Neural substrates of psychosis revealed by altered dependencies between brain activity and white-matter architecture in individuals with 22q11 deletion syndrome.

BACKGROUND: Dysconnectivity has been consistently proposed as a major key mechanism in psychosis. Indeed, disruptions in large-scale structural and functional brain networks have been associated with psychotic symptoms. However, brain activity is largely constrained by underlying white matter pathways and the study of function-structure dependency, compared to conventional unimodal analysis, allows a biologically relevant assessment of neural mechanisms. The 22q11.2 deletion syndrome (22q11DS) constitutes a remarkable opportunity to study the pathophysiological processes of psychosis. METHODS: 58 healthy controls and 57 deletion carriers, aged from 16 to 32 years old,underwent resting-state functional and diffusion-weighted magnetic resonance imaging. Deletion carriers were additionally fully assessed for psychotic symptoms. Firstly, we used a graph signal processing method to combine brain activity and structural connectivity measures to obtain regional structural decoupling indexes (SDIs). We use SDI to assess the differences of functional structural dependency (FSD) across the groups. Subsequently we investigated how alterations in FSDs are associated with the severity of positive psychotic symptoms in participants with 22q11DS. RESULTS: In line with previous findings, participants in both groups showed a spatial gradient of FSD ranging from sensory-motor regions (stronger FSD) to regions involved in higher-order function (weaker FSD). Compared to controls, in participants with 22q11DS, and further in deletion carriers with more severe positive psychotic symptoms, the functional activity was more strongly dependent on the structure in parahippocampal gyrus and subcortical dopaminergic regions, while it was less dependent within the cingulate cortex. This analysis revealed group differences not otherwise detected when assessing the structural and functional nodal measures separately. CONCLUSIONS: Our findings point toward a disrupted modulation of functional activity on the underlying structure, which was further associated to psychopathology for candidate critical regions in 22q11DS. This study provides the first evidence for the clinical relevance of function-structure dependency and its contribution to the emergence of psychosis.

Abnormal nodal and global network organization in resting state functional MRI from subjects with the 22q11 deletion syndrome.

The 22q11 deletion syndrome is a genetic disorder associated with a high risk of developing psychosis, and is therefore considered a neurodevelopmental model for studying the pathogenesis of schizophrenia. Studies have shown that localized abnormal functional brain connectivity is present in 22q11 deletion syndrome like in schizophrenia. However, it is less clear whether these abnormal cortical interactions lead to global or regional network disorganization as seen in schizophrenia. We analyzed from a graph-theory perspective fMRI data from 40 22q11 deletion syndrome patients and 67 healthy controls, and reconstructed functional networks from 105 brain regions. Between-group differences were examined by evaluating edge-wise strength and graph theoretical metrics of local (weighted degree, nodal efficiency, nodal local efficiency) and global topological properties (modularity, local and global efficiency). Connectivity strength was globally reduced in patients, driven by a large network comprising 147 reduced connections. The 22q11 deletion syndrome network presented with abnormal local topological properties, with decreased local efficiency and reductions in weighted degree particularly in hub nodes. We found evidence for abnormal integration but intact segregation of the 22q11 deletion syndrome network. Results suggest that 22q11 deletion syndrome patients present with similar aberrant local network organization as seen in schizophrenia, and this network configuration might represent a vulnerability factor to psychosis.

Disruption of the blood-brain barrier in 22q11.2 deletion syndrome.

Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia. As the blood-brain barrier is the immunological interface between the brain and the periphery, we investigated whether this vascular phenotype is intrinsically compromised in the most common genetic risk factor for schizophrenia, the 22q11.2 deletion syndrome (22qDS). Blood-brain barrier like endothelium differentiated from human 22qDS+schizophrenia-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 was upregulated in 22qDS+schizophrenia-induced blood-brain barrier and in 22qDS mice, indicating compromise of the blood-brain barrier immune privilege. This immune imbalance resulted in increased migration/activation of leucocytes crossing the 22qDS+schizophrenia blood-brain barrier. We also found heightened astrocyte activation in murine 22qDS, suggesting that the blood-brain barrier promotes astrocyte-mediated neuroinflammation. Finally, we substantiated these findings in post-mortem 22qDS brain tissue. Overall, the barrier-promoting and immune privilege properties of the 22qDS blood-brain barrier are compromised, and this might increase the risk for neuropsychiatric disease.

