Abstract
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.
Highlights
22q11.2 deletion syndrome (22q11DS) arises from the deletion of a segment of chromosome 22 due to misalignment of low copy repeats (LCR) during nonallelic homologous recombination. It occurs in approximately 1 in 3000–4000 births and spans a ∼2.6 megabase (Mb) region that results in the hemizygous deletion of 46 protein-coding genes in 85–90% of patients (Guna et al 2015), with ∼10–15% of 22q11DS patients carrying a smaller, nested deletion (McDonald-McGinn et al 2015). 22q11DS is associated with a broad phenotype that includes heart anomalies, immune dysfunction, and high rates of neuropsychiatric and neurodevelopmental disorders such as schizophrenia, intellectual disability, and autism spectrum disorder (ASD; Jonas et al 2014; Schneider et al 2014)
As cortical gray matter volume reflects the product of cortical surface area (SA; i.e., area covered by the cortex) and cortical thickness (CT; i.e., thickness of the 6 neocortical layers), which appear to be determined through relatively independent genetic and neurodevelopmental mechanisms (Panizzon et al 2009; Winkler et al 2010; Chen et al 2013; Grasby et al 2020, but see Schmitt et al 2018), recent studies have examined these morphometric characteristics separately
A prominent rostro-caudal gradient of gene expression has been found across the cortex (Bernard et al 2012; Hawrylycz et al 2012; Miller et al 2014), which is thought to reflect the rostrocaudal gradient of neurogenesis and cell composition in which posterior brain regions have a higher density of neurons that are smaller in size, while anterior regions tend to have a lower density of neurons that are larger in size and spine density (Cahalane et al 2012; Charvet et al 2015; Fornito et al 2019)
Summary
22q11.2 deletion syndrome (22q11DS) arises from the deletion of a segment of chromosome 22 due to misalignment of low copy repeats (LCR) during nonallelic homologous recombination. Recent studies have used the Allen Human Brain Atlas (AHBA), a transcriptomic dataset quantifying the expression of over 20 000 genes across postmortem brain tissue from six psychiatrically healthy individuals, to elucidate mechanisms underlying cellular and neural circuit variation in healthy individuals and in populations with neuropsychiatric and neurodegenerative disorders (Fornito et al 2019). Prior studies of neurodevelopmental, neuropsychiatric, and neurodegenerative populations suggest that identifying genes with expression patterns that are spatially correlated with neuroimaging phenotypes can offer a useful strategy to elucidate genetic drivers of altered brain structure and function. By characterizing the spatial convergence between regional expression of each individual 22q11.2 gene and the severity of morphometric alterations within patients, we sought to systematically prioritize individual genes within the 22q11.2 locus that may be causally related to these alterations and elucidate potential underlying molecular mechanisms
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
