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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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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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]

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]

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]

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 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]

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]

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]

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]

Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to "dual diagnosis", have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the benefit of anatomical muscle dissection repair for velopharyngeal insufficiency (VPI) in patients with submucous cleft palate (SMCP) with 22q11.2 deletion syndrome. Design: Retrospective blinded randomised analysis of a surgeon's management over 10 years. Setting: The study was performed at a specialised Paediatric hospital in the United Kingdom. Patients: Children with SMCP and 22q11.2 deletion syndrome. Interventions: All participants underwent radical muscle dissection veloplasty. Outcomes measured: Pre- and post- operative measurements included severity of anatomical defect, speech samples and lateral images which were digitised, randomised then externally and blindly analysed using validated techniques. Stata software was used to perform statistical analysis. Results: 57 children with 22q11.2 deletion syndrome were included in this analysis. Intra-operatively, the majority of cases were identified as SMCP Grade I anomalies. Post-operatively, a statistically significant improvement in hypernasality, resting palate length, palate length at maximum closure, palate excursion and gap size at maximum closure was observed. Secondary surgery was performed for 59% of patients by ten years. Conclusion: Muscle dissection repair improves hypernasality, palate closure function and the closure gap in patients with 22q11.2 deletion syndrome. Although over 50% of patients may require further surgery, muscle dissection repair should be a first step due to its utility at a younger age, when invasive investigations are impossible, its lower morbidity, speech and language benefits or altering the plans for less obstructive secondary surgery when it lead to reduced velo-pharyngeal gap and improved palate mobility even when adequate velo-pharyngeal closure was not achieved. [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]

Introduction: Structural brain connectivity abnormalities have been associated with several psychiatric disorders. Schizophrenia (SCZ) is a chronic disabling disorder associated with accelerated aging and increased risk of dementia, though brain findings in the disorder have rarely been directly compared to those that occur with aging. Methods: We used an automated approach to reconstruct key white matter tracts and assessed tract integrity in five participant groups. We acquired one-hour-long high-directional diffusionMRI data from young control (CON, n =28), bipolar disorder (BPD, n =21), and SCZ (n =22) participants aged 18-30, and healthy elderly (ELD, n =15) and dementia (DEM, n =9) participants. Volume, fractional (FA), radial diffusivity (RD) and axial diffusivity (AD) of seven key white matter tracts (anterior thalamic radiation, ATR; dorsal and ventral cingulum bundle, CBD and CBV; corticospinal tract, CST; and the three superior longitudinal fasciculi: SLF-1, SLF-2 and SLF-3) were analyzed with TRACULA. Group comparisons in tract metrics were performed using multivariate and univariate analyses. Clinical relationships of tract metrics with recent and chronic symptoms were assessed in SCZ and BPD participants. Results: A MANOVA showed group differences in FA (l=0.5; p=0.0002) and RD (l=0.35; p<0.0001) across the seven tracts, but no significant differences in tract AD and volume. Post-hoc analyses indicated lower tract FA and higher RD in ELD and DEM groups compared to CON, BPD and SCZ groups. Lower FA and higher RD in SCZ compared to CON did not meet statistical significance. In SCZ participants, a significant negative correlation was found between chronic psychosis severity and FA in the SLF-1 (r= -0.45; p=0.035), SLF-2 (r= -0.49; p=0.02) and SLF-3 (r= -0.44; p=0.042). Discussion: Our results indicate impaired white matter tract integrity in elderly populations consistent with myelin damage. Impaired tract integrity in SCZ is most prominent in patients with advanced illness. [ABSTRACT FROM AUTHOR]

Background: 4q21 microdeletion syndrome is an emergent non‐recurrent genomic disorder characterized by facial dysmorphy, progressive growth retardation, severe intellectual deficit, and absent or severely delayed speech. Deletions occur in clusters along 4q interstitial or terminal regions. 4q chromosomal aberrations are variable in type, size, and breakpoint. Genotype–phenotype correlation is a challenging task. The recurrent antenatal feature associated a posteriori with this syndrome is intrauterine growth retardation. There are very few precise antenatal descriptions of this syndrome. Methods: We report here the first antenatal history of one of the largest deletion of this region. Results: Our case harbored a 16.9 Mb deletion encompassing 135 protein coding genes including 20 OMIM morbid genes involved in neurological and cognitive abilities. Those breakpoints overlap two clusters of described microdeletion syndromes of cytogenetic band 4q13 and 4q21. Conclusion: From the end of the second trimester, set of call signs associated with this syndrome can be completed by: excess of amniotic fluid, mild growth retardation, short long bones, bony anomalies of the extremities, and bulging cheeks. So, emphasis should be placed on the examination of the extremities, and the face during the routine targeted prenatal ultrasound. [ABSTRACT FROM AUTHOR]

