Adaptive living skills, sleep problems, and mental health disorders in adults with 22q11.21 deletion syndrome.

BACKGROUND: 22q11.21 deletion syndrome (22q11DS) is a neurodevelopmental syndrome caused by a microdeletion of genes at the 22q11.21 locus. It has a prevalence of 1:2000. This study investigated the prevalence of adaptive living skills, sleep problems, and mental health disorders in adults with 22q11DS and examined the relationship between these factors. METHODS: Parents with an adult son or daughter with 22q11DS completed the following: A bespoke Demographic Information Questionnaire, Sleep Questionnaire (SQ-SP), Psychopathology in Autism Checklist (PAC), and Activities of Daily Living (ADL) scale. Descriptive statistics, correlations, and one-way between groups analysis of variance (ANOVA) were conducted. RESULTS: Mental health difficulties, sleep problems, and low levels of adaptive living skills are prevalent in adults with 22q11DS. Strong positive correlations were identified between sleep problems, depression, and anxiety subscale scores and moderate negative correlations between depression, psychosis, and activities of daily living skills. CONCLUSION: Adults with 22q11DS need screening and treatment for mental health and sleep problems.

[Analysis of genome copy number variations in fetuses with isolated ventricular septal defect and a literature review].

OBJECTIVE: To assess the value of copy number variation sequencing (CNV-seq) for revealing the genetic etiology of fetuses with isolated ventricular septal defect (VSD). METHODS: From December 2017 to December 2020, 69 fetuses with isolated VSD were identified at the First Affiliated Hospital of Zhengzhou University. Meanwhile, 839 similar prenatal cases were selected from public databases including Wanfang data, Wanfang Medicine, and China National Knowledge Infrastructure (CNKI) by using keywords such as "Ventricular septal defect", "Copy number variation", and "Prenatal". A total of 908 fetuses with isolated VSD were analyzed. CNV-seq was carried out for 69 fetuses. RESULTS: Among the 908 fetuses, 33 (3.63%) were found to harbor pathogenic CNVs, which included 11 chromosomal aneuploidies (1.21%) and 22 pathogenic CNVs (2.42%). The pathogenic CNVs have involved 12 genetic syndromes, with those known to involve the heart development including 5 cases of 22q11.21 deletion syndrome, 2 cases of 4q terminal deletion syndrome, and 1 case of 9q subtelomere deletion syndrome. The outcome of pregnancies for 15 fetuses with pathogenic CNVs was known, of which 12 were terminated, and 3 had spontaneous closure of the ventricular septum after birth, but 1 of them had other abnormalities. CONCLUSION: Fetuses with isolated VSD have a relatively high risk for chromosomal abnormalities, for which CNV-seq should be recommended.

Endocrine Abnormalities and Growth Characterization in Colombian Pediatric Patients with 22q11 Deletion Syndrome

Objective: Several endocrine manifestations have been described in patients with 22q11 deletion syndrome, including growth retardation, hypoparathyroidism, and thyroid disorders. This study aimed to characterize these abnormalities in a Colombian retrospective cohort of children with this condition. Methods: A retrospective study comprising a cohort of children with 22q11 deletion syndrome in Medellín, Colombia followed up between 2011 and 2017 was conducted. Results: Thirty-seven patients with a confirmed diagnosis of 22q11 deletion syndrome were included. 37.8% had some endocrinopathy, the most frequent being hypoparathyroidism (21.6%), followed by hypothyroidism (13.5%), hyperthyroidism (2.7%) and growth hormone deficiency (2.7%). There was wide heterogeneity in the clinical presentation, with late onset of severe hypocalcemia associated with seizure or precipitated in postoperative cardiac surgery, which highlights the importance of continuous follow-up as indicated by the guidelines. Short stature was mainly related to nutritional factors. Growth monitoring is required with the use of syndrome-specific charts and careful monitoring of the growth rate. Conclusion: As previously reported, a significant proportion of patients with endocrine abnormalities were found in this cohort. This highlights that it is essential to carry out an adequate multidisciplinary follow-up, based on the specific clinical guidelines, in order to avoid serious complications such as convulsions due to hypocalcemia. It is important to track size with curves specific to the syndrome and analyze the growth rate.

