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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.

• First systematic review looking at suPAR as a biomarker in a psychiatric population. • Primary analyses showed elevated suPAR levels in those with depressive disorder. • Secondary analysis showed elevated plasma suPAR levels in those with schizophrenia. • Two studies found no difference in serum suPAR levels between groups. • Chronic inflammatory dysregulation may contribute to the pathogenesis of these disorders. There is some evidence of an association between inflammation in the pathogenesis of mental disorders. Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of chronic inflammation, which provides a more stable index of systemic inflammation than more widely used biomarkers. This review aims to synthesise studies that measured suPAR concentrations in individuals with a psychiatric disorder, to determine if these concentrations are altered in comparison to healthy participants. Comprehensive literature searches from inception to October 2023 were conducted of five relevant databases (PubMed, Web of Science, Embase, Scopus, APA PsychInfo). Random-effects meta-analyses were performed to compare the standardised mean difference of blood suPAR levels (i.e. plasma or serum) for individuals with any psychiatric disorder relative to controls. Separate meta-analyses of suPAR levels were conducted for individuals with schizophrenia or other psychotic disorder and depressive disorder. Risk of bias was assessed using the Newcastle Ottawa Scale. Post-hoc sensitivity analyses included excluding studies at high risk of bias, and analyses of studies that measured suPAR concentrations either in serum or in plasma separately. The literature search identified 149 records. Ten full-text studies were screened for eligibility and 9 studies were included for review. Primary analyses revealed no significant difference in suPAR levels between individuals with any psychiatric disorder compared to controls (k = 7, SMD = 0.42, 95 % CI [−0.20, 1.04]). However, those with depressive disorder had elevated suPAR levels relative to controls (k = 3, SMD = 0.61, 95 % CI [0.34, 0.87]). Similarly, secondary analyses showed no evidence of a significant difference in suPAR levels in individuals with any psychiatric disorder when studies at high risk of bias were excluded (k = 6, SMD = 0.54, 95 % CI [−0.14, 1.22]), but elevated suPAR concentrations for those with schizophrenia or other psychotic disorder were found (k = 3, SMD = 0.98, 95 % CI [0.39, 1.58]). Furthermore, studies that analysed plasma suPAR concentrations found elevated plasma suPAR levels in individuals with any psychiatric disorder relative to controls (k = 5, SMD = 0.84, 95 % CI [0.38, 1.29]), while studies measuring serum suPAR levels in any psychiatric disorder did not find a difference (k = 2, SMD = -0.61, 95 % CI [−1.27, 0.04]). For plasma, elevated suPAR concentrations were also identified for those with schizophrenia or other psychotic disorder (k = 3, SMD = 0.98, 95 % CI [0.39, 1.58]). When studies measuring either only serum or only plasma suPAR were considered, no significant difference in suPAR levels were observed between psychiatric disorder groups, although significantly elevated suPAR levels were detected in those with moderate to severe depressive disorder. However, plasma suPAR levels were significantly elevated in those with any psychiatric disorder relative to controls, while no difference in serum samples was found. A similar finding was reported for schizophrenia or other psychotic disorder. The plasma findings suggest that chronic inflammatory dysregulation may contribute to the pathology of schizophrenia and depressive disorder. Future longitudinal studies are required to fully elucidate the role of this marker in the psychopathology of these disorders. [ABSTRACT FROM AUTHOR]

Both anxiety symptoms and suicide risk are common in schizophrenia. However, previous findings about the association between anxiety and suicide risk in schizophrenia were controversial. This study is the first to examine the prevalence of suicide risk and related demographic, clinical features in a large sample of first episode drug-naïve (FEDN) schizophrenia patients with comorbid severe anxiety. In total, 316 patients with FEDN schizophrenia were enrolled in this study. Patients' symptoms were assessed using the Hamilton Depression Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), and Positive and Negative Syndrome Scale (PANSS). Serum levels of glucose, insulin, uric acid, and lipids including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), were evaluated. In the current study, 56.3% patients presented comorbid severe anxiety. The rate of suicide risk was higher in the severe anxiety group (55.6%) than in the mild-moderate anxiety group (33.3%). The interactions among severe anxiety, uric acid and HDL-C were associated with suicide risk. Compared with patients with normal uric acid, those with abnormal uric acid exhibited a stronger association between HAMA scores and HAMD-suicide item scores. This enhanced association was also observed for patients with abnormal HDL-C levels. In FEDN schizophrenia patients with comorbid severe anxiety, our findings suggested a high incidence of suicide risk. Abnormal levels of uric acid and low levels of HDL-C, as well as high depression may be associated with an increased risk of suicide in FEDN schizophrenia patients with comorbid severe anxiety. • The prevalence of severe anxiety was 56.3% in patients with FEDN schizophrenia. • The severe anxiety group had a higher rate of suicide risk. • HAMD scores, serum uric acid and HDL-C were associated with suicide risk. • The interactions between severe anxiety and metabolic aspects had an impact on suicide risk. [ABSTRACT FROM AUTHOR]

Emerging studies indicate that oxidative stress may contribute to deficit syndrome (DS) in patients with schizophrenia. Homocysteine (Hcy) is a well-known marker and mediator of oxidative stress that exhibits tight associations with schizophrenia. However, no previous studies have assessed the relationship of DS with Hcy. This study evaluated the prevalence, clinical characteristics, and association of DS with Hcy in 491 patients with schizophrenia. Plasma levels of Hcy and other metabolic parameters were measured. Positive and Negative Syndrome Scale and the proxy scale for deficit syndrome were employed to assess psychiatric symptoms and DS. The logistic regression model was conducted to assess independent factors associated with DS, and the Area Under the Curve (AUC) was used to assess the performance of our model. There was a high incidence of hyperhomocysteinemia (58.8%) and DS (24.4%). Plasma Hcy levels were significantly higher in patients with DS. Age, Hcy levels, and psychiatric symptoms were independently associated with DS. The combination of these variables perfectly differentiated DS and non-DS patients with an AUC value of 0.89. Our study suggests that elevated Hcy levels may be related to DS. Routine monitoring of Hcy is essential and may facilitate early detection of DS in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Despite the established knowledge that recurrent copy number variants (CNVs) at the 16p11.2 locus BP4–BP5 confer risk for behavioural and language difficulties, limited research has been conducted on the association between behavioural and social–communicative profiles. The current study aims to further delineate the prevalence, nature and severity of, and the association between, behavioural and social–communicative features of school‐aged children with 16p11.2 deletion syndrome (16p11.2DS) and 16p11.2 duplication (16p11.2Dup). Methods: A total of 68 individuals (n = 47 16p11.2DS and n = 21 16p11.2Dup) aged 6–17 years participated. Standardised intelligence tests were administered, and behavioural and social–communicative skills were assessed by standardised questionnaires. Scores of both groups were compared with population norms and across CNVs. The influence of confounding factors was investigated, and correlation analyses were performed. Results: Compared with the normative sample, children with 16p11.2DS showed high rates of social responsiveness (67%) and communicative problems (69%), while approximately half (52%) of the patients displayed behavioural problems. Children with 16p11.2Dup demonstrated even higher rates of social–communicative problems (80–90%) with statistically significantly more externalising and overall behavioural challenges (89%). In both CNV groups, there was a strong positive correlation between behavioural and social–communicative skills. Conclusions: School‐aged children with 16p11.2 CNVs show high rates of behavioural, social responsiveness and communicative problems compared with the normative sample. These findings point to the high prevalence of autistic traits and diagnoses in these CNV populations. Moreover, there is a high comorbidity between behavioural and social–communicative problems. Patients with difficulties in both domains are vulnerable and need closer clinical follow‐up and care. [ABSTRACT FROM AUTHOR]

