Magnitude and heterogeneity of brain structural abnormalities in 22q11.2 deletion syndrome: a meta-analysis

Abstract

The 22q11.2 deletion syndrome (22q11.2DS) is a neurodevelopmental disorder associated with a number of volumetric brain abnormalities. The syndrome is also associated with an increased risk for neuropsychiatric disorders including schizophrenia and autism spectrum disorder. An earlier meta-analysis showed reduced grey and white matter volumes in individuals with 22q11.2DS. Since this analysis was conducted, the number of studies has increased markedly, permitting more precise estimates of effects and more regions to be examined. Although 22q11.2DS is clinically heterogeneous, it is not known to what extent this heterogeneity is mirrored in neuroanatomy. The aim of this study was thus to investigate differences in mean brain volume and structural variability within regions, between 22q11.2DS and typically developing controls. We examined studies that reported measures of brain volume using MRI in PubMed, Web of Science, Scopus and PsycINFO from inception to 1 May 2019. Data were extracted from studies in order to calculate effect sizes representing case-control difference in mean volume, and in the variability of volume (as measured using the log variability ratio (lnVR) and coefficient of variation ratio (CVR)). We found significant overall decreases in mean volume in 22q11.2DS compared with control for: total brain (g = −0.96; p < 0.001); total grey matter (g = −0.81, p < 0.001); and total white matter (g = −0.81; p < 0.001). There was also a significant overall reduction of mean volume in 22q11.2DS subjects compared with controls in frontal lobe (g = −0.47; p < 0.001), temporal lobe (g = −0.84; p < 0.001), parietal lobe (g = −0.73; p = 0.053), cerebellum (g = −1.25; p < 0.001) and hippocampus (g = −0.90; p < 0.001). Significantly increased variability in 22q11.2DS individuals compared with controls was found only for the hippocampus (VR, 1.14; p = 0.036; CVR, 1.30; p < 0.001), and lateral ventricles (VR, 1.56; p = 0.004). The results support the notion that structural abnormalities in 22q11.2DS and schizophrenia are convergent, and also to some degree with findings in autism spectrum disorder. Finally, the increased variability seen in the hippocampus in 22q11.2DS may underlie some of the heterogeneity observed in the neuropsychiatric phenotype.

Brain morphometry in 22q11.2 deletion syndrome: an exploration of differences in cortical thickness, surface area, and their contribution to cortical volume

“…Further, we observed several clusters where neurodevelopmental trajectories of CV, CT and SA differed significantly in 22q11.2DS. Taking together, these findings highlight that the 22q11.2 microdeletion causes widespread neuroanatomical abnormalities that might arise as a consequence of an atypical developmental trajectory of brain maturation 22 . Despite these extensive neuroanatomical abnormalities in a large number of brain regions, previous studies also note that some areas of the brain (e.g.…”

“…Differences in neuroanatomy associated with 22q11.2DS are well established, both globally and regionally 3 , 22 . Our results are largely consistent with previous studies examining measures of CT in 22q11.2DS.…”

Structural and Functional Features of Developing Brain Capillaries, and Their Alteration in Schizophrenia

“…In mice engineered with a mutation in 22q11, claudin-5 expression is reduced by 75% in ECs, which was reproduced in cell culture ( Greene et al, 2018 ). Furthermore, using MRI in SCZ patients, the 22q11 mutation was associated with decreased brain volumes for both total grey ( g = −0.81) and total white matter ( g = −0.81) calculated by a meta-analysis of between-group differences in mean volumes, representing the effect size ( g ) ( Rogdaki et al, 2020 ). Considering that most investigations on vascular alterations in patients with SCZ are done using post-mortem tissue ( McGlashan, 2011 ; Harris et al, 2012 ; Katsel et al, 2017 ), it is difficult to have a good idea on the temporal development of those deficits.…”

Why Does the Face Predict the Brain? Neural Crest Induction, Craniofacial Morphogenesis, and Neural Circuit Development

“…We selected the microdeletion disorder 22q11.2 Deletion Syndrome (22q11DS), also known as DiGeorge or Velocardiofacial syndrome, to evaluate our hypothesis. 22q11DS is a global developmental disorder whose phenotypic spectrum includes highly penetrant cardiovascular malformations, as well as craniofacial anomalies, mild limb and digit anomalies, and a high frequency of behavioral difficulties that resemble clinically diagnosed neurodevelopmental disorders, including schizophrenia, autistic spectrum disorder, and attention deficit disorder, accompanied by altered brain morphology and function (Schneider et al, 2014;McDonald-McGinn et al, 2015;Rogdaki et al, 2020). 22q11DS, as the name suggests, is not caused by a single loss-of-function mutation but deletion of a limited number of genes: minimally 32 in humans (Morrow et al, 2018) and their subsequent approximately 50% diminished expression (Meechan et al, 2006;Maynard et al, 2008Maynard et al, , 2013Maynard et al, , 2020a).…”