The genesis of a mature complement of neurons is thought to require, at least in part, precursor cell lineages in which neural progenitors have distinct identities recognized by exclusive expression of one or a few molecular markers. Nevertheless, limited progenitor types distinguished by specific markers and lineal progression through such subclasses cannot easily yield the magnitude of neuronal diversity in most regions of the nervous system. The late Verne Caviness, to whom this edition of Developmental Neuroscience is dedicated, recognized this mismatch. In his pioneering work on the histogenesis of the cerebral cortex, he acknowledged the additional flexibility required to generate multiple classes of cortical projection and interneurons. This flexibility may be accomplished by establishing cell states in which levels rather than binary expression or repression of individual genes vary across each progenitor's shared transcriptome. Such states may reflect local, stochastic signaling via soluble factors or coincidence of cell surface ligand/receptor pairs in subsets of neighboring progenitors. This probabilistic, rather than determined, signaling could modify transcription levels via multiple pathways within an apparently uniform population of progenitors. Progenitor states, therefore, rather than lineal relationships between types may underlie the generation of neuronal diversity in most regions of the nervous system. Moreover, mechanisms that influence variation required for flexible progenitor states may be targets for pathological changes in a broad range of neurodevelopmental disorders, especially those with polygenic origins. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study is to evaluate the benefit of cytogenetic testing by amniocentesis after an ultrasound diagnosis of isolated bilateral talipes equinovarus. Material and methods: This multicenter observational retrospective study includes all prenatally diagnosed cases of isolated bilateral talipes equinovarus in five fetal medicine centers from 2012 through 2021. Ultrasound data, amniocentesis results, biochemical analyses of amniotic fluid and parental blood samples to test neuromuscular diseases, pregnancy outcomes, and postnatal outcomes were collected for each patient. Results: In all, 214 fetuses with isolated bilateral talipes equinovarus were analyzed. A first‐degree family history of talipes equinovarus existed in 9.8% (21/214) of our cohort. Amniocentesis was proposed to 86.0% (184/214) and performed in 70.1% (129/184) of cases. Of the 184 karyotypes performed, two (1.6%) were abnormal (one trisomy 21 and one triple X syndrome). Of the 103 microarrays performed, two (1.9%) revealed a pathogenic copy number variation (one with a de novo 18p deletion and one with a de novo 22q11.2 deletion) (DiGeorge syndrome). Neuromuscular diseases (spinal muscular amyotrophy, myasthenia gravis, and Steinert disease) were tested for in 56 fetuses (27.6%); all were negative. Overall, 97.6% (165/169) of fetuses were live‐born, and the diagnosis of isolated bilateral talipes equinovarus was confirmed for 98.6% (139/141). Three medical terminations of pregnancy were performed (for the fetuses diagnosed with Down syndrome, DiGeorge syndrome, and the 18p deletion). Telephone calls (at a mean follow‐up age of 4.5 years) were made to all parents to collect medium‐term and long‐term follow‐up information, and 70 (33.0%) families were successfully contacted. Two reported a rare genetic disease diagnosed postnatally (one primary microcephaly and one infantile glycine encephalopathy). Parents did not report any noticeably abnormal psychomotor development among the other children during this data collection. Conclusions: Despite the low rate of pathogenic chromosomal abnormalities diagnosed prenatally after this ultrasound diagnosis, the risk of chromosomal aberration exceeds the risks of amniocentesis. These data may be helpful in prenatal counseling situations. [ABSTRACT FROM AUTHOR]

