Convergent and Divergent Cerebellar Alterations in 22q11.2 Copy Number Variants

Copy number variants (CNVs) at 22q11.2 confer substantial risk for neurodevelopmental and psychiatric disorders. Both the 22q11.2 deletion (22qDel) and 22q11.2 duplication (22qDup) are associated with increased risk for autism spectrum disorder and intellectual disability. In contrast, while 22qDel markedly increases risk for schizophrenia, 22qDup may be protective. Prior neuroimaging work has focused primarily on the cerebrum, leaving cerebellar contributions understudied, despite growing evidence for their relevance to cognition and psychopathology. Here, we characterized regional cerebellar structure and examined multivariate cerebellar-behavior associations in individuals with reciprocal 22q11.2 CNVs.

We analyzed 514 structural magnetic resonance imaging scans from 315 participants (mean age = 16.4 ± 8.8 years; 52% female), comprising 22qDel carriers (n = 111), 22qDup carriers (n = 37), and typically developing (TD) control participants (n = 167). The cerebellum was parcellated into 28 subregions using ACAPULCO. Group differences in total and regional cerebellar volumes were examined using linear mixed-effects models with false discovery rate correction. Multivariate brain-behavior associations were assessed using partial least squares correlation (PLSC).

Relative to TD control participants, 22qDel carriers showed widespread cerebellar volume reductions, whereas alterations in 22qDup were milder and regionally selective. Vermis VII was reduced in both 22q11.2 CNVs, indicating a shared site of anatomical vulnerability. PLSC identified domain-specific cerebellar patterns, with posterior regions-most prominently bilateral lobule VIIIA-associated with cognitive and social functioning and bilateral crus II and medial regions associated with psychosis-risk symptoms.

Reciprocal 22q11.2 CNVs showed shared and divergent cerebellar alterations, with distinct subregions contributing to different behavioral domains, underscoring the cerebellum's multifaceted role in neurodevelopment and psychiatric disease risk.