ReviewBridging the gene–behavior divide through neuroimaging deletion syndromes: Velocardiofacial (22q11.2 Deletion) and Williams (7q11.23 Deletion) syndromes
Introduction
Parallel advancement in both genetic and neuroimaging technologies in recent years has offered neuroscience an opportunity to elucidate the relationships between genes, neural function, and behavior, as never before. “Top-down” approaches – using what is known about the clinical presentation, combined with neuroimaging of neurochemical, neuroanatomical, and neurophysiological features of the illness to infer and test for specific genetic effects – have offered insights into the biological plausibility of the involvement of certain genes of interest and their mechanism. However, such approaches are intrinsically limited in scope, and, moreover, large-scale population-based investigations, such as genome-wide association studies for a particular psychiatric illness, have lent increasing support for the principle that clinical behavioral phenotypes are rooted in many gene variants, potentially of small individual effects, which have been challenging to characterize. Thus, to dissect specific molecular contributions to human brain development and function, bottom-up approaches that study the neural and behavioral consequences of a well-described genetic variation are essential. Taking advantage of genetic accidents of nature, a number of investigators have begun to address this need by implementing in vivo neuroimaging experiments of individuals with classic microdeletion syndromes. Two of these have been best studied and will be reviewed here. Velocardiofacial syndrome (VCFS) and William's syndrome (WS) — result from circumscribed, small hemideletions in chromosomal bands 22q11.2 and 7q11.23, respectively, and are remarkable for their distinctive behavioral sequelae. Though these two syndromes arise from deletion of different genes, have different clinical and neuropsychological profiles, and demonstrate distinct neuroimaging phenotypes (Campbell et al., 2009), by virtue of their shared molecular etiology (i.e., microdeletion), they both present tremendous opportunities for understanding the genetic foundations of physiological brain function and neuropsychiatric illness. In contrast to many other studied genetic variations in humans (e.g., single nucleotide polymorphisms (SNPs)), the hemideletions in VCFS and WS represent alterations definitively targeted to the involved genes (e.g., no linkage disequilibrium confound), show clinically relevant effect sizes at the behavioral level, and confer generally unambiguous, categorical gene dose effects. The neuroimaging of these conditions, by examining structural and functional neural correlates of both the associated genetic defect and relevant behavioral measures, has begun to offer critical insight into the molecular regulation of human brain development and function at the systems level, but remains an ongoing endeavor with many important questions yet unanswered. Because neuroimaging investigations of these disorders require overcoming similar methodological challenges and testing similar fundamental hypotheses about the pathogenesis of specific neuropsychiatric phenotypes within a broader clinical syndrome, by considering the literatures of both VCFS and WS – which have made substantial but disparate advances toward these ends – this review intends to highlight ways in which these literatures inform each other and identify fertile ground for future study.
Section snippets
Background
Velocardiofacial syndrome (VCFS) or 22q11.2 deletion syndrome (previously termed “DiGeorge sequence”, “Sedlackova syndrome”, “conotruncal anomalies face syndrome”, “Cayler syndrome”, “Shprintzen syndrome”, and “CATCH 22”) results from a hemideletion in band q11.2 of chromosome 22, which spans a critical region harboring approximately 40 known genes, and occurs with an estimated frequency between 1:2000 and 1:4000 (Maynard et al., 2003, Oskarsdottir et al., 2004, Shprintzen, 2008). There is no
Background
Relative to VCFS, Williams syndrome (WS) is a more infrequent disorder (prevalence of 1:7500–1:20,000 live births) that is caused by a hemizygous deletion of ∼ 1.6 megabases (Mb) typically containing approximately 28 genes on chromosomal location 7q11.23 (Stromme et al., 2002, Osborne and Mervis, 2007, Schubert, 2009), which occurs regardless of parental origin of the affected chromosome (Schubert, 2009). The hemideleted region is flanked by low-copy-repeat sequences (LCR), and the deletions
Discussion
Both VCFS and WS, as neurodevelopmental genetic disorders arising from well-delineated hemideletions and resulting in distinctive behavioral sequelae, pose unique opportunities to use neuroimaging to study the neural mechanisms by which genes contribute to complex cognitive and behavioral phenotypes in a bottom-up fashion. This approach, in taking advantage of an intermediate brain phenotypes tactic (Gottesman and Sheilds, 1972) and capitalizing on restricted genetic anomalies with large
Acknowledgments
This research was supported by the Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892. All authors report no financial conflict of interest with regard to this manuscript.