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Objectives: To examine the distribution of nuchal translucency thickness (NT), free β‐human chorionic gonadotropin (β‐hCG) and pregnancy‐associated plasma protein‐A (PAPP‐A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first‐trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed. Methods: This was a nationwide registry‐based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio‐25.0mio) diagnosed pre‐ or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22‐A to ‐H) and pregnancies with a classic deletion or duplication (LCR22‐A to ‐D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient‐specific risks for classic 22q11.2 deletions based on NT, PAPP‐A and β‐hCG. Detection rates and false‐positive rates at different risk cut‐offs were calculated. Results: We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). β‐hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP‐A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen‐positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false‐positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss. Conclusions: The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP‐A. However, classic 22q11.2 deletions are associated with increased levels of PAPP‐A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP‐A and β‐hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a newborn with tetralogy of Fallot and features similar to DiGeorge syndrome. The child underwent genetic testing, including chromosomal microarray analysis and whole exome sequencing, which identified a de novo variant in the HIRA gene resulting in the loss of the start codon. The HIRA gene has been associated with hematopoiesis, neurodevelopment, and cardiac development. This case adds to the current knowledge of HIRA-related phenotypes and suggests a potential association between HIRA gene variants and tetralogy of Fallot. [Extracted from the article]

The clinical expression of 22q11.2 deletion syndrome (22q11.2 DS) is extremely variable, as patients can present with recurrent or severe infections, immune dysregulation, atopic diseases, or extra-immunological manifestations. The immunological background underlying the different disease manifestations is not completely elucidated. The aim of this study was to identify the immunophenotypic peculiarities of 22q11.2 DS patients presenting with different disease expressions. This study included 34 patients with 22q11.2 DS, divided into three groups according to the clinical phenotype: isolated extra-immunological manifestations (G1), infectious phenotype with increased/severe infections (G2), and immune dysregulation (G3). The patients underwent extended immunophenotyping of the T and B lymphocytes and analysis of the circulating dendritic cells (DCs). In patients with an infectious phenotype, a significant reduction in CD3+ and CD4+ cells and an expansion of CD8 naïve cells was evidenced. On the other hand, the immunophenotype of the patients with immune dysregulation showed a skewing toward memory T cell populations, and reduced levels of recent thymic emigrants (RTEs), while the highest levels of RTEs were detected in the patients with isolated extra-immunological manifestations. This study integrates the current literature, contributing to elucidating the variability in the immune status of patients with 22q11.2DS with different phenotypic expressions, particularly in those with infectious phenotype and immune dysregulation. [ABSTRACT FROM AUTHOR]

Objective: In the study, we investigated the genetic etiology of the ventricular septal defect (VSD) and comprehensively evaluated the diagnosis rate of prenatal chromosomal microarray analysis (CMA) and exome sequencing (ES) for VSD to provide evidence for genetic counseling. Methods: We carried out chromosomal microarray analysis (CMA) on 468 fetuses with VSD and exome sequencing (ES) on 51 fetuses. Results: In our cohort, 68 (14.5%) VSD fetuses received a genetic diagnosis, including 61 (13.03%, 61/468) cases with chromosomal abnormalities and seven (13.7%, 7/51) cases with gene sequence variants. The detection rate of total pathogenic and likely pathogenic gene variations in the non-isolated VSD group (61/335, 18.2%, 55 by QF-PCR/karyotype/CMA + 6 by ES) was significantly higher than that in the isolated VSD group (7/133, 5.3%, 6 by QF-PCR/karyotype/ CMA + 1 by ES, p = 0.000). The most common copy number variation (CNV) was 22q11.2 microdeletion syndrome. Additionally, we found six previously unreported variants, which expanded the variation spectrum of VSD-related genes. Conclusion: In this study, CNVs and sequence variants were found in 13.03% and 13.7% of cases, respectively. ES can be recommended for fetuses with VSD without chromosome abnormalities and pathogenic CNVs, especially those that are combined with other ultrasound abnormalities. [ABSTRACT FROM AUTHOR]

