Genes, brain development and psychiatric phenotypes in velo‐cardio‐facial syndrome

Abstract

Velo-cardio-facial syndrome (VCFS) has been in the focus of intensive research over the last 15 years. The syndrome represents a homogeneous model for studying the effect of a decreased dosage of genes on the development of brain structure and function and, consequently, on the emergence of schizophrenia-like psychotic disorder. In this review, we describe the psychiatric phenotype of children, adolescents, and young adults with VCFS. We redefine the concept of "behavioral phenotype" and suggest that psychosis fulfills the criteria of a behavioral phenotype of the syndrome. Identifying the risk factors for the emergence of psychosis in VCFS is a major goal of several large-scale longitudinal studies that are currently underway. We review the knowledge gained so far about risk factors for psychosis in VCFS, including early neuropsychiatric symptoms, development of brain structure and function, and the effect of a reduced dosage of genes from the 22q11 deletion region. Although the brain structure in subjects with VCFS is not drastically different from typically developing controls, newer imaging modalities that measure white matter tracts, cortical thickness, and cortical gyrification are likely to identify more subtle and specific neuroanatomical substrates of the syndrome. Among the 24 genes within the deletion region, the role of catechol-O-methyltransferase (COMT) on the VCFS phenotype has been investigated in depth. The findings suggest that because of haploinsufficiency of the COMT gene individuals with VCFS are exposed to a high level of prefrontal dopamine, and this interferes with their prefrontal cognitive functioning and may contribute to their high rate of psychosis and other psychiatric disorders. The other genes and environmental factors that shape the unique neuropsychiatric phenotype of VCFS are yet to be discovered.

Resting-state networks in adolescents with 22q11.2 deletion syndrome: Associations with prodromal symptoms and executive functions

“…Consistently, parietal lobe gray matter volumes are often found to be reduced in children with 22q11DS (Eliez et al, 2000;Kates et al, 2001), and a recent report suggests that gyrification in the precuneus/PCC regions is more affected in children with 22q11DS as a result of congenital heart defects associated with this deletion syndrome (Schaer et al, 2009b). Observing parietal resting-state functional dysconnectivity for the first time provides the missing link between previously reported structural alterations of parietal gray and white matter (Gothelf et al, 2008) and visuo-spatial/ arithmetic impairments in 22q11DS (Bearden et al, 2001;De Smedt et al, 2007b;Simon et al, 2008). Most probably, this altered cerebral development is sustained by cerebral structure dysmaturation, functional dysconnectivity and their interactions with developing skills in the visuo-spatial domain (Simon et al, 2005(Simon et al, , 2008.…”

Identifying 22q11.2 Deletion Syndrome and Psychosis Using Resting-State Connectivity Patterns

“…Furthermore, function does not only reflect underlying structural alterations but can also be the result of an adaptation to a different structural background. Such complex relationships could explain why we observe only few discriminative connections in the functional network of the parietal lobe whereas structural alterations are consistently reported in this region (Antshel et al 2008b;Gothelf et al 2008). Investigation of brain connectivity with multimodal neuroimaging approaches, task-related fMRI or dynamic measurements of connectivity will be necessary to provide new a b Fig.…”

Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): A cross-sectional and longitudinal study

“…Introduction 22q11.2 deletion syndrome (22q11DS) is a neurogenetic condition which draws particular interest as a model to understand the pathogenesis of schizophrenia . A variety of genes have been identified in the 3Mb deletion associated with 22q11DS, among which haploinsufficiency of the catechol-O-methyltransferase (COMT) gene has received a large emphasis (Gothelf et al, 2008). From the point of view of structural neuroimaging, a large body of literature is aimed at delineating the cerebral phenotype in these individuals at risk for developing schizophrenia.…”

“…From the point of view of structural neuroimaging, a large body of literature is aimed at delineating the cerebral phenotype in these individuals at risk for developing schizophrenia. Numerous studies have reported specific patterns of volumetric alterations in children and adults with the syndrome (Schaer and Eliez, 2007;Gothelf et al, 2008). However, between-group comparisons in sample with restrained age ranges only provide snapshots over the dynamic unfolding of structural brain changes with age.…”