Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome

Deletion of the 1.5-3 Mb region of chromosome 22 at locus 11.2 gives rise to the chromosome 22q11.2 deletion syndrome (22q11DS), also known as DiGeorge and Velocardiofacial Syndromes. It is the most common micro-deletion disorder in humans and one of the most common multiple malformation syndromes. The syndrome is characterized by a broad phenotype, whose characterization has expanded considerably within the last decade and includes many associated findings such as craniofacial anomalies (40%), conotruncal defects of the heart (CHD; 70-80%), hypocalcemia (20-60%), and a range of neurocognitive anomalies with high risk of schizophrenia, all with a broad phenotypic variability. These phenotypic features are believed to be the result of a change in the copy number or dosage of the genes located in the deleted region. Despite this relatively clear genetic etiology, very little is known about which genes modulate phenotypic variations in humans or if they are due to combinatorial effects of reduced dosage of multiple genes acting in concert. Here, we report on decreased expression levels of genes within the deletion region of chromosome 22, including DGCR8, in peripheral leukocytes derived from individuals with 22q11DS compared to healthy controls. Furthermore, we found dysregulated miRNA expression in individuals with 22q11DS, including miR-150, miR-194 and miR-185. We postulate this to be related to DGCR8 haploinsufficiency as DGCR8 regulates miRNA biogenesis. Importantly we demonstrate that the level of some miRNAs correlates with brain measures, CHD and thyroid abnormalities, suggesting that the dysregulated miRNAs may contribute to these phenotypes and/or represent relevant blood biomarkers of the disease in individuals with 22q11DS

Neural correlates of socio-emotional perception in 22q11.2 deletion syndrome.

BACKGROUND: Social impairments are described as a common feature of the 22q11.2 deletion syndrome (22q11DS). However, the neural correlates underlying these impairments are largely unknown in this population. In this study, we investigated neural substrates of socio-emotional perception. METHODS: We used event-related functional magnetic resonance imaging (fMRI) to explore neural activity in individuals with 22q11DS and healthy controls during the visualization of stimuli varying in social (social or non-social) or emotional (positive or negative valence) content. RESULTS: Neural hyporesponsiveness in regions of the default mode network (inferior parietal lobule, precuneus, posterior and anterior cingulate cortex and frontal regions) in response to social versus non-social images was found in the 22q11DS population compared to controls. A similar pattern of activation for positive and negative emotional processing was observed in the two groups. No correlation between neural activation and social functioning was observed in patients with the 22q11DS. Finally, no social × valence interaction impairment was found in patients. CONCLUSIONS: Our results indicate atypical neural correlates of social perception in 22q11DS that appear to be independent of valence processing. Abnormalities in the social perception network may lead to social impairments observed in 22q11DS individuals

Source‐based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1‐weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source‐based morphometry (SBM) pipeline (SS‐Detect) to generate structural brain patterns (SBPs) that capture co‐varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV‐SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel‐based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism

Atypical attentional filtering of visual information in youth with chromosome 22q11.2 deletion syndrome as indexed by event-related potentials.

BackgroundYouth with chromosome 22q11.2 deletion syndrome (22q) face one of the highest genetic risk factors for the development of schizophrenia. Previous research suggests impairments in attentional control and potential interactions with elevated anxiety and reduced adaptive functioning may increase the risk for developing psychosis in this population. Here, we examined how variations in attentional control relate to the presence or severity of psychosis-proneness symptoms in these individuals.MethodsTo achieve this, we measured attentional control in youth (12-18 years) with 22q (N = 35) compared to a typically developing group (N = 45), using a flanker task (the Distractor Target task) while measuring neural activity with event-related potentials.ResultsSimilar to previous findings observed in people with schizophrenia, greater attentional capture by, and reduced suppression of, non-target flanker stimuli characterized participants with 22q and was indexed by the N2pc (N2-posterior-contralateral) and PD (distractor positivity) components. Although we observed no relationships between these components and measures of psychosis-proneness in youth with 22q, these individuals endorsed a relatively low incidence of positive symptoms overall.ConclusionsOur results provide neural evidence of an attentional control impairment in youth with 22q that suggests these individuals experience sustained attentional focus on irrelevant information and reduced suppression of distracting stimuli in their environment. Impairments in attentional control might be a valid biomarker of the potential to develop attenuated positive symptoms or frank psychosis in high-risk individuals long before the age at which such symptoms typically arise. The evaluation of such a hypothesis, and the preventive potential for the putative biomarker, should be the focus of future studies