Analysis of genome copy number variations in fetuses with isolated ventricular septal defect and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of copy number variation sequencing (CNV-seq) for revealing the genetic etiology of fetuses with isolated ventricular septal defect (VSD).@*METHODS@#From December 2017 to December 2020, 69 fetuses with isolated VSD were identified at the First Affiliated Hospital of Zhengzhou University. Meanwhile, 839 similar prenatal cases were selected from public databases including Wanfang data, Wanfang Medicine, and China National Knowledge Infrastructure (CNKI) by using keywords such as "Ventricular septal defect", "Copy number variation", and "Prenatal". A total of 908 fetuses with isolated VSD were analyzed. CNV-seq was carried out for 69 fetuses.@*RESULTS@#Among the 908 fetuses, 33 (3.63%) were found to harbor pathogenic CNVs, which included 11 chromosomal aneuploidies (1.21%) and 22 pathogenic CNVs (2.42%). The pathogenic CNVs have involved 12 genetic syndromes, with those known to involve the heart development including 5 cases of 22q11.21 deletion syndrome, 2 cases of 4q terminal deletion syndrome, and 1 case of 9q subtelomere deletion syndrome. The outcome of pregnancies for 15 fetuses with pathogenic CNVs was known, of which 12 were terminated, and 3 had spontaneous closure of the ventricular septum after birth, but 1 of them had other abnormalities.@*CONCLUSION@#Fetuses with isolated VSD have a relatively high risk for chromosomal abnormalities, for which CNV-seq should be recommended.

Comunicación en personas con el síndrome de deleción de 22q11: voz y habla / Communication in people with 22q11 deletion syndrome: Voice and speech

Antecedentes y objetivos: En la actualidad hay pocos estudios que definan el perfil psicolingüístico de las personas con el síndrome de deleción de 22q11 (S22q11) con el castellano y/o el catalán como lengua materna. El objetivo de este estudio fue definir las características de la voz y el habla de las personas con el S22q11. Método: Se realizó un estudio con una muestra de 30 sujetos de entre 5 y 21 años (12.14±4.20) con S22q11. Se administraron cuestionarios ad hoc a los padres y se evaluó la voz, la ejecución de praxias bucofonatorias, la discriminación auditiva y el habla de los participantes. Resultados: Más de la mitad de los participantes tenían una voz más aguda de lo esperado por sexo y edad, y la mitad mostraba signos de hipofonía, a pesar de que los resultados de intensidad máxima mostraban que podrían utilizar una mayor intensidad. En cuanto al habla, los participantes más jóvenes presentaban un retraso en la adquisición de fonemas (excepto consonantes nasales) en comparación con su grupo normativo, y la mayoría hizo uso del sonido compensatorio ʔ. Los participantes mayores de 8 años producían correctamente los fonemas de adquisición tardía, aunque persistieron dificultades específicas de articulación. Conclusiones: Los participantes mostraron características específicas de voz y habla.(AU)

Background and objectives: Currently there are few studies that define the psycholinguistic profile of people with 22q11 deletion syndrome (S22q11) with Spanish and/or Catalan as their mother tongue. The aim of this study was to define the characteristics of the voice and speech of people with S22q11. Method: A study was performed with a sample of 30 subjects aged between 5 and 21 years (12.14±4.20) with S22q11. Ad hoc questionnaires were administered to parents, and participants’ voice, execution of oral praxis, hearing discrimination, and speech were assessed. Results: More than half of the participants had a sharper voice than expected by sex and age, and half showed signs of hypophonia, although the maximum intensity results showed that they could use more intensity. In terms of speech, the younger participants had a delay in the acquisition of phonemes (except nasal consonants) compared to their normative group, and most made use of the compensatory sound ʔ. Participants older than 8 years correctly produced late-acquisition phonemes, although specific articulation difficulties persisted. Conclusions: Participants showed specific voice and speech characteristics.(AU)

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.

Synaptic Plasticity Dysfunctions in the Pathophysiology of 22q11 Deletion Syndrome: Is There a Role for Astrocytes?

