Meta-analysis of magnetic resonance imaging studies in chromosome 22q11.2 deletion syndrome (velocardiofacial syndrome)
Introduction
Chromosome 22q11.2 deletion syndrome (22q11.2DS), affects approximately 1 in 5000 live births (Tézenas Du Montcel et al., 1996) and refers to a group of previously distinct genetically determined disorders (velocardiofacial syndrome, Shprintzen syndrome, DiGeorge syndrome, conotruncal anomaly face syndrome, Cayler cardiofacial syndrome, and CATCH 22 syndrome) caused by a microdeletion on the long arm of chromosome 22 (Scambler et al., 1992). VCFS is characterised by a distinct phenotype including a typical facial appearance, cleft palate, velopharyngeal insufficiency, cardiac anomalies (McDonald-McGinn et al., 1999, Swillen et al., 1997), learning disabilities and by an increased risk for psychotic disorders (Henry et al., 2002, Gothelf et al., 2004a, Gothelf et al., 2004b, Baker and Skuse, 2005, Papolos et al., 1996, Niklasson et al., 2002) particularly schizophrenia (Murphy et al., 1999). More specifically, psychotic symptoms have been diagnosed in up to 30% of adolescents and adults with 22q11.2DS (Murphy et al., 1999). Moreover, the deletion has been found in 1–6% of people with schizophrenia (Murphy et al., 1998, Yan et al., 1998).
This association has led to considerable research to morphologically characterise 22q11.2DS brain abnormalities and potential similarities with schizophrenia. Magnetic resonance imaging (MRI) has allowed detailed in vivo examination of brain structures in people with 22q11.2DS but the evidence is inconclusive (Eliez et al., 2000, Kates et al., 2001, Simon et al., 2005, Eliez et al., 2002, Kates et al., 2006, Campbell et al., 2006, Gothelf et al., 2007, Deboer et al., 2007; Shashi et al., 2004). This is in part due to the relative rarity of the disorder and the tendency for studies to be small and potentially underpowered. Nevertheless, even taking this into account, the literature appears heterogeneous and published significant effect sizes differ in both direction and magnitude.
The aim of this meta-analysis was to apply quantitative methods to characterise morphometric differences in 22q11.2DS in comparison with healthy controls by 1) identifying region of interest (ROI) studies which offered measurements of brain regions in 22q11.2DS and 2) synthesizing findings using random effects meta-analysis. We also assessed heterogeneity to clarify the role of a number of variables including year of publication, age, sex, IQ, scanner strength and slice thickness.
Section snippets
Search strategy and inclusion/exclusion criteria
A comprehensive search from a range of electronic databases, including Medline, EMBASE, PsycINFO, and PubMED was conducted up to March 2008 that reported structural MRI data in people with 22q11.2DS and unaffected controls. Search terms used to identify the studies included ‘Velocardiofacial syndrome’, ‘DiGeorge syndrome’, ‘22q11.2 deletion syndrome’ and related terms combined using the AND operator with ‘Magnetic Resonance Imaging’. The search was also supplemented by a manual and
Systematic search
The literature search identified 156 publications of which 48 were retrieved in full text format. Fig. 1 summarises the study flow and reasons for exclusion. Twenty-two studies met inclusion criteria and were included in the final analysis which provided information on 35 regions of interest (Table 1). Images were manually traced reflecting similar anatomical borders and used different software programs to aid image processing. In some cases a semiautomated stereotactic based parcellation
Discussion
Findings from this meta-analysis show that 22q11.2DS is associated with global brain volumetric reduction affecting both gray and white matter, and with reductions of the prefrontal cortex and hippocampi, while the corpus callosum area was increased. These relatively large effect sizes were found in the absence of either heterogeneity or publication bias.
Diffuse global brain volumetric reduction is consistent with the common occurrence of a learning disability in the 22q11.2DS population and
Role of funding source
GMT is currently supported by the Baily Thomas Charitable Fund. DA is currently supported by the UK Medical Research Council. AM is currently supported by the Health Foundation.
Contributors
GMT and DA were involved in literature searches, data extraction and analyses, and in writing the first draft of the report. AM provided supervision, statistical expertise, offered guidance in the interpretation of the results and participated at all stages of development of the final report. KPE had a role in overall supervision and final drafting of the report. All the authors contributed to and have approved the final manuscript.
Conflict of interest
Nothing to declare.
Acknowledgements
GMT and DA would like to thank Drs. Amelsvoort, Bearden, DeBoer, Kates and Simon for supplementing their work with unpublished data to complete this meta-analysis. GMT would like to thank the Baily Thomas Charitable Fund for their support and Professor Declan Murphy for his guidance and encouragement.
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2019, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Although these two methodologies seem to provide prima facie inconsistent results, the meta-analysis only included a sub-group of the identified articles. Similarly, the current results are inconsistent with those of a previous meta-analysis on 22q11.2 DS (Tan et al., 2009), which identified alteration in 22q11.2 DS compared to controls in the prefrontal cortex, hippocampi and corpus callosum. The differences between the results obtained in the previous (Tan et al., 2009) and the current meta-analysis might be easily explained by significant methodological differences.
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2017, Psychiatry Research - NeuroimagingCitation Excerpt :Thus, understanding brain dysfunction in 22q11DS may elucidate critical neural mechanisms in psychosis. Structural brain abnormalities, including lower gray matter volume (Schneider et al., 2014; Tan et al., 2009), cortical thickness (Bearden et al., 2007; Schaer et al., 2008), surface area (Jalbrzikowski et al., 2013) and gyral complexity (Schaer et al., 2008, 2006; Schmitt et al., 2015), are common in 22q11DS. Neural dysfunction in 22q11DS extends into structural connectivity of the brain, which can be measured using diffusion tensor imaging (DTI).
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Authors contributed equally to the work.