Prioritizing Genetic Contributors to Cortical Alterations in 22q11.2 Deletion Syndrome Using Imaging Transcriptomics.

22q11.2 deletion syndrome (22q11DS) results from a hemizygous deletion that typically spans 46 protein-coding genes and is associated with widespread alterations in brain morphology. The specific genetic mechanisms underlying these alterations remain unclear. In the 22q11.2 ENIGMA Working Group, we characterized cortical alterations in individuals with 22q11DS (n = 232) versus healthy individuals (n = 290) and conducted spatial convergence analyses using gene expression data from the Allen Human Brain Atlas to prioritize individual genes that may contribute to altered surface area (SA) and cortical thickness (CT) in 22q11DS. Total SA was reduced in 22q11DS (Z-score deviance = -1.04), with prominent reductions in midline posterior and lateral association regions. Mean CT was thicker in 22q11DS (Z-score deviance = +0.64), with focal thinning in a subset of regions. Regional expression of DGCR8 was robustly associated with regional severity of SA deviance in 22q11DS; AIFM3 was also associated with SA deviance. Conversely, P2RX6 was associated with CT deviance. Exploratory analysis of gene targets of microRNAs previously identified as down-regulated due to DGCR8 deficiency suggested that DGCR8 haploinsufficiency may contribute to altered corticogenesis in 22q11DS by disrupting cell cycle modulation. These findings demonstrate the utility of combining neuroanatomic and transcriptomic datasets to derive molecular insights into complex, multigene copy number variants.

Quantitative facial phenotyping for Koolen-de Vries and 22q11.2 deletion syndrome.

The Koolen-de Vries syndrome (KdVS) is a multisystem syndrome with variable facial features caused by a 17q21.31 microdeletion or KANSL1 truncating variant. As the facial gestalt of KdVS has resemblance with the gestalt of the 22q11.2 deletion syndrome (22q11.2DS), we assessed whether our previously described hybrid quantitative facial phenotyping algorithm could distinguish between these two syndromes, and whether there is a facial difference between the molecular KdVS subtypes. We applied our algorithm to 2D photographs of 97 patients with KdVS (78 microdeletions, 19 truncating variants (likely) causing KdVS) and 48 patients with 22q11.2DS as well as age, gender and ethnicity matched controls with intellectual disability (n = 145). The facial gestalts of KdVS and 22q11.2DS were both recognisable through significant clustering by the hybrid model, yet different from one another (p = 7.5 × 10-10 and p = 0.0052, respectively). Furthermore, the facial gestalts of KdVS caused by a 17q21.31 microdeletion and KANSL1 truncating variant (likely) causing KdVS were indistinguishable (p = 0.981 and p = 0.130). Further application to three patients with a variant of unknown significance in KANSL1 showed that these faces do not match KdVS. Our data highlight quantitative facial phenotyping not only as a powerful tool to distinguish syndromes with overlapping facial dysmorphisms but also to establish pathogenicity of variants of unknown clinical significance.

Neurobiological perspective of 22q11.2 deletion syndrome.