References (210)
- et al.
Impaired activation of face processing networks revealed by functional magnetic resonance imaging in 22q11.2 deletion syndrome
Biol. Psychiatry
(2008) - et al.
Behavior and corpus callosum morphology relationships in velocardiofacial syndrome (22q11.2 deletion syndrome)
Psychiatry Res. Neuroimaging
(2005) - et al.
Adhd, major depressive disorder, and simple phobias are prevalent psychiatric conditions in youth with velocardiofacial syndrome
J. Am. Acad. Child Adolesc. Psychiatry
(2006) - et al.
Comt val108/158met modifies mismatch negativity and cognitive function in 22q11 deletion syndrome
Biol. Psychiatry
(2005) - et al.
Arithmetic ability and parietal alterations: a diffusion tensor imaging study in velocardiofacial syndrome
Cogn. Brain Res.
(2005) - et al.
Catechol-o-methyl transferase and expression of schizophrenia in 73 adults with 22q11 deletion syndrome
Biol. Psychiatry
(2007) - et al.
Mutational mechanisms of Williams–Beuren syndrome deletions
Am. J. Hum. Genet.
(2003) - et al.
Domain specific attentional impairments in children with chromosome 22q11.2 deletion syndrome
Brain Cogn.
(2007) - et al.
Parieto-occipital grey matter abnormalities in children with Williams syndrome
Neuroimage
(2006) - et al.
A comparative study of cognition and brain anatomy between two neurodevelopmental disorders: 22q11.2 deletion syndrome and Williams syndrome
Neuropsychologia
(2009)
3D pattern of brain abnormalities in Williams syndrome visualized using tensor-based morphometry
Neuroimage
Qualitative mri findings in adults with 22q11 deletion syndrome and schizophrenia
Biol. Psychiatry
Structural brain abnormalities in patients with schizophrenia and 22q11 deletion syndrome
Biol. Psychiatry
Distributed brain sites for the g-factor of intelligence
NeuroImage
The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis
Cell
Hippocampal volume reduction in 22q11.2 deletion syndrome
Neuropsychologia
Anomalous sylvian fissure morphology in Williams syndrome
Neuroimage
Functional brain imaging study of mathematical reasoning abilities in velocardiofacial syndrome (del22q11.2)
Genet. Med.
A quantitative MRI study of posterior fossa development in velocardiofacial syndrome
Biol. Psychiatry
Increased basal ganglia volumes in velo-cardio-facial syndrome (deletion 22q11.2)
Biol. Psychiatry
The neural basis of mental imagery
Trends Neurosci.
Lim-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition
Cell
Increased local gyrification mapped in Williams syndrome
Neuroimage
Polymicrogyria in chromosome 22q11 deletion syndrome
Eur. J. Paediatr. Neurol.
Language skills in children with velocardiofacial syndrome (deletion 22q11.2)
J. Pediatr.
Structural changes to the fusiform gyrus: a cerebral marker for social impairments in 22q11.2 deletion syndrome?
Schizophr. Res.
Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: a longitudinal study
Schizophr. Res.
From thought to action: the parietal cortex as a bridge between perception, action, and cognition
Neuron
In-depth analysis of spatial cognition in Williams syndrome: a critical assessment of the role of the LIMK1 gene
Neuropsychologia
Individual differences in social behavior predict amygdala response to fearful facial expressions in Williams syndrome
Neuropsychologia
Structural brain variation and general intelligence
NeuroImage
Foreshortened dorsal extension of the central sulcus in Williams syndrome
Cortex
Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis
Biol. Psychiatry
Temporal lobe anatomy and psychiatric symptoms in velocardiofacial syndrome (22q11.2 deletion syndrome)
J. Am. Acad. Child Adolesc. Psychiatry
The neural correlates of non-spatial working memory in velocardiofacial syndrome (22q11.2 deletion syndrome)
Neuropsychologia
Emotions and hemispheric specialization
Psychiatr. Clin. North Am.
Cognitive neuroscience of human social behaviour
Nat. Rev. Neurosci.
The social brain: neural basis of social knowledge
Annu. Rev. Psychol.
Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia
J. Hum. Genet.
Adolescents and young adults with 22q11 deletion syndrome: psychopathology in an at-risk group
Br. J. Psychiatry
Investigation of white matter structure in velocardiofacial syndrome: a diffusion tensor imaging study
Am. J. Psychiatry
Clinical features of 78 adults with 22q11 deletion syndrome
Am. J. Med. Genet. A
The neurocognitive phenotype of the 22q11.2 deletion syndrome: selective deficit in visual-spatial memory
J. Clin. Exp. Neuropsychol.
Mapping cortical thickness in children with 22q11.2 deletions, Cereb
Cortex
Alterations in midline cortical thickness and gyrification patterns mapped in children with 22q11.2 deletions, Cereb
Cortex
The computation of social behavior
Science
Towards the neural basis for hypersociability in a genetic syndrome
Neuroreport
Supravalvular aortic stenosis in association with mental retardation and a certain facial appearance
Circulation
Polymicrogyria in chromosome 22 deletion syndrome
Neurology
Cortical dysgenesis in 2 patients with chromosome 22q11 deletion
Clin. Genet.
Cited by (21)
Neuroemergentism: A framework for studying cognition and the brain
2019, Journal of NeurolinguisticsCitation Excerpt :The brain in individuals with WS is different than a typical adult brain. It is generally smaller and it has overall reduced curvature, increased gyral complexity, in addition to reductions in parietal and limbic regional volumes (Eisenberg, Jabbi, & Berman, 2010). Furthermore, while the typical adult brain develops gradual specialization and hemispheric localization of function over ontogenetic development (i.e. left hemisphere for language), this tends not to occur in the mature brain of individuals with WS, which continues instead to process faces and language bilaterally (Karmiloff-Smith et al., 2004).
Neurocomputational Emergentism as a Framework for Language Development
2018, Psychology of Learning and Motivation - Advances in Research and TheoryCitation Excerpt :This behavioral profile coexists with a mean IQ of 56 (Mervis et al., 2000) and with very impaired spatial and numerical cognition (Karmiloff-Smith et al., 2004). The brain in individuals with WS is generally smaller and it has overall reduced curvature and increased gyral complexity, in addition to reductions in parietal and limbic regional volumes compared to the typical adult brain (Eisenberg, Jabbi, & Berman, 2010). Furthermore, while the typical adult brain develops gradual specialization and hemispheric localization of function over ontogenetic development (i.e. left hemisphere for language), this does not to occur in the mature brain of individuals with WS, which continues instead to process faces and language bilaterally (Karmiloff-Smith et al., 2004).
Looking and thinking: How individuals with Williams syndrome make judgements about mental states
2013, Research in Developmental DisabilitiesCitation Excerpt :Individuals with Williams syndrome (WS) are known for their friendly, sociable and outgoing nature (Jones et al., 2000; Mervis & Klein-Tasman, 2000); but this characterisation hides an array of atypicalities of social perception, social cognition and struggles with everyday functioning. WS is a genetic disorder caused by a hemizygous deletion of around 1.6 megabase, containing 26–28 genes on chromosomal 7q11.23 (Eisenberg, Jabbi, & Berman, 2010). The disorder is characterised by a unique pattern of relative strengths and difficulties of cognition; for instance, more severe difficulties with visuo-spatial processing compared to a relative proficiency of verbal skill, all against a backdrop of mild-moderate intellectual impairment and cognitive heterogeneity (Porter & Coltheart, 2005; Searcy et al., 2004).
Resting-state networks in adolescents with 22q11.2 deletion syndrome: Associations with prodromal symptoms and executive functions
2012, Schizophrenia ResearchCitation Excerpt :Indeed, in this deletion syndrome where 25–30% are thought to evolve into formal schizophrenia spectrum disorders by adulthood (Murphy et al., 1999), neurodevelopment during adolescence may provide key insights to understanding the unfolding of psychotic symptoms. To date, neuroimaging studies have mainly focused on the structural determinants of cerebral development in 22q11DS, and reports typically highlight deviant maturational courses as characterized by local reductions in brain volume, gray matter density, white matter density, gyrification and cortical thickness (Eisenberg et al., 2010). No study to our knowledge has yet to examine the baseline neural processes that characterize the architecture of functional connectivity in youths with 22q11DS.