We developed a generally applicable method, CRISPR/Cas9-targeted long-read sequencing (CTLR-Seq), to resolve, haplotype-specifically, the large and complex regions in the human genome that had been previously impenetrable to sequencing analysis, such as large segmental duplications (SegDups) and their associated genome rearrangements. CTLR-Seq combines in vitro Cas9-mediated cutting of the genome and pulse-field gel electrophoresis to isolate intact large (i.e., up to 2,000 kb) genomic regions that encompass previously unresolvable genomic sequences. These targets are then sequenced (amplification-free) at high on-target coverage using long-read sequencing, allowing for their complete sequence assembly. We applied CTLR-Seq to the SegDup-mediated rearrangements that constitute the boundaries of, and give rise to, the 22q11.2 Deletion Syndrome (22q11DS), the most common human microdeletion disorder. We then performed de novo assembly to resolve, at base-pair resolution, the full sequence rearrangements and exact chromosomal breakpoints of 22q11.2DS (including all common subtypes). Across multiple patients, we found a high degree of variability for both the rearranged SegDup sequences and the exact chromosomal breakpoint locations, which coincide with various transposons within the 22q11.2 SegDups, suggesting that 22q11DS can be driven by transposon-mediated genome recombination. Guided by CTLR-Seq results from two 22q11DS patients, we performed three-dimensional chromosomal folding analysis for the 22q11.2 SegDups from patient-derived neurons and astrocytes and found chromosome interactions anchored within the SegDups to be both cell type-specific and patient-specific. Lastly, we demonstrated that CTLR-Seq enables cell-type specific analysis of DNA methylation patterns within the deletion haplotype of 22q11DS. [ABSTRACT FROM AUTHOR]

Introduction: Schizophrenia (SCZ) is a severe psychiatric disorder whose pathophysiology remains elusive. Recent investigations have underscored the significance of systemic inflammation, particularly the impact of circulating inflammatory proteins, in SCZ. Methods: This study explores the potential causal association between certain inflammatory proteins and SCZ. Bidirectional Mendelian randomization (MR) analyses were conducted utilizing data from expansive genome-wide association studies (GWAS). Data regarding circulating inflammatory proteins were sourced from the GWAS Catalog database, encompassing 91 inflammatory cytokines. SCZ-related data were derived from the Finngen database, incorporating 47,696 cases and 359,290 controls. Analytical methods such as inverse variance weighted, MR-Egger, weighted median, simple mode, and weighted mode were employed to evaluate the association between inflammatory cytokines and SCZ. Sensitivity analyses were also performed to affirm the robustness of the results. Results: Following FDR adjustment, significant associations were observed between levels of inflammatory cytokines, including Fibroblast Growth Factor 5 (OR = 1.140, 95%CI = 1.045, 1.243, p = 0.003, FDR=0.015), C-C Motif Chemokine 4 (OR = 0.888, 95%CI = 0.816, 0.967, p = 0.006, FDR = 0.015), C-X-C Motif Chemokine 1 (OR = 0.833, 95%CI = 0.721, 0.962, p = 0.013, FDR = 0.064), and CX-C Motif Chemokine 5 (OR = 0.870, 95%CI = 0.778, 0.973, p = 0.015, FDR = 0.074), and the risk of SCZ. Conclusion: Our results from MR analysis suggest a potential causal link between circulating inflammatory cytokines and SCZ, thereby enriching our understanding of the interactions between inflammation and SCZ. Furthermore, these insights provide a valuable foundation for devising therapeutic strategies targeting inflammation. [ABSTRACT FROM AUTHOR]

• Maternal obesity alters the neurological and behavioral phenotype in the offspring. • Treatment with cannabidiol rescues anxiety and social disturbances in the offspring. • Both perinatal maternal obesity and CBD present sexually dimorphic influences. • CBD modulates glial reactivity, oxytocin, glutamate and endocannabinoid signaling. Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions. Therefore, here we tested whether CBD treatment could mitigate anxiety-like and social behavioral alterations, as well as neurochemical disruptions in both male and female offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) from weaning for 3 weeks. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and neurochemical markers were evaluated in the prefrontal cortex (PFC) and hippocampus. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, followed by rescuing effects on imbalanced neurotransmitter and endocannabinoid concentrations and altered expression of glial markers, CB1, oxytocin and dopamine receptors, with important differences between sexes. Overall, the findings of this study provide insight into the signaling pathways for the therapeutic benefits of CBD on neuroinflammation and neurochemical imbalances caused by perinatal maternal obesity in the PFC and the hippocampus, which translates into the behavioral manifestations, highlighting the sexual dimorphism encompassing both the transgenerational effect of obesity and the endocannabinoid system. [ABSTRACT FROM AUTHOR]

22q11.2 deletion syndrome (22q11DS) is one of the most robust genetic predictors of psychosis and other psychiatric illnesses. In this study, we examined 22q11DS subjects' acoustic startle responses (ASRs), which putatively index psychosis risk. Latency of the ASR is a presumptive marker of neural processing speed and is prolonged (slower) in schizophrenia. ASR measures correlate with increased psychosis risk, depend on glutamate and dopamine receptor signaling, and could serve as translational biomarkers in interventions for groups at high psychosis risk. Startle magnitude, latency, and prepulse inhibition were assessed with a standard acoustic startle paradigm in 31 individuals with 22q11.2DS and 32 healthy comparison (HC) subjects. Surface electrodes placed on participants' orbicularis oculi recorded the electromyographic signal in ASR eyeblinks. Individuals without measurable startle blinks in the initial habituation block were classified as non-startlers. Across the startle session, the ASR magnitude was significantly lower in 22q11DS subjects than HCs because a significantly higher proportion of 22q11DS subjects were non-startlers. Latency of the ASR to pulse-alone stimuli was significantly slower in 22q11DS than HC subjects. Due to the overall lower 22q11DS startle response frequency and magnitudes prepulse inhibition could not be analyzed. Reduced magnitude and slow latency of 22q11DS subjects' responses suggest reduced central nervous system and neuronal responsiveness. These findings are consistent with significant cognitive impairments observed in 22q11DS subjects. Further research is needed to untangle the connections among basic neurotransmission dysfunction, psychophysiological responsiveness, and cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: 22q11.2 deletion syndrome (22q11.2DS) has been linked to an increased risk of early‐onset Parkinson's disease. However, the pathophysiological mechanisms underlying parkinsonism remain poorly understood. Objective: The objective is to investigate salivary total α‐synuclein levels in 22q11.2DS patients with and without parkinsonian motor signs. Methods: This cross‐sectional study included 10 patients with 22q11.2DS with parkinsonism (Park+), ten 22q11.2DS patients without parkinsonism (Park−), and 10 age and sex‐comparable healthy subjects (HS). Salivary and serum α‐synuclein levels were measured using enzyme‐linked immunosorbent assay. Results: Salivary total α‐synuclein concentration was significantly lower in Park (+) patients than in Park (−) patients and HS (P = 0.007). In addition, salivary α‐synuclein showed good accuracy in discriminating Park (+) from Park (−) patients (area under the curve = 0.86) and correlated with motor severity and cognitive impairment. Conclusion: This exploratory study suggests that the parkinsonian phenotype of 22q11.2DS is associated with a reduced concentration of monomeric α‐synuclein in biological fluids. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is the treatment-resistant depression (TRD) phenotype transmitted within a family? Findings: This cohort study found that, compared with control individuals match for birth year, sex, and kinship, first-degree-relatives of individuals with TRD had an increased risk of developing TRD and increased suicide mortality. Meaning: The findings suggest that a family history of TRD might be a clinically significant risk factor for resistance to antidepressant treatment and increased suicide mortality, indicating that combining or altering therapies for depression might be considered instead of monotherapy at an earlier treatment stage. This cohort study evaluates susceptibility to treatment-resistant depression by family. Importance: Antidepressant responses and the phenotype of treatment-resistant depression (TRD) are believed to have a genetic basis. Genetic susceptibility between the TRD phenotype and other psychiatric disorders has also been established in previous genetic studies, but population-based cohort studies have not yet provided evidence to support these outcomes. Objective: To estimate the TRD susceptibility and the susceptibility between TRD and other psychiatric disorders within families in a nationwide insurance cohort with extremely high coverage and comprehensive health care data. Design, Setting, and Participants: This cohort study assessed data from the Taiwan national health insurance database across entire population (N = 26 554 001) between January 2003 and December 2017. Data analysis was performed from August 2021 to April 2023. TRD was defined as having experienced at least 3 distinct antidepressant treatments in the current episode, each with adequate dose and duration, based on the prescribing records. Then, we identified the first-degree relatives of individuals with TRD (n = 34 467). A 1:4 comparison group (n = 137 868) of first-degree relatives of individuals without TRD was arranged for the comparison group, matched by birth year, sex, and kinship. Main Outcomes and Measures: Modified Poisson regression analyses were performed and adjusted relative risks (aRRs) and 95% CIs were calculated for the risk of TRD, the risk of other major psychiatric disorders, and different causes of mortality. Results: This study included 172 335 participants (88 330 male and 84 005 female; mean [SD] age at beginning of follow-up, 22.9 [18.1] years). First-degree relatives of individuals with TRD had lower incomes, more physical comorbidities, higher suicide mortality, and increased risk of developing TRD (aRR, 9.16; 95% CI, 7.21-11.63) and higher risk of other psychiatric disorders than matched control individuals, including schizophrenia (aRR, 2.36; 95% CI, 2.10-2.65), bipolar disorder (aRR, 3.74; 95% CI, 3.39-4.13), major depressive disorder (aRR, 3.65; 95% CI, 3.44-3.87), attention-deficit/hyperactivity disorders (aRR, 2.38; 95% CI, 2.20-2.58), autism spectrum disorder (aRR, 2.26; 95% CI, 1.86-2.74), anxiety disorder (aRR, 2.71; 95% CI, 2.59-2.84), and obsessive-compulsive disorder (aRR, 3.14; 95% CI, 2.70-3.66). Sensitivity and subgroup analyses validated the robustness of the findings. Conclusions and Relevance: To our knowledge, this study is the largest and perhaps first nationwide cohort study to demonstrate TRD phenotype transmission across families and coaggregation with other major psychiatric disorders. Patients with a family history of TRD had an increased risk of suicide mortality and tendency toward antidepressant resistance; therefore, more intensive treatments for depressive symptoms might be considered earlier, rather than antidepressant monotherapy. [ABSTRACT FROM AUTHOR]

