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

Area of Science:

• Neuroimaging
• Genetics
• Developmental Neuroscience

Background:

• Copy number variants (CNVs) at 22q11.2, including deletions (22qDel) and duplications (22qDup), are linked to neurodevelopmental and psychiatric disorders like autism, intellectual disability, and schizophrenia.
• Previous research on 22q11.2 CNVs has primarily focused on the cerebrum, with limited investigation into the cerebellum's role despite its known involvement in cognition and psychopathology.

Purpose of the Study:

• To investigate regional cerebellar structural differences between individuals with 22q11.2 deletion (22qDel) and 22q11.2 duplication (22qDup) compared to typically developing controls.
• To explore multivariate associations between cerebellar structure and behavioral domains, including cognitive, social, and psychosis-risk symptoms.

Main Methods:

• Analysis of 514 structural MRI scans from 315 participants (22qDel, 22qDup, and typically developing controls).
• Cerebellar parcellation into 28 subregions using ACAPULCO.
• Linear mixed-effects models and false discovery rate correction to assess group differences in cerebellar volumes.
• Partial least squares correlation (PLSC) to examine brain-behavior associations.

Main Results:

• 22qDel carriers exhibited widespread cerebellar volume reductions compared to controls.
• 22qDup carriers showed milder, regionally selective cerebellar alterations.
• Vermis VII was reduced in both 22qDel and 22qDup groups, indicating a shared vulnerability.
• Posterior cerebellar regions (lobule VIIIA) were associated with cognitive and social functioning, while medial regions and crus II were linked to psychosis-risk symptoms.

Conclusions:

• Reciprocal 22q11.2 CNVs result in both shared and distinct cerebellar structural alterations.
• Specific cerebellar subregions are differentially associated with distinct behavioral domains, highlighting the cerebellum's complex role in neurodevelopment and psychiatric risk.