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Introduction Impaired spatial working memory is a core cognitive deficit observed in people with 22q11 Deletion syndrome (22q11DS) and has been suggested as a candidate endophenotype for schizophrenia. However, to date, the neuroanatomical mechanisms describing its structural and functional underpinnings in 22q11DS remain unclear. We quantitatively investigate the cognitive processes and associated neuroanatomy of spatial working memory in people with 22q11DS compared to matched controls. We examine whether there are significant between-group differences in spatial working memory using task related fMRI, Voxel based morphometry and white matter fiber tractography. Materials and Methods Multimodal magnetic resonance imaging employing functional, diffusion and volumetric techniques were used to quantitatively assess the cognitive and neuroanatomical features of spatial working memory processes in 22q11DS. Twenty-six participants with genetically confirmed 22q11DS aged between 9 and 52 years and 26 controls aged between 8 and 46 years, matched for age, gender, and handedness were recruited. Results People with 22q11DS have significant differences in spatial working memory functioning accompanied by a gray matter volume reduction in the right precuneus. Gray matter volume was significantly correlated with task performance scores in these areas. Tractography revealed extensive differences along fibers between task-related cortical activations with pronounced differences localized to interhemispheric commissural fibers within the parietal section of the corpus callosum. Conclusions Abnormal spatial working memory in 22q11DS is associated with aberrant functional activity in conjunction with gray and white matter structural abnormalities. These anomalies in discrete brain regions may increase susceptibility to the development of psychiatric disorders such as schizophrenia. Hum Brain Mapp 37:4689–4705, 2016. © 2016 Wiley Periodicals, Inc.

Deletion of chr22q11 gives rise to velo-cardio facial syndrome (VCFS) and increases schizophrenia risk. The source of this elevated risk although unknown could result from stochastic, environmental, or genetic factors, the latter encompassing a range of complexity from polygenic mechanisms to "second-hit" mutations. For this study we tested the two-hit hypothesis where additional risk is conferred through a second CNV. We identified large (100 kb) CNVs in 48 VCFS cases (23 with psychosis--25 without) and show in the psychotic VCFS group there is a significant (P = 0.02) increase in the average size of CNVs (354-227 kb). To identify second-hit loci we focused on individuals possessing gene-centric CNVs and through literature mining identified 4 (31%) psychotic VCFS individuals (n = 13) that overlapped loci previously implicated in neuropsychiatric disorders compared to 1 (10%) from the non-psychotic VCFS individuals (n = 10). For replication 17 VCFS patients with schizophrenia from the molecular genetics of schizophrenia dataset were used to identify further CNVs. Thirteen individuals possessing gene-centric CNVs were identified including 3 (23%) individuals possessing a potential second-hit, taking the overall total in the psychotic VCFS group (n = 26) to 7 (27%) potential second-hit loci. Notably a deletion in a psychotic VCFS patient at 2q23.1 hit the gene MBD5 which when deleted gives rise to intellectual disability, epilepsy, and autistic features. Through this study we potentially extend this phenotypic spectrum to include schizophrenia. Our results suggest the two-hit hypothesis may be relevant to a proportion of VCFS patients with psychosis but sample sizes are small and further studies warranted.

Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome-wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling-pairs and two avuncular pairs) with DSM-IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling-pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ∼10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome-wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome-wide covariate linkage analysis for symptom dimensions and illness history variables in sibling-pairs with schizophrenia. The significant within-pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome-wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation.

