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Prioritizing genetic contributors to cortical alterations in 22q11.2 deletion syndrome using imaging transcriptomics

Forsyth, Jennifer K., Mennigen, Eva, Lin, Amy, Sun, Daqiang, Vajdi, Ariana, Kushan-Wells, Leila, Ching, Christopher R. K., Villalon-Reina, Julio E., Thompson, Paul M., Bearden, Carrie E., Cunningham, Adam, Doherty, Joanne L., Linden, David E., Moss, Hayley, Owen, Michael and Van den Bree, Marianne 2021. Prioritizing genetic contributors to cortical alterations in 22q11.2 deletion syndrome using imaging transcriptomics. Cerebral Cortex 31 (7) , pp. 3285-3298. 10.1093/cercor/bhab008

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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. In the 22q11.2 ENIGMA Working Group, we characterized cortical alterations in individuals with 22q11DS (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 genes that may contribute to altered surface area (SA) and cortical thickness (CT) in 22q11DS. Total SA was reduced in 22q11DS (Z-score deviance = −1.04), with prominent reductions in midline posterior and lateral association regions. Mean CT was thicker in 22q11DS (Z-score deviance = +0.64), with focal thinning in a subset of regions. Regional expression of DGCR8 was robustly associated with regional severity of SA deviance in 22q11DS; AIFM3 was also associated with SA deviance. Conversely, P2RX6 was associated with CT deviance. Exploratory analysis of gene targets of microRNAs previously identified as down-regulated due to DGCR8 deficiency suggested that DGCR8 haploinsufficiency may contribute to altered corticogenesis in 22q11DS by disrupting cell cycle modulation. These findings demonstrate the utility of combining neuroanatomic and transcriptomic datasets to derive molecular insights into complex, multigene copy number variants.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: Cardiff authors contributed as part of the 22q11.2 ENIGMA Consortium. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
Publisher: Oxford University Press
ISSN: 1047-3211
Date of First Compliant Deposit: 12 April 2021
Date of Acceptance: 2 May 2020
Last Modified: 29 Jul 2022 07:46

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