22q11.2 deletion syndrome is characterised by a well defined microdeletion that is associated with a high risk of neuropsychiatric disorders, including intellectual disability, schizophrenia, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety disorders, seizures and epilepsy, and early-onset Parkinson's disease. Preclinical and clinical data reveal substantial variability of the neuropsychiatric phenotype despite the shared underlying deletion in this genetic model. Factors that might explain this variability include genetic background effects, additional rare pathogenic variants, and potential regulatory functions of some genes in the 22q11.2 deletion region. These factors might also be relevant to the pathophysiology of these neuropsychiatric disorders in the general population. We review studies that might provide insight into pathophysiological mechanisms underlying the expression of neuropsychiatric disorders in 22q11.2 deletion syndrome, and potential implications for these common disorders in the general (non-deleted) population. The recurrent hemizygous 22q11.2 deletion, associated with 22q11.2 deletion syndrome, has attracted attention as a genetic model for common neuropsychiatric disorders because of its association with substantially increased risk of such disorders.1 Studying such a model has many advantages. First, 22q11.2 deletion has been genetically well characterised.2 Second, most genes present in the region typically deleted at the 22q11.2 locus are expressed in the brain.3-5 Third, genetic diagnosis might be made early in life, long before recognisable neuropsychiatric disorders have emerged. Thus, this genetic condition offers a unique opportunity for early intervention, and monitoring individuals with 22q11.2 deletion syndrome throughout life could provide important information on factors contributing to disease risk and protection. Despite the commonly deleted region being shared by about 90% of individuals with 22q11.2 deletion syndrome, neuropsychiatric outcomes are highly variable between individuals and across the lifespan. A clear link remains to be established between genotype and phenotype.3,5 In this Review, we summarise preclinical and clinical studies investigating biological mechanisms in 22q11.2 deletion syndrome, with a focus on those that might provide insight into mechanisms underlying neuropsychiatric disorders in 22q11.2 deletion syndrome and in the general population.

[Child psychiatry interventions in patients with 22q11 deletion syndrome: From treatment to prevention]. / Prise en charge pédopsychiatrique des patients présentant un syndrome microdélétionnel 22q11.2 : du soin à la prévention.

22q11.2DS is one of the more frequent genetic syndromes associated to psychiatric symptoms. It has been associated to an increased risk to develop schizophrenia in adolescence or early adulthood. However, psychiatric symptoms appear early on, and should be recognized as soon as possible by child psychiatrists in order to improve the present well-being of children and their family, and to prevent further risks of developing severe and chronic psychiatric diseases later on. In this paper, we present a review of the recent literature concerning the 22q11.2DS syndrome focused on the risk factors that may be associated to an increased risk of psychotic transition. We advocate for the development of systematic specialized child psychiatry consultations for these patients, included in networks with geneticists, adult psychiatrists, and family associations, in order to improve their psychiatric prognosis and to support the development of translational research.

Abnormalities in gray matter microstructure in young adults with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is a genetic, neurodevelopmental disorder characterized by a chromosomal deletion and a distinct cognitive profile. Although abnormalities in the macrostructure of the cortex have been identified in individuals with 22q11DS, it is not known if there are additional microstructural changes in gray matter regions in this syndrome, and/or if such microstructural changes are associated with cognitive functioning. METHODS: This study employed a novel diffusion MRI measure, the Heterogeneity of Fractional Anisotropy (HFA), to examine variability in the microstructural organization of the cortex in healthy young adults (N = 30) and those with 22q11DS (N = 56). Diffusion MRI, structural MRI, clinical and cognitive data were acquired. RESULTS: Compared to controls, individuals with 22q11DS evinced increased HFA in cortical association (p = .003, d = 0.86) and paralimbic (p < .0001, d = 1.2) brain areas, whereas no significant differences were found between the two groups in primary cortical brain areas. Additionally, increased HFA of the right paralimbic area was associated with poorer performance on tests of response inhibition, i.e., the Stroop Test (rho = -0.37 p = .005) and the Gordon Diagnostic System Vigilance Commission (rho = -0.41 p = .002) in the 22q11DS group. No significant correlations were found between HFA and cognitive abilities in the healthy control group. CONCLUSIONS: These findings suggest that cortical microstructural disorganization may be a neural correlate of response inhibition in individuals with 22q11DS. Given that the migration pattern of neural crest cells is disrupted at the time of early brain development in 22q11DS, we hypothesize that these neural alterations may be neurodevelopmental in origin, and reflect cortical dysfunction associated with cognitive deficits.

