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As children with velocardiofacial syndrome (VCFS) develop, they are at increased risk for psychopathology; one third will eventually develop schizophrenia. Because VCFS and the concomitant symptomatology result from a known genetic origin, the biological and behavioral characteristics of the syndrome provide an optimal framework for conceptualizing...
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... ANOVA comparisons (Table 2) indicated a sig- nificant difference between the control and VCFS sub- groups when comparing total volume of cerebral gray (F 2,33 = 7.8; P.01; Figure 1) and white (F 2,33 = 12.2; P.001) matter. When both subgroups were compared with the controls (follow-up Scheffé tests), the VCFS sub- group with maternal-origin deletions showed signifi- cantly decreased volumes of gray (P.005) and white (F 2,33 =12.2; ...
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... A study conducted by Seaver et al. (1994) suggested a potential impact of the maternal origin of the deletion on the presence of pulmonary atresia [21]. Another study, conducted by Eliez et al. (2001), indicated that the parental origin of the deletion could significantly affect brain development and morphology, with reduction in gray matter development attributed to presence of a 22q11.2 microdeletion on the maternal chromosome [22]. ...
... Another study, conducted by Eliez et al. (2001), indicated that the parental origin of the deletion could significantly affect brain development and morphology, with reduction in gray matter development attributed to presence of a 22q11.2 microdeletion on the maternal chromosome [22]. More recently, McGinn et al. (2022) investigated the influence of the parent of origin on intellectual outcomes in patients with 22q11.2DS ...
... Although a major contribution of parental origin on the phenotype is not expected in the 22q11.2 region, very few studies in the literature have compared the clinical features of patients with deletions of maternal or paternal origin [21][22][23]. Previous studies described random imprinting of the genes DGCR6 and DGCR6L, which are mapped within the most common region deleted in the 22q11.2DS ...
22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus, pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings.
... It exhibits various syndromal features such as congenital heart defects (CHDs), cognitive impairments, hypoparathyroidism, immune deficiency, cleft palate, and a distinct facial appearance [8,9]. Especially the impartments of cognitive phenotype are associated with psychopathology such as the learning difficulties, autism spectrum disorder (ASD), cognitive deficits and early language delays, deficits in visuospatial abilities and arithmetic, attention deficit disorder (ADHD), and coordination deficits [10][11][12][13]. Furthermore, about 30% of patients with 22q11.2 ...
22q11.2 deletion is a common microdeletion that causes an array of developmental defects including 22q11.2 deletion syndrome (22q11DS) or DiGeorge syndrome and velocardiofacial syndrome. About 30% of patients with 22q11.2 deletion develop schizophrenia. Mice with deletion of the ortholog region in mouse chromosome 16qA13 exhibit schizophrenia-like abnormal behaviors. It is suggested that the genes deleted in 22q11DS are involved in the pathogenesis of schizophrenia. Among these genes, COMT, ZDHHC8, DGCR8, and PRODH have been identified as schizophrenia susceptibility genes. And DGCR2 is also found to be associated with schizophrenia. In this review, we focused on these five genes and reviewed their functions in the brain and the potential pathophysiological mechanisms in schizophrenia, which will give us a deeper understanding of the pathology of schizophrenia.
... Individuals with 22q11.2DS have an elevated risk for psychotic illness and approximately one in every 4-5 adults develop schizophrenia [3]. It is imperative to find the best possible pharmacological treatment for these patients. ...
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Abstract
In the recent study by Verhoeven and Egger, 2015 and the recent letter to the editor by Boot et al. 2015 an emphasis is given to the best possible pharmacological treatment of 22q11-2 Deletion-Syndrome related psychoses. We would like to present the case of a 23-year old Cypriot patient with 22q11.2 deletion syndrome who fulfilled criteria for treatment resistant schizophrenia (TRS). He was sequentially treated with aripiprazole, risperidone, olanzapine, haloperidol and a combination treatment with olanzapine and haloperidol. Clozapine was the only antipsychotic medication that has improved his condition.
... deletion syndrome have been found to have a substantially greater risk for the development of schizophrenia and bipolar disorder with approximately 25-30% presenting psychotic symptoms in adolescence. 3 ...
The 22q11.2 deletion syndrome (di George syndrome) is one of the most prevalent genetic disorders. The clinical features of the syndrome are distinct facial appearance, velopharyngeal insufficiency, conotruncal heart disease, parathyroid and immune dysfunction; however, little is known about possible neurodegenerative diseases. We describe the case of an 18-year old patient suffering from 22q11.2 deletion syndrome. Since adolescence, he presented with behavioral disorders, recommended treatment with 2 mg aloperidin and he presented cervical dystonia and emergence of torticollis and trunk dystonia. Antipsychotic medications either accelerate or reveal dys-tonic symptoms.
... deletion syndrome have been found to have a substantially greater risk for the development of schizophrenia and bipolar disorder with approximately 25-30% presenting psychotic symptoms in adolescence. 3 ...