The 22q11 deletion syndrome (DS) is the most common microdeletion syndrome in humans and gives a high probability of developing psychiatric disorders. Synaptic and neuronal malfunctions appear to be at the core of the symptoms presented by patients. In fact, it has long been suggested that the behavioural and cognitive impairments observed in 22q11DS are probably due to alterations in the mechanisms regulating synaptic function and plasticity. Often, synaptic changes are related to structural and functional changes observed in patients with cognitive dysfunctions, therefore suggesting that synaptic plasticity has a crucial role in the pathophysiology of the syndrome. Most interestingly, among the genes deleted in 22q11DS, six encode for mitochondrial proteins that, in mouse models, are highly expressed just after birth, when active synaptogenesis occurs, therefore indicating that mitochondrial processes are strictly related to synapse formation and maintenance of a correct synaptic signalling. Because correct synaptic functioning, not only requires correct neuronal function and metabolism, but also needs the active contribution of astrocytes, we summarize in this review recent studies showing the involvement of synaptic plasticity in the pathophysiology of 22q11DS and we discuss the relevance of mitochondria in these processes and the possible involvement of astrocytes.

Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs.

BACKGROUND: Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS). PURPOSE: To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS. METHODS: Subjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed. RESULTS: At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells. CONCLUSIONS: This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring. CLINICAL IMPLICATIONS: This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices.

Agency Deficits in a Human Genetic Model of Schizophrenia: Insights From 22q11DS Patients.

Schizophrenia is a chronic and disabling mental illness characterized by a disordered sense of self. Current theories suggest that deficiencies in the sense of control over one's actions (Sense of Agency, SoA) may underlie some of the symptoms of schizophrenia. However, it is not clear if agency deficits are a precursor or a result of psychosis. Here, we investigated full body agency using virtual reality in a cohort of 22q11 deletion syndrome participants with a genetic propensity for schizophrenia. In two experiments employing virtual reality, full body motion tracking, and online feedback, we investigated SoA in two separate domains. Our results show that participants with 22q11DS had a considerable deficit in monitoring their actions, compared to age-matched controls in both the temporal and spatial domain. This was coupled with a bias toward erroneous attribution of actions to the self. These results indicate that nonpsychotic 22q11DS participants have a domain general deficit in the conscious sensorimotor mechanisms underlying the bodily self. Our data reveal an abnormality in the SoA in a cohort with a genetic predisposition for schizophrenia, but without psychosis, providing evidence that deficits in delineation of the self may be a precursor rather than a result of the psychotic state.

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.

Novel Combination of Surface Markers for the Reliable and Comprehensive Identification of Human Thymic Epithelial Cells by Flow Cytometry: Quantitation and Transcriptional Characterization of Thymic Stroma in a Pediatric Cohort.

Thymic epithelial cells (TECs) are essential in supporting the development of mature T cells from hematopoietic progenitor cells and facilitate their lineage-commitment, proliferation, T-cell receptor repertoire selection and maturation. While animal model systems have greatly aided in elucidating the contribution of stromal cells to these intricate processes, human tissue has been more difficult to study, partly due to a lack of suitable surface markers comprehensively defining human TECs. Here, we conducted a flow cytometry based surface marker screen to reliably identify and quantify human TECs and delineate medullary from cortical subsets. These findings were validated by transcriptomic and histologic means. The combination of EpCAM, podoplanin (pdpn), CD49f and CD200 comprehensively identified human TECs and not only allowed their reliable distinction in medullary and cortical subsets but also their detailed quantitation. Transcriptomic profiling of each subset in comparison to fibroblasts and endothelial cells confirmed the identity of the different stromal cell subsets sorted according to the proposed strategy. Our dataset not only demonstrated transcriptional similarities between TEC and cells of mesenchymal origin but furthermore revealed a subset-specific distribution of a specific set of extracellular matrix-related genes in TECs. This indicates that TECs significantly contribute to the distinct compartmentalization - and thus function - of the human thymus. We applied the strategy to quantify TEC subsets in 31 immunologically healthy children, which revealed sex-specific differences of TEC composition early in life. As the distribution of mature CD4- or CD8-single-positive thymocytes was correspondingly altered, the composition of the thymic epithelial compartment may directly impact on the CD4-CD8-lineage choice of thymocytes. We prove that the plain, reliable strategy proposed here to comprehensively identify human TEC subpopulations by flow cytometry based on surface marker expression is suitable to determine their frequency and phenotype in health and disease and allows sorting of live cells for downstream analysis. Its use reaches from a reliable diagnostic tool for thymic biopsies to improved phenotypic characterization of thymic grafts intended for therapeutic use.

[Prenatal ultrasonic characteristics and genetic analysis of fetuses with chromosome 22q11 microdeletion syndrome].

