Functional connectivity alterations were comparatively limited overall, with significant hypoconnectivity detected only in 22qDel. Integrating volume, microstructure, and connectivity into multimodal profiles improved discrimination of CNV groups, with cerebellar volume contributing most strongly to 22qDel-related distinctions and peduncular diffusion measures contributing most strongly to 22qDup-related distinctions. The third manuscript tests whether this cerebellar vulnerability is specific to 22qDel or reflects a more general mechanism of neuropsychiatric risk, using normative modeling to directly compare cerebellar volume deviations in 22qDel and 3q29Del within a common analytic framework. Both syndromes showed substantial reductions in total cerebellar volume relative to a large normative reference sample, with no statistically detectable difference in the magnitude of reduction between CNVs. Regional analyses revealed broad convergence, alongside a smaller subset of regions showing CNV-specific differences. Together, these findings identify the cerebellum as a robust but multidimensional substrate of neurodevelopmental risk. Distinct genomic perturbations converge on substantial cerebellar volume reduction, while reciprocal 22q11.2 dosage produces divergent effects on cerebellar white matter and functional circuitry. This work demonstrates the value of a genetics-first, multimodal approach for identifying neurobiological phenotypes that may be obscured by the etiological heterogeneity of conventional psychiatric diagnoses, and provides a foundation for investigating how distinct genetic risk factors converge on shared brain systems while producing different patterns of circuit-level dysfunction.