Infertility in a man with oligoasthenozoospermia associated with mosaic chromosome 22q11 deletion.

BACKGROUND: A 30-year-old oligoasthenozoospermia man was found to have unbalance mosaic translocation between chromosome 22 and four other chromosomes (5, 6, 13, and 15) during the investigations for a couple with infertility for 3 years, which is a rare event in human pathology. METHODS: Classical cytogenetics analysis, fluorescence in situ hybridization (FISH), and chromosome microarray analyses (CMA) were performed on peripheral blood lymphocytes; copy number variation sequencing (CNV-Seq) analysis was performed on sperm DNA. RESULTS: Classical cytogenetics analysis showed the presence of six cell lines on peripheral blood lymphocytes: 45, XY, der (13) t(13;22),-22[10]/46, XY, t(13;22)[6]/45, XY, der(15)t(15;22),-22[4]/46, XY, t(13;22)[1]/45, XY, der(5)t(5;22),-22[1]/45, XY, der(6)t(6;22)[1]. FISH and CMA performed on peripheral blood cells showed the presence of a 6.9 Mb mosaic 22q11 deletion (approximately 50% of cells); it is unexpected that the phenotypes of this man were merely oligoasthenozoospermia, mild bradycardia, and mild tricuspid regurgitation. CNV-Seq analysis performed on sperm DNA revealed the rate of 22q11 deletion cells was obviously lower compared with peripheral blood cells. And the frequency of gametes exhibiting a normal or balance chromosomal equipment was above 80% in sperm samples. CONCLUSION: To the best of our knowledge, this report is the first case of a de novo gonosomal mosaic of chromosome 22q11 deletion just associated with male infertility.

Failed Progenitor Specification Underlies the Cardiopharyngeal Phenotypes in a Zebrafish Model of 22q11.2 Deletion Syndrome.

Microdeletions involving TBX1 result in variable congenital malformations known collectively as 22q11.2 deletion syndrome (22q11.2DS). Tbx1-deficient mice and zebrafish recapitulate several disease phenotypes, including pharyngeal arch artery (PAA), head muscle (HM), and cardiac outflow tract (OFT) deficiencies. In zebrafish, these structures arise from nkx2.5+ progenitors in pharyngeal arches 2-6. Because pharyngeal arch morphogenesis is compromised in Tbx1-deficient animals, the malformations were considered secondary. Here, we report that the PAA, HM, and OFT phenotypes in tbx1 mutant zebrafish are primary and arise prior to pharyngeal arch morphogenesis from failed specification of the nkx2.5+ pharyngeal lineage. Through in situ analysis and lineage tracing, we reveal that nkx2.5 and tbx1 are co-expressed in this progenitor population. Furthermore, we present evidence suggesting that gdf3-ALK4 signaling is a downstream mediator of nkx2.5+ pharyngeal lineage specification. Collectively, these studies support a cellular mechanism potentially underlying the cardiovascular and craniofacial defects observed in the 22q11.2DS population.

Isolation of right internal carotid artery, persistent proatlantal 1 artery and rete mirabile in a child with 22q11 deletion syndrome.

We report a case of a 2-year-old girl with 22q11 deletion syndrome who underwent studies for cardiac murmur. Ultrasound, computed tomography angiography and digital subtraction angiography revealed an aberrant right subclavian artery and an isolated right internal carotid artery (ICA) originating from the right pulmonary artery. A right carotid rete mirabile (CRM) and a proatlantal (Pa) type 1 artery were also found. We hypothesize that Pa type 1 persistence and CRM development are secondary to the reversal of flow of the isolated ICA.

Mapping 22q11.2 Gene Dosage Effects on Brain Morphometry.

Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age- and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion < control < duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion > control > duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric patterns extended into subcortical regions: 22q-dup carriers had a significantly larger right hippocampus, on average, but lower right caudate and corpus callosum volume, relative to 22q-del carriers. Novel subcortical shape analysis revealed greater radial distance (thickness) of the right amygdala and left thalamus, and localized increases and decreases in subregions of the caudate, putamen, and hippocampus in 22q-dup relative to 22q-del carriers. This study provides the first evidence that 22q11.2 is a genomic region associated with gene-dose-dependent brain phenotypes. Pervasive effects on cortical surface area imply that this copy number variant affects brain structure early in the course of development.SIGNIFICANCE STATEMENT Probing naturally occurring reciprocal copy number variation in the genome may help us understand mechanisms underlying deviations from typical brain and cognitive development. The 22q11.2 genomic region is particularly susceptible to chromosomal rearrangements and contains many genes crucial for neuronal development and migration. Not surprisingly, reciprocal genomic imbalances at this locus confer some of the highest known genetic risks for developmental neuropsychiatric disorders. Here we provide the first evidence that brain morphology differs meaningfully as a function of reciprocal genomic variation at the 22q11.2 locus. Cortical thickness and surface area were affected in opposite directions with more widespread effects of gene dosage on cortical surface area.

Confined placental mosaicism for 22q11.2 deletion as the etiology for discordant positive NIPT results.

22q11.2 deletion, the most common microdeletion syndrome within the general population, is estimated to have a prevalence of 1 in 3000 to 6000. Non-invasive prenatal testing has recently expanded to include screening for several microdeletions including 22q11.2. Given the expansion of prenatal screening options to include microdeletions, it is important to understand the limits of this technology and the variety of reasons that a discordant positive result can occur. Here, we describe a case of a pregnant woman who received a positive non-invasive prenatal maternal plasma screen for 22q11.2 deletion. Maternal and postnatal neonatal peripheral blood cytogenetic, PCR, and fluorescence in situ hybridization studies were normal, but the placenta was mosaic for 22q11.2 deletion in two of three biopsy sites. This case illustrates both the complexities of pre- and post-test counseling for microdeletion screening and the potential for a discordant positive microdeletion result because of confined placental mosaicism. © 2017 John Wiley & Sons, Ltd.

Analysis of induced pluripotent stem cells carrying 22q11.2 deletion.

Given the complexity and heterogeneity of the genomic architecture underlying schizophrenia, molecular analyses of these patients with defined and large effect-size genomic defects could provide valuable clues. We established human-induced pluripotent stem cells from two schizophrenia patients with the 22q11.2 deletion (two cell lines from each subject, total of four cell lines) and three controls (total of four cell lines). Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. As an underlying mechanism, we focused on the role of DGCR8, a key gene for microRNA (miRNA) processing and mapped in the deleted region. In mice, Dgcr8 hetero-knockout is known to show a similar phenotype of reduced neurosphere size (Ouchi et al., 2013). The miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38α, and conformingly the levels of p38α were upregulated in the patient-derived cells. p38α is known to drive gliogenic differentiation. The inhibition of p38 activity by SB203580 in patient-derived neurospheres partially restored neurogenic competence. Furthermore, we detected elevated expression of GFAP, a gliogenic (astrocyte) marker, in postmortem brains from schizophrenia patients without the 22q11.2 deletion, whereas inflammation markers (IL1B and IL6) remained unchanged. In contrast, a neuronal marker, MAP2 expressions were decreased in schizophrenia brains. These results suggest that a dysregulated balance of neurogenic-to-gliogenic competence may underlie neurodevelopmental disorders such as schizophrenia.

[Catch-22? Wide variety of phenotypes associated with the chromosome 22q11 deletion syndrome in two patients]. / A 22-es csapdája? A 22q11 kromoszóma deletiós szindróma változatos klinikai megjelenése két eset kapcsán.