OBJECTIVE: To analyze the prenatal ultrasonic characteristics and genetic features of 14 fetuses with chromosome 22q11 microdeletion syndrome (22q11DS). METHODS: 4989 fetuses were analyzed by using single nucleotide polymorphism array (SNP array) in the Fujian Maternal and Child Health Hospital from November 2016 to November 2019. RESULTS: SNP array showed that 11 fetuses had classic 3 Mb microdeletion in 22q11 region, one fetus had 2.0 Mb microdeletion, and two fetuses had 1.0 Mb microdeletion. The 1.0 Mb microdeletion in 22q11 region contains SNAP29 and CRKL genes, which may increase the risk of congenital renal malformation and cardiovascular malformation. CONCLUSION: Prenatal ultrasonic characteristics of fetuses with 22q11 microdeletion syndrome vary, and SNP array is a powerful tool to diagnose such diseases, which can provide accurate genetic diagnosis and enable prenatal diagnosis.

Altered cortical thickness development in 22q11.2 deletion syndrome and association with psychotic symptoms.

Schizophrenia has been extensively associated with reduced cortical thickness (CT), and its neurodevelopmental origin is increasingly acknowledged. However, the exact timing and extent of alterations occurring in preclinical phases remain unclear. With a high prevalence of psychosis, 22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder that represents a unique opportunity to examine brain maturation in high-risk individuals. In this study, we quantified trajectories of CT maturation in 22q11DS and examined the association of CT development with the emergence of psychotic symptoms. Longitudinal structural MRI data with 1-6 time points were collected from 324 participants aged 5-35 years (N = 148 22q11DS, N = 176 controls), resulting in a total of 636 scans (N = 334 22q11DS, N = 302 controls). Mixed model regression analyses were used to compare CT trajectories between participants with 22q11DS and controls. Further, CT trajectories were compared between participants with 22q11DS who developed (N = 61, 146 scans), or remained exempt of (N = 47; 98 scans) positive psychotic symptoms during development. Compared to controls, participants with 22q11DS showed widespread increased CT, focal reductions in the posterior cingulate gyrus and superior temporal gyrus (STG), and accelerated cortical thinning during adolescence, mainly in frontotemporal regions. Within 22q11DS, individuals who developed psychotic symptoms showed exacerbated cortical thinning in the right STG. Together, these findings suggest that genetic predisposition for psychosis is associated with increased CT starting from childhood and altered maturational trajectories of CT during adolescence, affecting predominantly frontotemporal regions. In addition, accelerated thinning in the STG may represent an early biomarker associated with the emergence of psychotic symptoms.

Setd5 is required in cardiopharyngeal mesoderm for heart development and its haploinsufficiency is associated with outflow tract defects in mouse.

Congenital heart defects are a feature of several genetic haploinsufficiency syndromes, often involving transcriptional regulators. One property of haploinsufficient genes is their propensity for network interactions at the gene or protein level. In this article we took advantage of an online dataset of high throughput screening of mutations that are embryonic lethal in mice. Our aim was to identify new genes where the loss of function caused cardiovascular phenotypes resembling the 22q11.2 deletion syndrome models, that is, heterozygous and homozygous loss of Tbx1. One gene with a potentially haploinsufficient phenotype was identified, Setd5, thought to be involved in chromatin modification. We found murine Setd5 haploinsufficiency to be associated with double outlet right ventricle and perimembranous ventricular septal defect, although no genetic interaction with Tbx1 was detected. Conditional mutagenesis revealed that Setd5 was required in cardiopharyngeal mesoderm for progression of the heart tube through the ballooning stage to create a four-chambered heart.

Is there a correlation between skull base flexure and palatal anomalies in patients with 22q11 deletion syndrome and velopharyngeal dysfunction?

The study aimed at assessing the relationship between skull base morphology, represented by skull base and nasopharyngeal angles, and palatal anatomy among patients with 22q11DS and velopharyngeal dysfunction. Retrospective analysis of patients with 22q11DS and velopharyngeal dysfunction. Age, sex, severity of velopharyngeal dysfunction, type of cleft (overt cleft palate, submucous cleft palate, occult submucous cleft palate, or no-CP, and cephalometric skull base angles were reviewed. Correlations between type of palatal anomaly and the angles were assessed. Among 132 patients, 71 were male (53.8%) and 61 were female (46.2%), ages 3.3-40.0 years (mean 8.3 ± 6.10). No difference in the mean cranial-base angle (P = 0.353) or in the distribution of the three types of cranial base angle sizes was found among the palatal anomaly groups (P = 0.137). More men had normal cranial base angles and more women had acute angulation (P = 0.008). A positive correlation was found between the skull base and nasopharyngeal angles (P = 0.001, r = -0.590). No direct correlation was found between cranial base morphology and palatal anomalies in patients with 22q11DS, and velopharyngeal dysfunction. This is probably because skull base and palate morphology contribute independently to velopharyngeal dysfunction.

