Leveraging Clinical Neuroimaging to Chart Brain Structure in 22q11.2 Deletion Syndrome
Abstract
Background
22q11.2 deletion syndrome (22q11DS) is a common microdeletion linked to brain alterations and high psychiatric risk. However, prospective research studies often exclude severely affected individuals, potentially failing to capture the full neurobiological heterogeneity. Retrospective clinical MRI offers a powerful data source to address this gap.
Methods
This study utilized a cohort of 92 patients with 22q11DS (0.5-21 years, 49% female) and 252 matched controls. The authors applied normative modeling to calculate standardized deviation scores for imaging-derived phenotypes. They compared case-control effect size maps to data from the ENIGMA-22q consortium, correlated cortical deviation patterns with Allen Human Brain Atlas gene expression data, and generated 22q11DS-specific brain growth charts, mapping them to cognitive outcomes.
Results
22q11DS was associated with widespread brain deviations, including smaller volumes (max Cohen’s d=−1.31) and cortical surface area (d=−0.71) alongside increased cortical thickness (d=0.39). These findings were highly convergent with the ENIGMA-22q research cohort (r=0.61-0.87). A substantial portion of patients (40%) exhibited at least one global brain measure below the 2.5th percentile. Cortical deviations were spatially correlated with expression patterns of genes within the 22q11.2 locus. Deviations from the 22q11DS-specific growth charts were associated with clinical outcomes; smaller cerebellar volume relative to 22q11DS peers was associated with lower language scores (p<0.03).
Conclusions
This study validates the use of heterogeneous clinical imaging to robustly characterize brain structure in rare genetic disorders. Syndrome-specific growth charts provide a novel framework to quantify within-syndrome variability and demonstrate potential prognostic value by linking individual brain structure to cognitive outcomes.
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