Introduction: A plethora of biological molecules regulate chondrogenesis in the epiphyseal growth plate. Disruptions of the quantity and function of these molecules can manifest clinically as stature abnormalities of various etiologies. Traditionally, the growth hormone/insulin-like growth factor 1 (IGF1) axis represents the etiological centre of final stature attainment. Of note, little is known about the molecular events that dominate the growth of the craniofacial complex and its correlation with somatic stature. Aim: Given the paucity of relevant data, this review discusses available information regarding potential applications of lateral cephalometric radiography as a potential clinical indicator of genetic short stature in children. Materials and Methods: A literature search was conducted in the PubMed electronic database using the keywords: cephalometric analysis and short stature; cephalometric analysis and achondroplasia; cephalometric analysis and hypochondroplasia; cephalometric analysis and skeletal abnormalities; cephalometr* and SHOX; cephalometr* and CNP; cephalometr* and ACAN; cephalometr* and CNVs; cephalometr* and IHH; cephalometr* and FGFR3; cephalometr* and Noonan syndrome; cephalometr* and "Turner syndrome"; cephalometr* and achondroplasia. Results: In individuals with genetic syndromes causing short stature, linear growth of the craniofacial complex is confined, following the pattern of somatic short stature regardless of its aetiology. The angular and linear cephalometric measurements differ from the measurements of the average normal individuals and are suggestive of a posterior placement of the jaws and a vertical growth pattern of the face. Conclusions: The greater part of the existing literature regarding cephalometric measurements in short-statured children with genetic syndromes provides qualitative data. Furthermore, cephalometric data for individuals affected with specific rare genetic conditions causing short stature should be the focus of future studies. These quantitative data are required to potentially establish cut-off values for reference for genetic testing based on craniofacial phenotypes. [ABSTRACT FROM AUTHOR]

The 22q11.2 deletion syndrome (DS) can have a significant impact on functionality. The purpose was to describe 22q11.2DS children with functioning from a biopsychosocial perspective, focusing on the impact of children's health condition from domains of the International Classification of Functioning, Disability, and Health (ICF). Methods: A descriptive, cross-sectional case series study with seven 22q11.2DS children. A questionnaire with an ICF checklist for 22q11.2DS was completed using a structured interview. The Wechsler Abbreviated Scale of Intelligence (WASI) was used to determine the Intelligence Quotient (IQ). Results: Seven participants from 7 to 12 years old, presented some level of IQ impairment. It was observed that 22q11.2DS children experience significant intellectual, cognitive, and speech impairments across ICF Body Function domains. Impairments related to nose and pharynx were found in only one patient. The most relevant categories considered limitations in the Activity and Participation components pertained to producing nonverbal messages, communication, handling stress, and social interaction. Family, health professionals, and acquaintances were perceived as facilitators in the component Environmental Factors. Conclusion: The sample has its functioning affected by aspects that go beyond impairments in body structure and function. The organization of information from the perspective of the ICF is a different approach that helps clinical reasoning. [ABSTRACT FROM AUTHOR]

Background: Minor physical anomalies (MPAs) are congenital morphological abnormalities linked to disruptions of fetal development. MPAs are common in 22q11.2 deletion syndrome (22q11DS) and psychosis spectrum disorders (PS) and likely represent a disruption of early embryologic development that may help identify overlapping mechanisms linked to psychosis in these disorders. Methods: Here, 2D digital photographs were collected from 22q11DS (n = 150), PS (n = 55), and typically developing (TD; n = 93) individuals. Photographs were analyzed using two computer-vision techniques: (1) DeepGestalt algorithm (Face2Gene (F2G)) technology to identify the presence of genetically mediated facial disorders, and (2) Emotrics—a semi-automated machine learning technique that localizes and measures facial features. Results: F2G reliably identified patients with 22q11DS; faces of PS patients were matched to several genetic conditions including FragileX and 22q11DS. PCA-derived factor loadings of all F2G scores indicated unique and overlapping facial patterns that were related to both 22q11DS and PS. Regional facial measurements of the eyes and nose were smaller in 22q11DS as compared to TD, while PS showed intermediate measurements. Conclusions: The extent to which craniofacial dysmorphology 22q11DS and PS overlapping and evident before the impairment or distress of sub-psychotic symptoms may allow us to identify at-risk youths more reliably and at an earlier stage of development. [ABSTRACT FROM AUTHOR]