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.

Two novel mouse models mimicking minor deletions in 22q11.2 deletion syndrome revealed the contribution of each deleted region to psychiatric disorders.

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by the segmental deletion of human chromosome 22. This chromosomal deletion is known as high genetic risk factors for various psychiatric disorders. The different deletion types are identified in 22q11.2DS patients, including the most common 3.0-Mb deletion, and the less-frequent 1.5-Mb and 1.4-Mb deletions. In previous animal studies of psychiatric disorders associated with 22q11.2DS mainly focused on the 1.5-Mb deletion and model mice mimicking the human 1.5-Mb deletion have been established with diverse genetic backgrounds, which resulted in the contradictory phenotypes. On the other hand, the contribution of the genes in 1.4-Mb region to psychiatric disorders is poorly understood. In this study, we generated two mouse lines that reproduced the 1.4-Mb and 1.5-Mb deletions of 22q11.2DS [Del(1.4 Mb)/+ and Del(1.5 Mb)/+] on the pure C57BL/6N genetic background. These mutant mice were analyzed comprehensively by behavioral tests, such as measurement of locomotor activity, sociability, prepulse inhibition and fear-conditioning memory. Del(1.4 Mb)/+ mice displayed decreased locomotor activity, but no abnormalities were observed in all other behavioral tests. Del(1.5 Mb)/+ mice showed reduction of prepulse inhibition and impairment of contextual- and cued-dependent fear memory, which is consistent with previous reports. Furthermore, apparently intact social recognition in Del(1.4 Mb)/+ and Del(1.5 Mb)/+ mice suggests that the impaired social recognition observed in Del(3.0 Mb)/+ mice mimicking the human 3.0-Mb deletion requires mutations both in 1.4-Mb and 1.5 Mb regions. Our previous study has shown that Del(3.0 Mb)/+ mice presented disturbance of behavioral circadian rhythm. Therefore, we further evaluated sleep/wakefulness cycles in Del(3.0 Mb)/+ mice by electroencephalogram (EEG) and electromyogram (EMG) recording. EEG/EMG analysis revealed the disturbed wakefulness and non-rapid eye moving sleep (NREMS) cycles in Del(3.0 Mb)/+ mice, suggesting that Del(3.0 Mb)/+ mice may be unable to maintain their wakefulness. Together, our mouse models deepen our understanding of genetic contributions to schizophrenic phenotypes related to 22q11.2DS.

Bleeding Severity and Phenotype in 22q11.2 Deletion Syndrome-A Cross-Sectional Investigation.

OBJECTIVES: To prospectively quantify bleeding severity and elaborate hemorrhagic symptoms in children with 22q11.2 deletion syndrome (22q11DS) using 2 validated bleeding assessment tools (BATs), namely the Pediatric Bleeding Questionnaire and the International Society on Thrombosis and Hemostasis BAT (ISTH-BAT). We also sought to compare subjects' bleeding scores to unaffected first-degree family members. STUDY DESIGN: Children with 22q11DS and unaffected first-degree family members were recruited for the study. Two validated BATs were administered by a pediatric hematologist. Additional clinical and laboratory data were abstracted from patient medical records. Standard descriptive and nonparametric statistical methods were used. RESULTS: In total, 29 eligible subjects and controls were assessed. Median age (range) of subjects and controls was 8 (5-17) years and 38 (9-56) years, respectively. In total, 17 of 29 subjects had a positive bleeding score on ISTH-BAT compared with 1 of 29 control patients (P < .0001). Median ISTH-BAT score in subjects was 3 (0-12), compared with 2 (0-6) in control patients (P = .022). Median Pediatric Bleeding Questionnaire score in subjects was 2 (-1 to 12). The most frequent bleeding symptoms reported in subjects with 22q11DS were epistaxis (69%) and bruising (52%). Eighteen subjects had been surgically challenged, and 6 were noted to have increased perioperative hemorrhage. CONCLUSIONS: Children with 22q11DS have increased bleeding scores compared with their first-degree unaffected relatives. The majority of the bleeding symptoms described were mucocutaneous.

