Background: 22q11.2 deletion syndrome (22q11DS) results from a hemizygous deletion that typically spans 46 protein-coding genes and is associated with widespread alterations in brain morphology. The specific genetic mechanisms underlying these alterations remain unclear.

Methods: In the 22q11.2 ENIGMA Working Group, we characterized cortical alterations in individuals with 22q11.2 deletions spanning the typical A-D region (n = 232) versus healthy individuals (n = 290) and conducted spatial convergence analyses using gene expression data from the Allen Human Brain Atlas to prioritize individual gene drivers of altered surface area (SA) and cortical thickness (CT).

Results: Total SA was reduced in 22q11DS, with prominent reductions in midline posterior and lateral association regions. Overall, CT was thicker in 22q11DS, with focal thinning in a subset of regions. Regional expression of DGCR8 and AIFM3 were associated with regional severity of SA deviance in 22q11DS. Conversely, expression of P2RX6 was associated with regional severity of CT deviance. Exploratory gene-set analysis of gene targets of microRNAs previously found to be downregulated due to DGCR8 deficiency suggested that DGCR8 haploinsufficiency contributes to altered corticogenesis in 22q11DS by disrupting cell cycle modulation.

Conclusions: These results highlight DGCR8, AIFM3, and P2RX6 as candidate drivers of altered cortical morphology in 22q11DS and demonstrate the utility of combining neuroanatomic and transcriptomic datasets to derive molecular insights into complex, multi-gene CNVs.