NF1 microdeletion syndrome, accounting for 5–11% of NF1 patients, is caused by a deletion in the NF1 region and it is generally characterized by a severe phenotype. Although 70% of NF1 microdeletion patients presents the same 1.4 Mb type-I deletion, some patients may show additional clinical features. Therefore, the contribution of several pathogenic mechanisms, besides haploinsufficiency of some genes within the deletion interval, is expected and needs to be defined. We investigated an altered expression of deletion flanking genes by qPCR in patients with type-1 NF1 deletion, compared to healthy donors, possibly contributing to the clinical traits of NF1 microdeletion syndrome. In addition, the 1.4-Mb deletion leads to changes in the 3D chromatin structure in the 17q11.2 region. Specifically, this deletion alters DNA-DNA interactions in the regions flanking the breakpoints, as demonstrated by our 4C-seq analysis. This alteration likely causes position effect on the expression of deletion flanking genes. Interestingly, 4C-seq analysis revealed that in microdeletion patients, an interaction was established between the RHOT1 promoter and the SLC6A4 gene, which showed increased expression. We performed NGS on putative modifier genes, and identified two "likely pathogenic" rare variants in RAS pathway, possibly contributing to incidental phenotypic features. This study provides new insights into understanding the pathogenesis of NF1 microdeletion syndrome and suggests a novel pathomechanism that contributes to the expression phenotype in addition to haploinsufficiency of genes located within the deletion.This is a pivotal approach that can be applied to unravel microdeletion syndromes, improving precision medicine, prognosis and patients' follow-up. [ABSTRACT FROM AUTHOR]

Objectives: We aim to verify velopharyngeal sphincter function in 22q11.2 deletion syndrome patients (22q11.2DS) to establish correlations between aerodynamic and perceptual measures of nasality, and to identify aerodynamic measures differentiating typical from atypical velopharyngeal behavior. Methods: Eleven subjects with 22q11.2DS and twenty similar-age control subjects were recruited. The aerodynamic measures were mean Sound Pressure Level, air pressure peak, pressure wave duration, airflow pattern and nasal airflow during the sequence /pi/. The nasality perceptual measures were rhinolalia, rhinophony and nasal air escape. Results: Airflow patterns and perceptual measures were statistically different in the two groups. Pressure wave duration and air pressure peak were lower in study subjects than in controls. Air pressure peak and nasal airflow were negatively correlated with rhinolalia; pressure wave duration was negatively correlated with nasal air escape and rhinolalia in 22q11.2DS patients. Conclusions: This aerodynamic study identified velopharyngeal qualitative and quantitative dysfunctions, suggesting heterogeneous models of velopharyngeal function in syndromic subjects as compared to controls. [ABSTRACT FROM AUTHOR]

Increased risk for somatic comorbidity in individuals with schizophrenia has been well established. In addition, psychiatric patients with somatic illnesses are more likely to have more psychiatric readmissions. Increased burden of treatment related to chronic somatic comorbidities may be associated with lower adherence to psychiatric medication. Cross-sectional study of 275 patients with schizophrenia spectrum disorder. A general practitioner performed a complete physical health checkup for all participants, including a complete medical examination and laboratory tests. Patients' adherence, attitudes, insight, and side-effects were evaluated using the Attitudes toward Neuroleptic Treatment Scale. Overall symptomatology was measured using the Brief Psychiatric Rating Scale. Regression analysis was used to investigate interactions and associations among health beliefs, disease burden, and treatment adherence. Separate regression models were utilized to account for the complexity of health behavior and treatment adherence pathways. Patients' somatic comorbidity and health behavior were not associated with adherence or attitudes toward antipsychotic treatment. High dose of antipsychotics and obesity were related to the need for medical interventions, while a healthy diet reduced the risk. Higher BPRS score and older age were associated with having somatic symptoms. Somatic comorbidities had no negative effects on treatment adherence or attitudes. This study focuses on exploring possible associations between health beliefs and treatment adherence pathways in patients with psychotic disorders. Contrary to our hypotheses, we found no evidence to support our health belief and diseases burden models and their associations. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the utility of preoperative imaging before velopharyngeal dysfunction (VPD) surgery in children with 22q11 Deletion Syndrome (22qDS) in evaluating internal carotid artery (ICA) medialization. Data Sources: PubMed, Scopus, and CINAHL. Review Methods: Following PRISMA guidelines, a systematic review was performed. Studies of children with 22qDS who underwent preoperative imaging (MRA or CTA) to identify ICA anomalies were included. High‐risk medialized ICAs were defined as either submucosal, retropharyngeal, Pfeiffer Grade III‐IV, or <3 mm from the pharyngeal mucosa. Meta‐analyses of proportions were performed. Results: Eleven studies met inclusion criteria, comprising 398 patients with 22qDS (weighted mean age 7.6 years). In 372 patients with imaging, the rate of ICA medialization on imaging was 47.1% (95%CI 29.2–65.5), of which 46.3% (95%CI 27.4–65.8) were determined high risk. Operative plans were modified in 19.4% (95%CI 5.7–38.8) of 254 surgeries due to medialized ICA. In studies attempting to use nasopharyngoscopy pulsations to identify medialization for 214 patients, the true‐positive rate was 53.9% (95%CI 27.5–79.2) and the false‐positive rate was 16.2% (95%CI 7.9–26.8). Nine of eleven studies (81.8%) recommended universal preoperative imaging of the ICAs in children with 22qDS undergoing VPD surgery. No cases of perioperative bleeding secondary to ICA injury were identified. Conclusion: Although most studies endorse routine preoperative imaging to assess for ICA medialization in children with 22qDS undergoing VPD surgery, only a minority of these cases led to surgical modification. Additional studies are needed to compare outcomes in children with and without preoperative imaging given the low rates of ICA injury in the literature. Level of Evidence: N/A Laryngoscope, 134:2551–2561, 2024 [ABSTRACT FROM AUTHOR]

A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of the human genome as direct (H1) and inverted (H2) haplotype clades. This inversion region demonstrates high linkage disequilibrium, but the frequency of each haplotype differs across ancestries. While the H1 haplotype exists in all populations and shows a normal pattern of genetic variability and recombination, the H2 haplotype is enriched in European ancestry populations, is less frequent in African ancestry populations, and nearly absent in East Asian ancestry populations. H1 is a known risk factor for several neurodegenerative diseases, and has been associated with many other traits, suggesting its importance in cellular phenotypes of the brain and entire body. Conversely, H2 is protective for these diseases, but is associated with predisposition to recurrent microdeletion syndromes and neurodevelopmental disorders such as autism. Many single nucleotide variants and copy number variants define H1/H2 haplotypes and sub-haplotypes, but identifying the causal variant(s) for specific diseases and phenotypes is complex due to the extended linkage equilibrium. In this review, we assess the current knowledge of this inversion region regarding genomic structure, gene expression, cellular phenotypes, and disease association. We discuss recent discoveries and challenges, evaluate gaps in knowledge, and highlight the importance of understanding the effect of the 17q21.31 haplotypes to promote advances in precision medicine and drug discovery for several diseases. [ABSTRACT FROM AUTHOR]

Introduction: People with serious mental illness (SMI), such as schizophrenia and bipolar disorder, have a higher risk of premature morbidity and mortality. In the general population, impaired lung function is associated with increased morbidity and mortality. We compared lung function between people with and without serious mental illnesses using a cross-sectional study in 9 community mental health units. Methods: Subjects aged 40-70 years with a diagnosis of schizophrenia or bipolar disorder were recruited consecutively. The controls had no psychiatric diagnosis and were not receiving any psychotropics. Spirometry was performed by a trained nurse. We used the 2021 American Thoracic Society/European Respiratory Society standards for the interpretation of the spirometry results. Results: We studied 287 subjects. People with SMI (n = 169) had lower spirometry values than those without a psychiatric diagnosis (n = 118). An abnormal spirometry pattern (36.1% vs 16.9%, p < 0.001), possible restriction or nonspecific (Preserved Ratio Impaired Spirometry [PRISm]) pattern (17.8% vs 7.6%, p = 0.014), and pattern of airflow obstruction or possible mixed disorder (18.3% vs 9.3%, p = 0.033) were more frequent in people with SMI. Multivariate analyses showed that the PRISm pattern was associated with abdominal circumference (odds ratio [OR] 1.05, 95%CI 1.03-1.08) and that the pattern of airflow obstruction or possible mixed disorder was associated with smoking behavior (OR 5.15, 95% CI 2.06-15.7). Conclusion: People with SMI have impaired lung function, with up to one-third of them showing an abnormal spirometry pattern. This suggests that regular monitoring of lung function and addressing modifiable risk factors, such as tobacco use and obesity, in this population is of paramount importance. [ABSTRACT FROM AUTHOR]