The chromosome 22q11 deletion syndrome may present with a variety of phenotypes. Its symptoms generally include a characteristic facial dysmorphisms and multiplex developmental disorders. Fluorescence in situ hybridization is the current method of choice for the diagnosis if typical multiple defects and/or symptoms are present. The authors present the history of two patients who were followed-up for minor anomalies and various developmental disorders for several years in the genetic counseling office of the authors, but definitive diagnosis was not established. However, when DNA samples of the two patients were recently tested with array comparative genome hybridization, a diagnostic method which has already been used in their institute for several years, the results indicated deletion of the 11.2 region on the long arm of chromosome 22 in both patients. The authors draw attention to the incidence and wide phenotypic spectrum of the chromosome 22q11 deletion syndrome, and show that its identification can be aided with the novel molecular cytogenetic method available in their laboratory.

[NEGATIVE IMPACT OF CHROMOSOME 22Q11 MICRODELETION ON RESULTS OF TREATMENT IN PATIENTS, SUFFERING CONONTRUNCAL FAILURES OF HEART AND MAIN AORTO-PULMONARY COLLATERAL ARTERIES].

Dependence of results of surgical treatment in 42 patients, suffering conotruncal failures and main aorto-pulmonary collateral arteries from presence of the chromosome 22q11 deletion syndrome, was analyzed. While presence of the chromosome 22q11 deletion syndrome duration of treatment of patients in intensive therapy unit and artificial pulmonary ventilation are longer, pressure in a pulmonary artery system after radical operative failures correction is higher, general lethality is bigger, than while the chromosome 22q11 deletion syndrome absence. The data obtained must be taken into account while determining tactics of treatment in patients with confirmed diagnosis of the chromosome 22q11 deletion syndrome.

An increased prevalence of thyroid disease in children with 22q11.2 deletion syndrome.

We reviewed the health records of pediatric patients with 22q11.2 deletion syndrome (22q11.2 DS) seen over a 5-year period in our 22q11.2 DS multidisciplinary clinic. We determined the prevalence of thyroid dysfunction in this population, in comparison to general population data. Statistical tests were applied to investigate trends in gender differences, thyroid disease subtype and co-morbid conditions in the patients identified with thyroid disease. Of 169 subjects (92 male, 77 female) 9.5% had overt thyroid disease; of these, 1.8% had hyperthyroidism and 7.7% had hypothyroidism; 42% of patients with subclinical or prodromal thyroid disease progressed to overt disease. Our data indicate that thyroid disease prevalence in the 22q11DS pediatric population is significantly higher than that in the general pediatric population Furthermore, over 1/3 of patients in our study population who presented with subclinical thyroid disease progressed to overt disease, requiring medical therapy. Thyroid disease screening should be incorporated into routine medical management of children with 22q11.2 DS. Guidelines for screening individuals with 22q11.2 DS are presented.

Microdeleción 12p12 que incluye el gen SOX5: un nuevo síndrome con alteración del neurodesarrollo / Microdeletion 12p12 involving SOX5 gene: a new syndrome with developmental delay

Introducción. El gen SOX5 codifica un factor de transcripción implicado en la regulación de la condrogenia y el desarrollo del sistema nervioso. Caso clínico. Niña de 10 años con discapacidad intelectual, alteración conductual y malformaciones menores de este nuevo síndrome con alteración en el neurodesarrollo, con una deleción 12p12 que incluye el gen SOX5. Conclusiones. Se revisan los casos publicados tanto de deleciones intragénicas de SOX5 como de deleciones más grandes que incluyen este gen, y se analizan las correlaciones enotipo-fenotipo y los genes implicados en esta paciente (AU)

Introduction. The SOX5 gene encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Case report. We report a 10 years-old girl with developmental delay, behavior problems and dysmorphic features of this new syndrome with developmental delay. She had a 12p12 deletion involving SOX5. Conclusions. We review the reported cases, intragenic SOX5 deletions and larger 12p12 deletions encompassing SOX5. We analyze the genotype-phenotype associations and the genes involved in our patient (AU)