The 22q11.2 deletion syndrome (di George syndrome) is one of the most prevalent genetic disorders. The clinical features of the syndrome are distinct facial appearance, velopharyngeal insufficiency, conotruncal heart disease, parathyroid and immune dysfunction; however, little is known about possible neurodegenerative diseases. We describe the case of an 18-year old patient suffering from 22q11.2 deletion syndrome. Since adolescence, he presented with behavioral disorders, recommended treatment with 2 mg aloperidin and he presented cervical dystonia and emergence of torticollis and trunk dystonia. Antipsychotic medications either accelerate or reveal dystonic symptoms.
... One study reported that 11 of 12 de novo cases with psychosis had a maternal origin of the deletion (5). While other studies have found quantitative endophenotypes-gray matter volume and language abilities-linked to maternal origin of the deletion (36,37), another research group found no evidence for an effect of parental origin of the deletion on schizophrenia risk (38). ...
Evidence is rapidly accumulating that rare, recurrent copy number variants represent large effect risk factors for neuropsychiatric disorders. 22q11.2 deletion syndrome (22q11DS) (velocardiofacial syndrome or DiGeorge syndrome) is the most common known contiguous gene deletion syndrome and is associated with diverse neuropsychiatric disorders across the life span. One of the most intriguing aspects of the syndrome is the variability in clinical and cognitive presentation: children with 22q11DS have high prevalence of autism spectrum, attention deficit, and anxiety disorders, as well as psychotic-like features, and up to 30% of adolescents and adults develop schizophrenia-like psychosis. Recently, cases of early-onset Parkinson's disease in adults have been reported, collectively suggesting a role for disrupted dopaminergic neurotransmission in the observed neuropsychiatric phenotypes. There is also some evidence that 22q11DS-associated autism spectrum disorder and schizophrenia represent two unrelated phenotypic manifestations, consistent with a neuropsychiatric pleiotropy model. This genetic lesion thus provides a unique model for the discovery of specific genomic risk and (potentially) protective factors for neuropsychiatric disease. Here, we provide an overview of neuropsychiatric findings to date, which highlight the value of this syndrome in mapping the developmental trajectory of dimensional phenotypes that traverse multiple diagnostic categories. Potential sources of genetic variability that may contribute to the disorder's heterogeneous presentation are reviewed. Because of its known genetic etiology, animal models can readily be developed that recapitulate specific aspects of the syndrome. Future research directions involve translational models and potential for drug screenable targets in the context of this human model system.
... One magnetic resonance imaging study and another involving the characterization of language reported that in children with 22q11DS gray-matter volume is more reduced and language disabilities are more severe when the deletion is on the maternal chromosome. 17,18 These findings suggest that the parent-of-origin of the deletion may differentially affect neurodevelopmental abnormalities. How the parental origin of a deletion can affect gene expression and psychological outcomes in individuals with 22q11DS has not been determined. ...
... 22q11DS is characterized by a multitude of neuropsychological abnormalities. 3 Two studies reported that maternal inheritance of the deletion was associated with a greater reduction in cortical gray matter and increased languagelearning disabilities. 17,18 This parental effect suggested a possible role for epigenetic regulation, such as genomic imprinting. Although mouse studies ruled out parent-of-originspecific expression of the 25 genes lying within the 22q11DS critical region, 26 computational analysis in our laboratory predicted DGCR6 to be monoallelically expressed in humans, with expression from the paternal allele. ...
Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans. It is typified by highly variable symptoms, which might be explained by epigenetic regulation of genes in the interval. Using computational algorithms, our laboratory previously predicted that DiGeorge critical region 6 (DGCR6), which lies within the deletion interval, is imprinted in humans. Expression and epigenetic regulation of this gene have not, however, been examined in 22q11DS subjects. The purpose of this study was to determine if the expression levels of DGCR6 and its duplicate copy DGCR6L in 22q11DS subjects are associated with the parent-of-origin of the deletion and childhood psychopathologies. Our investigation showed no evidence of parent-of-origin-related differences in expression of both DGCR6 and DGCR6L. However, we found that the variability in DGCR6 expression was significantly greater in 22q11DS children than in age and gender-matched control individuals. Children with 22q11DS who had anxiety disorders had significantly lower DGCR6 expression, especially in subjects with the deletion on the maternal chromosome, despite the lack of imprinting. Our findings indicate that epigenetic mechanisms other than imprinting contribute to the dysregulation of these genes and the associated childhood psychopathologies observed in individuals with 22q11DS. Further studies are now needed to test the usefulness of DGCR6 and DGCR6L expression and alterations in the epigenome at these loci in predicting childhood anxiety and associated adult-onset pathologies in 22q11DS subjects.
... The majority of deletions are most likely generated maternally during oogenic meiosis; however, paternal origin is also seen (Leana-Cox et al., 1996;Ryan et al., 1997). Despite speculation on potential maternal effects that modify 22q11DS phenotypes, especially in the brain (Eliez et al., 2001), there is currently no report of weak alleles generating effective nulls at specific loci, nor any evidence for paternal imprinting or allelic biasing that would result in loss of function of single 22q11 genes. Our analysis of parent of origin effects in the 26 contiguous murine orthologues of human 22q11 genes found on mouse chromosome 16 ( Fig. 1A; ) found neither paternal nor maternal imprinting (often conserved between species; (Morison et al., 2005;Paulsen et al., 2001). ...