Chromosome 22q13.3 deletion (Phelan‐McDermid) syndrome (PMS, OMIM 606232) is a rare genetic condition that impacts neurodevelopment. PMS most commonly results from heterozygous contiguous gene deletions that include the SHANK3 gene or likely pathogenic variants of SHANK3 (PMS‐SHANK3 related). Rarely, chromosomal rearrangements that spare SHANK3 share the same general phenotype (PMS‐SHANK3 unrelated). Very recent human and model system studies of genes that likely contribute to the PMS phenotype point to overlap in gene functions associated with neurodevelopment, synaptic formation, stress/inflammation and regulation of gene expression. In this review of recent findings, we describe the functional overlaps between SHANK3 and six partner genes of 22q13.3 (PLXNB2, BRD1, CELSR1, PHF21B, SULT4A1, and TCF20), which suggest a model that explains the commonality between PMS‐SHANK3 related and PMS‐SHANK3 unrelated classes of PMS. These genes are likely not the only contributors to neurodevelopmental impairments in the region, but they are the best documented to date. The review provides evidence for the overlapping and likely synergistic contributions of these genes to the PMS phenotype. [ABSTRACT FROM AUTHOR]

Objective: The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans with over 180 phenotypic expressions. Approximately 30–40% of affected individuals will develop psychosis and 25% meet the criteria for schizophrenia. Despite this, pharmacotherapy for managing psychosis in 22q11.2DS is poorly understood and 22q11.2DS psychosis is frequently labelled as treatment resistant. The objectives of this paper are to evaluate the effectiveness and tolerability of pharmacotherapy for 22q11.2DS psychosis and evaluate the evidence for treatment resistance. Method: A systematic search was performed using CINAHL, The Cochrane Library (Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials and Cochrane Clinical Answers), EMBASE, PsycINFO, PubMed, Scopus and Web of Science Core Collection from inception to December 2022. It yielded 39 case reports, 6 case series and 1 retrospective study which met the inclusion criteria. Results: Based on the current literature, individuals with 22q11.2DS psychosis experience a greater rate of medical co-morbidities such as cardiac arrhythmias, seizures and movement disorders, which complicate pharmacotherapy. Poor tolerability rather than poor clinical response motivates the switching of antipsychotics, which may explain the labelling of treatment resistance in the literature. Conclusion: There are insufficient data to recommend a single antipsychotic for 22q11.2DS psychosis. Nonetheless, with proactive management of co-morbidities, antipsychotic medication in 22q11.2DS psychosis is an effective treatment commonly resulting in improvement in quality of life. [ABSTRACT FROM AUTHOR]

There is some evidence that offspring of patients with schizophrenia have higher somatic morbidity, which is thought to be partially due to genetic links between somatic disorders and schizophrenia. This study explored differences in somatic diseases and conditions of adoptees with high genetic risk (HR) or low genetic risk (LR) for schizophrenia spectrum disorders. The study is part of the Finnish Adoptive Family Study of Schizophrenia. The adoptive research design used made it possible to examine how the somatic health of adoptees raised in similar adoptive families, is affected by their genetic susceptibility to schizophrenia. The study sample consisted of 373 adoptees, of whom 190 had HR and 183 had LR for schizophrenia spectrum disorders. Data on somatic morbidity were gathered from the hospital records and from the national registers of the Care Register of Health Care and the Social Insurance Institution. The only statistically significant difference found was in genitourinary diseases, the likelihood being twofold higher in HR adoptees compared to LR adoptees (16.8% vs. 8.2%; adj. OR = 2.13, 95% CI 1.06–4.25, p =.033). Adoptees who were female and aged over 40 had a higher prevalence of genitourinary illnesses than non-adoptees. The significant prevalence of genitourinary diseases in adoptees at risk for schizophrenia spectrum disorders suggests that some specific somatic diseases and schizophrenia may have a shared hereditary etiology. More research is required for specific somatic diseases in study populations that can differentiate between the effects of genetic and environmental factors. [ABSTRACT FROM AUTHOR]

Previous investigations have revealed substantial differences in neuroimaging characteristics between healthy controls (HCs) and individuals diagnosed with schizophrenia (SCZ). However, we are not entirely sure how brain activity links to symptoms in schizophrenia, and there is a need for reliable brain imaging markers for treatment prediction. In this longitudinal study, we examined 56 individuals diagnosed with 56 SCZ and 51 HCs. The SCZ patients underwent a three-month course of antipsychotic treatment. We employed resting-state functional magnetic resonance imaging (fMRI) along with fractional Amplitude of Low Frequency Fluctuations (fALFF) and support vector regression (SVR) methods for data acquisition and subsequent analysis. In this study, we initially noted lower fALFF values in the right postcentral/precentral gyrus and left postcentral gyrus, coupled with higher fALFF values in the left hippocampus and right putamen in SCZ patients compared to the HCs at baseline. However, when comparing fALFF values in brain regions with abnormal baseline fALFF values for SCZ patients who completed the follow-up, no significant differences in fALFF values were observed after 3 months of treatment compared to baseline data. The fALFF values in the right postcentral/precentral gyrus and left postcentral gyrus, and the left postcentral gyrus were useful in predicting treatment effects. Our findings suggest that reduced fALFF values in the sensory-motor networks and increased fALFF values in the limbic system may constitute distinctive neurobiological features in SCZ patients. These findings may serve as potential neuroimaging markers for the prognosis of SCZ patients. [ABSTRACT FROM AUTHOR]

This systematic review and meta-analysis investigates if ethnoracial groups in the US differ in risk of schizophrenia and other psychotic disorders, clinical high risk for psychosis, and psychotic symptoms and experiences. Key Points: Question: Do ethnoracial groups in the US differ in risk of schizophrenia and other psychotic disorders, clinical high risk for psychosis (CHR-P), and psychotic symptoms (PSs) and experiences (PEs)? Findings: In this systematic review and meta-analysis including 64 studies of which 47 studies were included in the meta-analysis, risk of schizophrenia diagnosis was significantly increased among Black individuals and those categorized as other ethnoracial group compared with White individuals, and risk of PSs/PEs was significantly increased among both Black and Latinx groups. Findings regarding CHR-P were equivocal. Meaning: Ethnoracial risk variation in the US is present across multiple psychosis-related outcomes, suggesting that factors other than diagnostic bias alone underlie these disparities. Importance: Studies suggest a higher risk of schizophrenia diagnoses in Black vs White Americans, yet a systematic investigation of disparities that include other ethnoracial groups and multiple outcomes on the psychosis continuum is lacking. Objective: To identify ethnoracial risk variation in the US across 3 psychosis continuum outcomes (ie, schizophrenia and other psychotic disorders, clinical high risk for psychosis [CHR-P], and psychotic symptoms [PSs] and psychotic experiences [PEs]). Data Sources: PubMed, PsycINFO and Embase were searched up to December 2022. Study Selection: Observational studies on ethnoracial differences in risk of 3 psychosis outcomes. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Using a random-effects model, estimates for ethnoracial differences in schizophrenia and PSs/PEs were pooled and moderation by sampling and setting was determined, along with the assessment of heterogeneity and risk of bias. Main Outcomes and Measures: Risk of schizophrenia and other psychotic disorder, CHR-P, and conversion to psychosis among CHR-P and PSs/PEs. Results: Of 64 studies in the systematic review, 47 were included in the meta-analysis comprising 54 929 people with schizophrenia and 223 097 with data on PSs/PEs. Compared with White individuals, Black individuals had increased risk of schizophrenia (pooled odds ratio [OR], 2.07; 95% CI, 1.64-2.61) and PSs/PEs (pooled standardized mean difference [SMD], 0.10; 95% CI, 0.03-0.16), Latinx individuals had higher risk of PSs/PEs (pooled SMD, 0.15; 95% CI, 0.08-0.22), and individuals classified as other ethnoracial group were at significantly higher risk of schizophrenia than White individuals (pooled OR, 1.81; 95% CI, 1.31-2.50). The results regarding CHR-P studies were mixed and inconsistent. Sensitivity analyses showed elevated odds of schizophrenia in Asian individuals in inpatient settings (pooled OR, 1.84; 95% CI, 1.19-2.84) and increased risk of PEs among Asian compared with White individuals, specifically in college samples (pooled SMD, 0.16; 95% CI, 0.02-0.29). Heterogeneity across studies was high, and there was substantial risk of bias in most studies. Conclusions and Relevance: Findings of this systematic review and meta-analysis revealed widespread ethnoracial risk variation across multiple psychosis outcomes. In addition to diagnostic, measurement, and hospital bias, systemic influences such as structural racism should be considered as drivers of ethnoracial disparities in outcomes across the psychosis continuum in the US. [ABSTRACT FROM AUTHOR]