Co‐occurring medical and behavioural conditions in children with Down syndrome with or without ADHD symptom presentation

BackgroundCo-occurring attention deficit hyperactivity disorder (ADHD) is a challenge to characterise in the presence of other medical conditions commonly present in children with Down syndrome (DS). The current study examined differences among children with DS with or without ADHD symptomatology in terms of demographics, developmental level, co-occurring medical conditions, and parent and teacher ratings of behaviour and executive functioning.MethodsParents and teachers of 108 school-age children with DS provided ratings of ADHD symptoms, behaviour problems and executive functioning skills. Children with DS and ADHD symptom presentation, as identified by a scoring algorithm, were compared with those without ADHD symptom presentation on demographic characteristics, developmental level, co-occurring medical conditions and parent-report and teacher-report measures of behaviours and executive functioning.ResultsSleep disorders, disruptive behaviour disorder, allergies and seizures were more common in children with DS and ADHD symptom presentation than in children without ADHD symptom presentation. After controlling for ADHD medication use, children with DS and ADHD symptom presentation had poorer performance than those without ADHD symptom presentation on parent behaviour ratings, teacher behaviour ratings and parent but not teacher ratings of executive functioning. No significant group differences in demographic characteristics or developmental level were identified.ConclusionsHigher rates of co-occurring medical conditions present in children with DS and ADHD symptom presentation support the need for thorough differential diagnoses. The different pattern of group differences between parent-report and teacher-report has implications for diagnostic practices across settings as well as for treatment

Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms.

ObjectivesMany studies have reported the increased presence of gastrointestinal (GI) symptoms in children with autism spectrum disorders (ASD). Altered microbiome profiles, pro-inflammatory responses and impaired intestinal permeability have been observed in children with ASD and co-morbid GI symptoms, yet few studies have compared these findings to ASD children without GI issues or similarly aged typical developing children. The aim of this study was to determine whether there are biological signatures in terms of immune dysfunction and microbiota composition in children with ASD with GI symptoms.MethodsChildren were enrolled in one of four groups: ASD and GI symptoms of irregular bowel habits (ASDGI), children with ASD but without current or previous GI symptoms (ASDNoGI), typically developing children with GI symptoms (TDGI) and typically developing children without current or previous GI symptoms (TDNoGI). Peripheral blood mononuclear cells (PBMC) were isolated from the blood, stimulated and assessed for cytokine production, while stool samples were analyzed for microbial composition.ResultsFollowing Toll-Like receptor (TLR)-4 stimulation, the ASDGI group produced increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17 compared to ASDNoGI. The production of the regulatory cytokine TGFβ1 was decreased in the ASDGI group compared with both the ASDNoGI and TDNoGI groups. Analysis of the microbiome at the family level revealed differences in microbiome composition between ASD and TD children with GI symptoms; furthermore, a predictive metagenome functional content analysis revealed that pathways were differentially represented between ASD and TD subjects, independently of the presence of GI symptoms. The ASDGI also showed an over-representation of the gene encoding zonulin, a molecule regulating gut permeability, compared to the other groups.ConclusionsOverall our findings suggest that children with ASD who experience GI symptoms have an imbalance in their immune response, possibly influenced by or influencing metagenomic changes, and may have a propensity to impaired gut barrier function which may contribute to their symptoms and clinical outcome

Sociodemographic Disparities in Intervention Service Utilization in Families of Children with Autism Spectrum Disorder

This study investigates whether sociodemographic factors are associated with utilization of intervention services for children with autism spectrum disorder (ASD) enrolled in the Childhood Autism Risks from Genetics and the Environment Study. Maternal ethnicity, insurance status, and education for 696 families of children with ASD were available. Children of Black mothers entered intervention earlier compared to White mothers (2 vs. 2.6 years; p = 0.001). Having public insurance was associated with receiving <15 h/week of individual services, while having a Bachelor degree was associated with receiving <15 h/week of classroom-based services. These differences suggest that SES may be a factor in utilization of services. Efforts should be made to ensure that interventions offered are culturally and linguistically accessible