DiGeorge, or 22q11 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by deletion of a minimum of 32 contiguous genes on human chromosome 22, and presumably results from diminished dosage of one, some, or all of these genes--particularly during development. Nevertheless, the normal functions of 22q11 genes in the embryo or neonate, and their contribution to developmental pathogenesis that must underlie 22q11DS are not well understood. Our data suggests that a substantial number of 22q11 genes act specifically and in concert to mediate early morphogenetic interactions and subsequent cellular differentiation at phenotypically compromised sites--the limbs, heart, face and forebrain. When dosage of a broad set of these genes is diminished, early morphogenesis is altered, and initial 22q11DS phenotypes are established. Thereafter, functionally similar subsets of 22q11 genes--especially those that influence the cell cycle or mitochondrial function--remain expressed, particularly in the developing cerebral cortex, to regulate neurogenesis and synaptic development. When dosage of these genes is diminished, numbers, placement and connectivity of neurons and circuits essential for normal behavior may be disrupted. Such disruptions likely contribute to vulnerability for schizophrenia, autism, or attention deficit/hyperactivity disorder seen in most 22q11DS patients.
... Previous studies on the effect of parent of origin on the VCFS neuropsychiatric phenotype have yielded mixed results. For example, Eliez et al. 36 and Glaser et al. 37 found that children with VCFS and maternal origin of the deletion had lower cerebral gray matter volumes and lower receptive language abilities, whereas Bassett et al. 38 found no significant effect of parental origin of the deletion on the risk for schizophrenia in adults with VCFS. More studies are needed to elucidate whether VCFS subjects with maternal origin of the deletion are indeed at increased risk for psychosis or other psychiatric disorders and cognitive deficits. ...
Velocardiofacial syndrome (VCFS) is associated with cognitive deficits and high rates of schizophrenia and other neuropsychiatric disorders. We report the data from two large cohorts of individuals with VCFS from Israel and Western Europe to characterize the neuropsychiatric phenotype from childhood to adulthood in a large sample.
Individuals with VCFS (n = 172) aged 5 to 54 years were evaluated with structured clinical interviews for psychiatric disorders and age-appropriate versions of the Wechsler intelligence tests.
The frequency of psychiatric disorders was high and remarkably similar between samples. Psychotic disorders and depression were uncommon during childhood but increased in rates during adulthood (depressive disorders: 40.7% in young adults [aged 18-24 years]; psychotic disorders: 32.1% in adults [age >24 years]). Cognitive scores were inversely associated with age in subjects with VCFS, including patients without psychosis. Specifically, Verbal IQ (VIQ) scores negatively correlated with age, and the subjects with VCFS and psychotic disorders had significantly lower VIQ scores than nonpsychotic VCFS subjects.
Neuropsychiatric deficits in individuals with VCFS seem to follow a developmental pattern. The VIQ scores are negatively associated with age and rates of mood, and psychotic disorders increase dramatically during young adulthood. The data presented here support careful monitoring of psychiatric symptoms during adolescence and young adulthood in VCFS. Prospective longitudinal studies are needed to examine the nature of age-related cognitive changes and their association with psychiatric morbidity in VCFS.
... The result of this is that some or all of the phenotypic effects of a PWS/AS-associated rearrangement can essentially skip generations in a manner that is dependent on whether the transmission occurs maternally or paternally, thus presenting with widely variable penetrance [Ming et al., 2000] . Although the involvement of imprinting in most other genomic disorders is generally thought to be minimal, it remains possible that imprinted genes may contribute toward more subtle phenotypes in many other diseases [Eliez et al., 2001]. However, the current lack of any comprehensive catalogue of imprinting in the human genome often means that only gross epigenetic defects can readily be identified unless sufficiently large populations of patients are studied in detail. ...
The widespread use of array-comparative genomic hybridization (array-CGH) for the detection of copy number variants (CNVs) in both research and clinical laboratories has created a renaissance in the field of molecular cytogenetics, revealing that the human genome contains both a wealth of structural polymorphism and many novel genomic disorders. A new generation of experimental platforms enable structural variants to be identified with increasing resolution, and will require the development of more sophisticated methods to assess the pathogenic significance of novel structural variants if these technologies are to be of clinical utility. Indeed, we are now entering an era in which technologies to detect CNVs have advanced much faster than our understanding of the consequences of these variants on human phenotypes, and I argue that over the last few years the problem has now become one of interpretation rather than identification. This problem is made more complex by the realization that many genomic disorders show highly variable penetrance, blurring the boundary of how to define benign vs. pathogenic variants. I discuss insights from recent research which shed light on potential mechanisms that may underlie this phenomenon, and possible methods to determine the genetic elements that are responsible for the associated phenotype. Furthermore, there is now a growing appreciation that the underlying chromosomal architecture which catalyses many genomic disorders is polymorphic within the general population, and I discuss potential mechanisms by which inversion polymorphisms might create predispositions to genomic disorders.