Objective: To provide a comprehensive understanding of the pathophysiology of cleft palate (CP) and future perspectives. Design: Literature review. Setting: Setting varied across studies by level of care and geographical locations. Interventions: No interventions were performed. Main Outcome Measure(s): Primary outcome measures were to summarize our current understanding of palatogenesis in humans and animal models, the pathophysiology of CP, and potential future treatment modalities. Results: Animal research has provided considerable insight into the pathophysiology, molecular and cellular mechanisms of CP that have allowed for the development of novel treatment strategies. However, much work has yet to be done to connect our mouse model investigations and discoveries to CP in humans. The success of innovative strategies for tissue regeneration in mice provides promise for an exciting new avenue for improved and more targeted management of cleft care with precision medicine in patients. However, significant barriers to clinical translation remain. Among the most notable challenges include the differences in some aspects of palatogenesis and tissue repair between mice and humans, suggesting that potential therapies that have worked in animal models may not provide similar benefits to humans. Conclusions: Increased translation of pathophysiological and tissue regeneration studies to clinical trials will bridge a wide gap in knowledge between animal models and human disease. By enhancing interaction between basic scientists and clinicians, and employing our animal model findings of disease mechanisms in concert with what we glean in the clinic, we can generate a more targeted and improved treatment algorithm for patients with CP. [ABSTRACT FROM AUTHOR]

The first article is about adolescents with a high risk of psychosis and traits of autism spectrum disorder. It was found that adolescents with traits of autism spectrum disorder presented a higher proportion of attenuated psychotic symptoms, although they were not associated with transitions to psychotic disorder. The second article revealed that the presence of childhood abuse increases the risk of suicidal behavior among young people. The third article describes a home treatment program called Home Treatment (HoT) for adolescents with severe anorexia nervosa. The results showed a significant increase in body mass index after 11 weeks of treatment. Other articles explored topics such as 22q11 deletion syndrome, adherence to follow-up in adulthood, transition programs in mental health, and alternative intervention programs to hospitalization for psychiatric crises in children and adolescents. [Extracted from the article]

The temporal variability of the thalamus in functional networks may provide valuable insights into the pathophysiology of schizophrenia. To address the complexity of the role of the thalamic nuclei in psychosis, we introduced micro‐co‐activation patterns (μCAPs) and employed this method on the human genetic model of schizophrenia 22q11.2 deletion syndrome (22q11.2DS). Participants underwent resting‐state functional MRI and a data‐driven iterative process resulting in the identification of six whole‐brain μCAPs with specific activity patterns within the thalamus. Unlike conventional methods, μCAPs extract dynamic spatial patterns that reveal partially overlapping and non‐mutually exclusive functional subparts. Thus, the μCAPs method detects finer foci of activity within the initial seed region, retaining valuable and clinically relevant temporal and spatial information. We found that a μCAP showing co‐activation of the mediodorsal thalamus with brain‐wide cortical regions was expressed significantly less frequently in patients with 22q11.2DS, and its occurrence negatively correlated with the severity of positive psychotic symptoms. Additionally, activity within the auditory–visual cortex and their respective geniculate nuclei was expressed in two different μCAPs. One of these auditory–visual μCAPs co‐activated with salience areas, while the other co‐activated with the default mode network (DMN). A significant shift of occurrence from the salience+visuo‐auditory‐thalamus to the DMN + visuo‐auditory‐thalamus μCAP was observed in patients with 22q11.2DS. Thus, our findings support existing research on the gatekeeping role of the thalamus for sensory information in the pathophysiology of psychosis and revisit the evidence of geniculate nuclei hyperconnectivity with the audio‐visual cortex in 22q11.2DS in the context of dynamic functional connectivity, seen here as the specific hyper‐occurrence of these circuits with the task‐negative brain networks. [ABSTRACT FROM AUTHOR]

Schizophrenia often occurs during youth, and psychosis risk syndrome occurs before the onset of psychosis. The aim of this study was to determine whether the visual event-related potential responses in youths with psychosis risk syndrome were defective in the presence of interference stimuli and associated with their clinical outcomes. A total of 223 participants, including 122 patients with psychosis risk syndrome, 50 patients with emotional disorders, and 51 healthy control subjects, were assessed. Baseline EEG was recorded during the three-stimulus visual oddball task. The event-related potentials induced by square pictures with different colors were measured. Almost all patients with psychosis risk syndrome were followed up for 12 months and were reclassified into three subgroups: conversion, symptomatic, and remission. The differences in baseline event-related potential responses were compared among the clinical outcome subgroups. The average N2 amplitude of the psychosis risk syndrome group was significantly less negative than that in the healthy control group (d=0.53). The baseline average N2 amplitude in the conversion subgroup was significantly less negative than that in the symptomatic (d=0.58) and remission (d=0.50) subgroups and in the healthy control group (d=0.97). The average N2 amplitude did not differ significantly between the symptomatic and remission subgroups (d=0.02). However, it was significantly less negative in the symptomatic and remission subgroups than in the healthy control group (d=0.46 and d=0.38). No statistically significant results were found in the P3 response. Youths with psychosis risk syndrome had significant N2 amplitude defects in attention processing with interference stimuli. N2 amplitude shows potential as a prognostic biomarker of clinical outcome in the psychosis risk syndrome. [ABSTRACT FROM AUTHOR]

Schizophrenia genetics is intricate, with common and rare variants' contributions not fully understood. Certain copy number variations (CNVs) elevate risk, pivotal for understanding mental disorder models. Despite CNVs' genome-wide distribution and variable gene and protein effects, we must explore beyond affected genes to interaction partners and molecular pathways. In this study, we developed machine-readable interactive pathways to enable analysis of functional effects of genes within CNV loci and identify ten common pathways across CNVs with high schizophrenia risk using the WikiPathways database, schizophrenia risk gene collections from GWAS studies, and a gene-disease association database. For CNVs that are pathogenic for schizophrenia, we found overlapping pathways, including BDNF signalling, cytoskeleton, and inflammation. Common schizophrenia risk genes identified by different studies are found in all CNV pathways, but not enriched. Our findings suggest that specific pathways - BDNF signalling - are critical contributors to schizophrenia risk conferred by rare CNVs. Our approach highlights the importance of not only investigating deleted or duplicated genes within pathogenic CNV loci, but also study their direct interaction partners, which may explain pleiotropic effects of CNVs on schizophrenia risk and offer a broader field for interventions. [ABSTRACT FROM AUTHOR]