Dysmaturation Observed as Altered Hippocampal Functional Connectivity at Rest Is Associated With the Emergence of Positive Psychotic Symptoms in Patients With 22q11 Deletion Syndrome.

BACKGROUND: Hippocampal alterations are among the most replicated neuroimaging findings across the psychosis spectrum. Moreover, there is strong translational evidence that preserving the maturation of hippocampal networks in mice models prevents the progression of cognitive deficits. However, the developmental trajectory of hippocampal functional connectivity (HFC) and its contribution to psychosis is not well characterized in the human population. 22q11 deletion syndrome (22q11DS) offers a unique model for characterizing early neural correlates of schizophrenia. METHODS: We acquired resting-state functional magnetic resonance imaging in 242 longitudinally repeated scans from 84 patients with 22q11DS (30 with moderate to severe positive psychotic symptoms) and 94 healthy control subjects in the age span of 6 to 32 years. We obtained bilateral hippocampus to whole-brain functional connectivity and employed a novel longitudinal multivariate approach by means of partial least squares correlation to evaluate the developmental trajectory of HFC across groups. RESULTS: Relative to control subjects, patients with 22q11DS failed to increase HFC with frontal regions such as the dorsal part of the anterior cingulate cortex, prefrontal cortex, and supplementary motor area. Concurrently, carriers of the deletion had abnormally higher HFC with subcortical dopaminergic areas. Remarkably, this aberrant maturation of HFC was more prominent during midadolescence and was mainly driven by patients exhibiting subthreshold positive psychotic symptoms. CONCLUSIONS: Our findings suggest a critical period of prefrontal cortex-hippocampal-striatal circuit dysmaturation, particularly during late adolescence, which in light of current translation evidence could be a target for short-term interventions to potentially achieve long-lasting rescue of circuit dysfunctions associated with psychosis.

Riesgo de Esquizofrenia y Síndrome Deleción 22Q11. 2 / RIsk of schizophrenia and 22q11. 2 deletion syndrome

INTRODUCCIÓN. La deleción 22q11.2 es una alteración cromosómica muy frecuente, en la cual un 60% de los afectados presenta patologías neuropsiquiátricas. Determinar si existe asociación entre el síndrome de deleción 22q11.2 (SD22q11.2) y patologías como la esquizofrenia (EQZ), ofrece una oportunidad para la intervención temprana, y seguimiento de personas con este síndrome. OBJETIVO. El objetivo del presente trabajo es determinar si existe mayor riesgo de EQZ en pacientes con síndrome deleción 22q11.2. MÉTODOS. Se realizó una búsqueda bibliográfica sistemática de publicaciones con fecha de 1990 a 2020. Las búsquedas se realizaron en PubMed y en la base de datos Cochrane. En total, se evaluaron 19 estudios, de los que se consideraron elegibles diez publicaciones para el análisis, lo que corresponde a 824 participantes. RESULTADOS. El riesgo de presentar EQZ en un individuo con SD22q11.2 es de 20-25%, en comparación al 1% de la población general. CONCLUSIONES. El riesgo para un individuo con SD22q11.2 de presentar EQZ se encuentra bien establecido. Considerar este riesgo podría ayudar a un adecuado seguimiento y una intervención temprana.

INTRODUCTION. 22q11.2 deletion syndrome is a very common chromosomal abnormality, in which 60% of those affected have neuropsychiatric disorders. Determining if there is an association between 22q11.2 deletion syndrome (22q11.2DS) and disorders such as schizophrenia (SCZ) offers an opportunity for early intervention and follow-up of people with this syndrome. OBJECTIVE. The objective of this study is to determine if there is a greater risk of SCZ in patients with 22q11.2 deletion syndrome. METHODS. A systematic review was performed for publications dated 1990 to 2020. The strategy was to search in PubMed and Cochrane databases for specific MeSH terms. In total, 19 studies were reviewed, of which 10 publications were eligible for analysis, corresponding to 824 participants. RESULTS. The risk of presenting SCZ in an individual with 22q11.2DS is 20-25%, compared to 1% in the general population.CONCLUSIONS. The risk of presenting SCZ in an individual with 22q11.2DS is well established. Considering this risk could help with adequate follow-up and early intervention.