It has been proposed that people with autism spectrum disorder (ASD) have abnormal morphometry and development of the amygdala and hippocampus (AH). However, previous reports are inconsistent, perhaps because they included people of different ASD diagnoses, ages, and health. We compared, using magnetic resonance imaging, the in vivo anatomy of the AH in 32 healthy individuals with Asperger syndrome (12-47 years) and 32 healthy controls who did not differ significantly in age or IQ. We measured bulk (gray + white matter) volume of the AH using manual tracing (MEASURE). We first compared the volume of AH between individuals with Asperger syndrome and controls and then investigated age-related differences. We compared differences in anatomy before, and after, correcting for whole brain size. There was no significant between group differences in whole brain volume. However, individuals with Asperger syndrome had a significantly larger raw bulk volume of total (P

There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk for the development of schizophrenia, with only a greater risk conferred by being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual. Both linkage and association studies of people with schizophrenia have implicated several susceptibility genes, of which three are in the 22q11.2 region; catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH), and Gnb1L. In addition, variation in Gnb1L is associated with the presence of psychosis in males with 22q11.2DS. In mouse models of 22q11.2DS, haploinsufficiency of Tbx1 and Gnb1L is associated with reduced prepulse inhibition, a schizophrenia endophenotype. The study of 22q11.2DS provides an attractive model to increase our understanding of the development and pathogenesis of schizophrenia and other psychiatric disorders in 22q11.2DS and in wider population.

Velo—cardio—facial syndrome (VCFS), the most frequent known interstitial deletion found in humans, occurs with an incidence of approx 1/4000 live births (1). VCFS is associated with chromosomal microdeletions in the ql l band of chromosome 22 in over 90% of those with the disorder (2). The VCFS phenotype is complex, with multiple congenital abnormalities affecting a wide range of tissues and organs, often occurring in different combinations and with widely differing severity. Although in excess of 100 phenotypic features have been described, the most common include characteristic dysmorphology, congenital heart disease, cleft palate, borderline learning disability, and psychiatric disorder (Fig. 1). Variability in phenotypic expression has resulted in the same deletion being linked to several syndromes including DiGeorge syndrome, conotruncal anomaly face syndrome, Cayler syndrome, and Opitz GBBB syndrome, and the term “22q11 deletion syndrome” has been proposed as a replacement term for these other designators.

Following reports of linkage between schizophrenia and markers in the chromosomal region 6p24-22 we have studied nine microsatellite markers spanning 40 cM of this region in our sample of 102 affected sibling pairs from 86 families. Allele sharing identity by descent was examined using likelihood based sib-pair analysis as implemented by the program SPLINK. No evidence for linkage was obtained and the highest lod score was only 0.192 for D6S309. We conclude that if there is a susceptibility locus for schizophrenia in this region then its effect size is so small as to render our study insufficiently powerful to detect it.

22q11.2 deletion syndrome (22q11.2DS), also known as velocardiofacial syndrome, is the most frequent known interstitial deletion found in humans. It is associated with high rates of psychiatric disorder and, in particular, schizophrenia (approximately 30%) and schizophrenia-spectrum disorders. The 22q11.2 region is rich in genes coding for brain development, and consequently, deletion of 22q11.2 provides a useful neurodevelopmental model for understanding the evolution of psychotic disorders in both 22q11.2DS and the nondeleted general population. 22q11.2DS is also associated with significant structural and functional neuroanatomical abnormalities, which underlie the high rates of psychosis seen in affected individuals. Further research is currently underway to determine the cognitive, genetic and neuroanatomical correlates of psychosis seen in the disorder. Key Concepts: 22q11.2DS provides for a genetic and neurodevelopmental model for understanding psychotic disorder seen not only with the syndrome but can also be extrapolated to the general nondeleted population. Although 22q11.2DS is associated with marked phenotypic variability, psychiatric disorder and, in particular, schizophrenia-spectrum disorders occur in approximately 30% of deleted individuals. Schizophrenia-spectrum disorders arise as prodromal or subthreshold psychotic symptoms during childhood and adolescence followed by subsequent expression during adulthood where it is largely indistinguishable from the psychosis seen in the nondeleted population. Apart from being the monozygotic co-twin of a proband with psychosis or being the offspring of parents with schizophrenia, 22q11.2 deletion is the highest known risk factor for the development of schizophrenia. Keywords: VCFS; velocardiofacial syndrome; schizophrenia; chromosome 22q11; psychosis; 22q11DS

Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinepherine, has been proposed as being involved in the aetiology of schizophrenia. Previous work identified a functional polymorphism at nucleotide 910 of the DBH gene that results in a codon change in the mature protein Ala304Ser, with the mutant allele being associated with a lower enzymatic activity. In this study we performed an RFLP analysis in an association study consisting of 178 unrelated schizophrenic patients and 178 unrelated control subjects, matched for age, sex, and ethnicity. The frequency of the Ser304 DBH allele was 0.10 in the patient group and 0.08 in the control group, with no significant allelic or genotypic association observed. Therefore, we were unable to obtain evidence that this polymorphism contributes directly to susceptibility to schizophrenia.

Velocardiofacial syndrome, the most frequent known interstitial deletion found in humans, is associated with high rates of psychiatric disorder, particularly schizophrenia. Keywords: VCFS; velo-cardio-facial syndrome; schizophrenia; chromosome 22q11; psychosis

We report a case control association study using markers D22S278 and D22S283 in 90 unrelated patients with DSMIII-R schizophrenia and 90 controls matched for ethnicity, age and sex. No differences between allele frequencies for either marker were observed when the two groups were compared (D22S278: chi 2 = 6.53, df = 7, P = 0.51; D22S283: chi 2 = 14.73, df = 15, P = 0.48). These findings fail to support previous work by others suggesting the presence of allelic association between the markers D22S278 and D22S283 and schizophrenia.

22q11 Deletion Syndrome (22q11DS) is a relatively common interstitial deletion disorder with a minimum prevalence of approximately 1:5000 live births. Although considerable phenotypic variability occurs, common clinical features include a typical dysmorphology, cleft palate, congenital heart defects and a characteristic behavioural phenotype. While much of the literature has focussed on the well documented association between 22q11DS and schizophrenia, there is now increasing attention on the prevalence of autistic spectrum disorders (ASD) in 22q11DS. The current evidence implicating ASD in 22q11DS and the implications for the clinical management of affected individuals will be discussed.

Background: 22q11.2 Deletion Syndrome (22q11.2 DS) is a common micro-deletion syndrome associated with intellectual disability, brain abnormalities and a complex spectrum of psychiatric disorders in both adults and children. Many previous studies have shown that adults with 22q11.2 DS have approximately thirty times greater risk for the developing schizophrenia compared to the general population. Furthermore, studies of children and adolescents with 22q11.2 DS have found high rates of psychotic symptoms, ADHD and anxiety disorders. In this study we initially aim to characterize the psychiatric and neuropsychological phenotype of all individuals in Ireland with 22q11.2 DS and then correlate our findings with genetic association studies and brain imaging. We then intend to undertake a longitudinal study to assess for risk factors of future psychotic illness. Methods: Forty-four individuals with 22q11.2 DS (Mean age = 14 years, SD = 9) were compared to 25 non-affected sibling controls (Mean age = 12 years, SD = 4). Psychiatric phenotype assessment was performed using a range of standardized clinical assessments including, the Diagnostic Interview Schedule for Children (DISC), Psychotic Supplement of K-SADS, Comprehensive Assessment of At Risk Mental State (CAARMS), the Schedule for Clinical Assessment in Neuropsychiatry (SCAN), Child Behaviour Checklist (CBCL) and the Social Communication Questionnaire (SCQ). Results: Preliminary data indicates that individuals in the 22q11.2 DS group have a higher prevalence of psychiatric disorders including; ADHD (41%), psychotic symptoms (19%), schizophrenia (2.7%), specific phobias (38%), depressive episodes (11%), and anxiety disorders (32%). Conclusion: This is the first stage in a longitudinal follow-up study of individuals with 22q11.2DS in Ireland. Our preliminary results are consistent with previous findings of high rates of psychiatric disorders in people with 22q11.2DS. The challenge remains to identify precursor symptoms in childhood that predicts the later development of psychiatric disorders, particularly schizophrenia in this vulnerable group.