Background: Neurocognitive functioning is an integral phenotype of 22q11.2 deletion syndrome relating to severity of psychopathology and outcomes. A neurocognitive battery that could be administered remotely to assess multiple cognitive domains would be especially beneficial to research on rare genetic variants, where in‐person assessment can be unavailable or burdensome. The current study compares in‐person and remote assessments of the Penn computerised neurocognitive battery (CNB). Methods: Participants (mean age = 17.82, SD = 6.94 years; 48% female) completed the CNB either in‐person at a laboratory (n = 222) or remotely (n = 162). Results: Results show that accuracy of CNB performance was equivalent across the two testing locations, while slight differences in speed were detected in 3 of the 11 tasks. Conclusions: These findings suggest that the CNB can be used in remote settings to assess multiple neurocognitive domains. [ABSTRACT FROM AUTHOR]

People with serious mental illness (SMI; schizophrenia, schizoaffective disorder, bipolar disorder) are at increased risk of suicidal ideation (SI). Over-attribution of social threat, or attributing threatening emotions to neutral faces, may contribute to social isolation through increased social avoidance and decreased social approach motivation. These factors are related to suicide, as well as perceived burdensomeness (PB) and thwarted belongingness (TB). This study examined how over-attribution of threat relates to PB, TB, and social motivations. N = 273 participants with SMI were assessed for current SI and behavior, and were stratified into SI (N = 130) vs. non-SI (N = 143) groups. Participants completed smartphone surveys (via ecological momentary assessments [EMA]) 3×/day for 10 days. They also completed the Mobile Ecological Test of Emotion Recognition (METER) 1×/day. Linear mixed models and multi-level mediation tested the relationships between over-attribution of threat, METER performance, PB/TB, and social motivations. Participants with and without SI did not significantly differ in over-attribution of threat or METER performance. In separate models, there was a relationship of over-attribution of threat with increased PB (B = 1.00, SE = 0.21, t = 4.72, p <.001), reduced social approach motivation (B = -0.74, SE = 0.22, t = −3.33, p <.001), and increased social avoidance (B = 0.90, SE = 0.24, t = 3.70, p <.001), all significant when adjusting for facial affect recognition ability. A model examining social motivations as a mediator between over-attribution of threat and PB/TB was not significant. These results suggest that over-attribution of threat relates to interpersonal constructs related to SI irrespective of facial affect abilities. This study may inform understanding of social cognitive processes related to suicide in SMI. [ABSTRACT FROM AUTHOR]

Objective: Schizophrenia belongs to a severe mental illness with complicated clinical presentations, an ill‐defined pathogenesis, and no known cause. Many genetic studies imply that polygenic interaction is important in the development of schizophrenia. The main mechanism of the RELN‐BDNF‐CREB‐DNMT signaling pathway in neurodevelopment involves RELN, brain‐derived neurotrophic factor (BDNF), transcription factor cyclic adenosine monophosphate response element binding protein (CREB), DNA methyltransferase 1 (DNMT1), as well as DNA methyltransferase 3B (DNMT3B). An early case–control research on 15 polymorphisms in the RELN, CREB, BDNF, DNMT1, and DNMT3B genes was done. A single gene variation has little effect on the pathogenesis of schizophrenia, but the combination of intergenic variation loci has a bigger impact because schizophrenia is a complex polygenic disorder. The objective of the current study sought to explore the impact of genetic interactions between RELN, BDNF, CREB, DNMT1, and DNMT3B on schizophrenia in order to further highlight the genetic factors influencing the risk of schizophrenia. Methods: Taking the case–control study design, with the Diagnostic and Statistical Manual of Mental Disorders‐Fifth Edition (DSM‐5) to be the evaluation norm, 134 individuals suffering from schizophrenia hospitalized in the Third People's Hospital of Zhongshan City within January 2018 to April 2020 (case group) were selected, and 64 healthy individuals (control group) from the same geographical area had been chosen as well. MassArray identified DNMT1 gene single nucleotide polymorphisms (rs2114724 and rs2228611) and DNMT3B gene SNPs (rs2424932, rs1569686, rs6119954, and rs2424908). Using the generalized multifactor dimensionality reduction (GMDR), the RELN‐BDNF‐CREB‐DNMT pathway's gene interactions were examined for their impact on schizophrenia. Results: GMDR analysis showed that the three‐order interaction model RELN (rs2073559, rs2229864)–DNMT3B (rs2424908) was the optimal model (p = 0.001), with the consistency of cross‐validation of 10/10 and the test accuracy of 0.8711. Conclusion: The interaction between the RELN (rs2073559, rs2229864)–DNMT3B (rs2424908) may be related to schizophrenia, and large sample sizes should be verified in different population. The paper designed a case–control genetic interaction study to investigate genetic interactions between RELN, BDNF, CREB, DNMT1, and DNMT3B on schizophrenia. The results generated from generalized multifactor dimensionality reduction (GMDR) suggested interaction between the specific RELN (rs2073559, rs2229864)–DNMT3B (rs2424908) could contribute to the susceptibility of schizophrenia. [ABSTRACT FROM AUTHOR]

Juvenile idiopathic arthritis is a heterogeneous group of diseases characterized by arthritis with poorly known causes, including monogenic disorders and multifactorial etiology. 22q11.2 proximal deletion syndrome is a multisystemic disease with over 180 manifestations already described. In this report, the authors describe a patient presenting with a short stature, neurodevelopmental delay, and dysmorphisms, who had an episode of polyarticular arthritis at the age of three years and eight months, resulting in severe joint limitations, and was later diagnosed with 22q11.2 deletion syndrome. Investigation through Whole Genome Sequencing revealed that he had no pathogenic or likely-pathogenic variants in both alleles of the MIF gene or in genes associated with monogenic arthritis (LACC1, LPIN2, MAFB, NFIL3, NOD2, PRG4, PRF1, STX11, TNFAIP3, TRHR, UNC13DI). However, the patient presented 41 risk polymorphisms for juvenile idiopathic arthritis. Thus, in the present case, arthritis seems coincidental to 22q11.2 deletion syndrome, probably caused by a multifactorial etiology. The association of the MIF gene in individuals previously described with juvenile idiopathic arthritis and 22q11.2 deletion seems unlikely since it is located in the distal and less-frequently deleted region of 22q11.2 deletion syndrome. [ABSTRACT FROM AUTHOR]

We present a case study of a young male with a history of 22q11.2 deletion syndrome (22qDS), diagnosed with systemic capillary leak syndrome (SCLS) who presented with acute onset of diffuse anasarca and sub-comatose obtundation. We hypothesized that his co-presentation of neurological sequelae might be due to blood-brain barrier (BBB) susceptibility conferred by the 22q11.2 deletion, a phenotype that we have previously identified in 22qDS. Using pre- and post-intravenous immunoglobulins (IVIG) patient serum, we studied circulating biomarkers of inflammation and assessed the potential susceptibility of the 22qDS BBB. We employed in vitro cultures of differentiated BBB-like endothelial cells derived from a 22qDS patient and a healthy control. We found evidence of peripheral inflammation and increased serum lipopolysaccharide (LPS) alongside endothelial cells in circulation. We report that the patient's serum significantly impairs barrier function of the 22qDS BBB compared to control. Only two other cases of pediatric SCLS with neurologic symptoms have been reported, and genetic risk factors have been suggested in both instances. As the third case to be reported, our findings are consistent with the hypothesis that genetic susceptibility of the BBB conferred by genes such as claudin-5 deleted in the 22q11.2 region promoted neurologic involvement during SCLS in this patient. [ABSTRACT FROM AUTHOR]

Redox regulatory drug (RRD) targets may be considered potential novel drug targets of psychosis due to the fact that the brain is highly susceptible to oxidative stress imbalance. The aim of the present study is to identify potential associations between RRD targets' perturbation and the risk of psychoses; to achieve this, Mendelian randomization analyses were conducted. The expression quantitative trait loci (eQTL) and protein QTL data were used to derive the genetic instrumental variables. We obtained the latest summary data of genome-wide association studies on seven psychoses as outcomes, including schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD), attention-deficit/hyperactivity disorder, autism, obsessive–compulsive disorder and anorexia nervosa. In total, 95 unique targets were included in the eQTL panel, and 48 targets in the pQTL one. Genetic variations in the vitamin C target (OGFOD2, OR = 0.784, p = 2.14 × 10−7) and melatonin target (RORB, OR = 1.263, p = 8.80 × 10−9) were significantly related to the risk of SCZ. Genetic variation in the vitamin E (PRKCB, OR = 0.248, p = 1.24 × 10−5) target was related to an increased risk of BD. Genetic variation in the vitamin C target (P4HTM: cerebellum, OR = 1.071, p = 4.64 × 10−7; cerebellar hemisphere, OR = 1.092, p = 1.98 × 10−6) was related to an increased risk of MDD. Cognitive function mediated the effects on causal associations. In conclusion, this study provides supportive evidence for a causal association between RRD targets and risk of SCZ, BD or MDD, which were partially mediated by cognition. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a female Maine Coon cat with classical Ehlers-Danlos syndrome (cEDS), a hereditary connective tissue disorder characterized by skin hyperextensibility, poor wound healing, and joint hypermobility. The cat exhibited symptoms such as nonhealing wounds, alopecia, and scarring. Through genomic sequencing, researchers identified a heterozygous deletion in the COL5A1 gene, which is known to be associated with cEDS in cats. This study highlights the potential of whole genome sequencing for precision medicine and diagnostics in veterinary medicine. [Extracted from the article]

22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes, involving ∼3 Mb of DNA. In a relatively large population of a Brazilian 22q11.2DS cohort (60 patients), we investigated genetic variants that could act as genetic modifiers and contribute to the phenotypic heterogeneity, using a targeted NGS (Next Generation Sequencing) with a specific Ion AmpliSeq panel to sequence nine candidate genes (CRKL, MAPK1, HIRA, TANGO2, PI4KA, HDAC1, ZDHHC8, ZFPM2, and JAM3), mapped in and outside the 22q11.2 hemizygous deleted region. In silico prediction was performed, and the whole-genome sequencing annotation analysis package (WGSA) was used to predict the possible pathogenic effect of single nucleotide variants (SNVs). For the in silico prediction of the indels, we used the genomic variants filtered by a deep learning model in NGS (GARFIELD-NGS). We identified six variants, 4 SNVs and 2 indels, in MAPK1, JAM3, and ZFPM2 genes with possibly synergistic deleterious effects in the context of the 22q11.2 deletion. Our results provide the opportunity for the discovery of the co-occurrence of genetic variants with 22q11.2 deletions, which may influence the patients´ phenotype. [ABSTRACT FROM AUTHOR]

Backgrounds: Social skills are frequently impaired in neurodevelopmental disorders and genetic conditions, including 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). Although often assessed with questionnaires, direct assessment provides a more valid estimate of the constructs. Role-plays (i.e., simulates situational settings) therefore appear to be an appropriate indicator of social skills in daily life. Methods: This co-registered study involved 53 individuals with 22q11DS, 34 individuals with ASD, and 64 typically developing (TD) peers aged 12–30 years. All participants were assessed with role-plays as well as parent-reported questionnaires and clinical interviews focusing on social skills, functioning and anxiety. Results: Both clinical groups showed impaired social skills compared to TD, but distinct social profiles emerged between the groups. Individuals with 22q11DS displayed higher social appropriateness and clarity of speech but weaker general argumentation and negotiation skills, with the opposite pattern observed in participants with ASD. No association was found between social skills measured by direct observation and caregiver reports. Social anxiety, although higher in clinical groups than in TD, was not associated with role-plays. Conclusions: This study highlights the need to train social skills through tailored interventions to target the specific difficulties of each clinical population. It also highlights the importance of combining measures as they do not necessarily provide the same outcome. [ABSTRACT FROM AUTHOR]

Background: Mutations in the gene DISC1 are associated with increased risk for schizophrenia, bipolar disorder and major depression. The study of mutated DISC1 represents a well-known and comprehensively characterized approach to understand neuropsychiatric disease mechanisms. However, previous studies have mainly used animal models or rather heterogeneous populations of iPSC-derived neurons, generated by undirected differentiation, to study the effects of DISC1 disruption. Since major hypotheses to explain neurodevelopmental, psychiatric disorders rely on altered neuronal connectivity observed in patients, an ideal iPSC-based model requires accurate representation of the structure and complexity of neuronal circuitries. In this study, we made use of an isogenic cell line with a mutation in DISC1 to study neuronal synaptic phenotypes in a culture system comprising a defined ratio of NGN2 and ASCL1/DLX2 (AD2)-transduced neurons, enriched for glutamatergic and GABAergic neurons, respectively, to mimic properties of the cortical microcircuitry. Results: In heterozygous DISC1 mutant neurons, we replicated the expected phenotypes including altered neural progenitor proliferation as well as neurite outgrowth, deregulated DISC1-associated signaling pathways, and reduced synaptic densities in cultures composed of glutamatergic neurons. Cultures comprising a defined ratio of NGN2 and AD2 neurons then revealed considerably increased GABAergic synapse densities, which have not been observed in any iPSC-derived model so far. Increased inhibitory synapse densities could be associated with an increased efficiency of GABAergic differentiation, which we observed in AD2-transduced cultures of mutant neurons. Additionally, we found increased neuronal activity in GABAergic neurons through calcium imaging while the activity pattern of glutamatergic neurons remained unchanged. Conclusions: In conclusion, our results demonstrate phenotypic differences in a co-culture comprising a defined ratio of DISC1 mutant NGN2 and AD2 neurons, as compared to culture models comprising only one neuronal cell type. Altered synapse numbers and neuronal activity imply that DISC1 impacts the excitatory/inhibitory balance in NGN2/AD2 co-cultures, mainly through increased GABAergic input. [ABSTRACT FROM AUTHOR]

We present a series of microdeletion and microduplication syndromes (MMSs) observed in our clinical practice over a three-year period from 2020 to 2023. Microdeletion and microduplication syndromes, characterized by chromosomal deletions or duplications of less than five megabases, pose challenges in terms of diagnosis, especially prenatal and clinical management. Clinically, MMSs encompass a broad spectrum of manifestations, ranging from intellectual disability and developmental delays to congenital anomalies, facial dysmorphisms, and neurobehavioral abnormalities. Notable examples include well-characterized syndromes such as DiGeorge syndrome (22q11.2 deletion), Prader–Willi syndrome (15q11–q13 deletion), and Williams syndrome (7q11 deletion). Our study focuses on the genetic foundations and prenatal ultrasound findings of these syndromes, with an emphasis on cases associated with intellectual disability. Using SNP array technology, we delve into the evolving landscape of diagnostic methods, providing a nuanced understanding of copy number variations (CNVs) and their implications. Prenatal diagnosis allows for the early detection of MMSs, enabling parents and healthcare providers to make informed decisions about the pregnancy and plan for appropriate medical care and interventions. Beyond theoretical considerations, our article bridges the gap between research and practical application by offering insights derived from clinical cases. Through the presentation of specific cases, we aim to contribute valuable data to the broader discourse on MMSs, fostering knowledge exchange and enhancing the medical community's awareness of these complex genetic conditions. [ABSTRACT FROM AUTHOR]