Background: For a variety of reasons, raising a child with 22q11.2DS has significant psychosocial and financial repercussions for the family caregivers. Our aim was to identify and explain the expectations and concerns of Polish parents of 22q11.2DS children. An online survey was developed consisting of four sections: demographics, emotions experienced by caregivers while performing their duties, attitudes of the respondents about providing care, and finally different aspects of the caregivers' life satisfaction. The study was conducted with the support of the Polish 22q11 Association. Results: Forty-four caregivers of Polish origin completed the survey, all but one of whom were mothers. Thirty-four per cent (n = 15/44) declared full-time employment. According to 73% (n = 32/44) of those surveyed, the child's disease has not harmed their relationship with the partner. In spite of the fact that the median diagnosis time was 1.9 years (ranging from 0 to 12 years), the caregivers indicated that they had contacted on average 3.9 doctors before obtaining the right diagnosis (range 1–17). The Internet was the main source of information and knowledge about their child's disease for 93% of respondents (n = 41/44), while for 54% (n = 24/44) it was the association for people with 22q11DS. Only 26% rated as very good or good the support for caregivers offered by the central and local government or its agendas. The physicians' knowledge about 22q11DS was positively rated by 14% of respondents (n = 6/44). The most frequently chosen source of support for 66% of respondents (n = 29/44) turned out to be their families, and for 34% – a Facebook support group (n = 15/44). Asked how often they rated their quality of life (QoL) highly, none of our respondents chose the option "always", although 64% (28/44) gave the answer "often". Conclusion: Our study is the first one in Poland to develop an online survey specifically for use with caregivers of paediatric patients with 22q11.2DS. Our respondents revealed that caring for 22q11.2 children entails a burden that extends far beyond clinical facets and has a significant impact on every dimension of the caregivers' lives, including their mental health, everyday activities, families, professional career and social lives. At the same time, caregivers are de facto left alone with the bureaucracy of the healthcare system. [ABSTRACT FROM AUTHOR]

Aim: Deficit schizophrenia (DS), defined by primary and enduring negative symptoms, has been proposed as a promising homogeneous subtype of schizophrenia. It has been demonstrated that unimodal neuroimaging characteristics of DS were different from non‐deficit schizophrenia (NDS), however, whether multimodal‐based neuroimaging features could identify deficit syndrome remains to be determined. Methods: Functional and structural multimodal magnetic resonance imaging of DS, NDS and healthy controls were scanned. Voxel‐based features of gray matter volume, fractional amplitude of low‐frequency fluctuations, and regional homogeneity were extracted. The support vector machine classification models were constructed using these features separately and jointly. The most discriminative features were defined as the first 10% of features with the greatest weights. Moreover, relevance vector regression was applied to explore the predictive values of these top‐weighted features in predicting negative symptoms. Results: The multimodal classifier achieved a higher accuracy (75.48%) compared with the single modal model in distinguishing DS from NDS. The most predictive brain regions were mainly located in the default mode and visual networks, exhibiting differences between functional and structural features. Further, the identified discriminative features significantly predicted scores of diminished expressivity factor in DS but not NDS. Conclusions: The present study demonstrated that local properties of brain regions extracted from multimodal imaging data could distinguish DS from NDS with a machine learning‐based approach and confirmed the relationship between distinctive features and the negative symptoms subdomain. These findings may improve the identification of potential neuroimaging signatures and improve the clinical assessment of the deficit syndrome. [ABSTRACT FROM AUTHOR]

Schizophrenia is associated with aberrations in the Default Mode Network (DMN), but the clinical implications remain unclear. We applied data-driven, unsupervised machine learning based on resting-state electroencephalography (rsEEG) functional connectivity within the DMN to cluster antipsychotic-naïve patients with first-episode schizophrenia. The identified clusters were investigated with respect to psychopathological profile and cognitive deficits. Thirty-seven antipsychotic-naïve, first-episode patients with schizophrenia (mean age 24.4 (5.4); 59.5% males) and 97 matched healthy controls (mean age 24.0 (5.1); 52.6% males) underwent assessments of rsEEG, psychopathology, and cognition. Source-localized, frequency-dependent functional connectivity was estimated using Phase Lag Index (PLI). The DMN-PLI was factorized for each frequency band using principal component analysis. Clusters of patients were identified using a Gaussian mixture model and neurocognitive and psychopathological profiles of identified clusters were explored. We identified two clusters of patients based on the theta band (4–8 Hz), and two clusters based on the beta band (12–30 Hz). Baseline psychopathology could predict theta clusters with an accuracy of 69.4% (p = 0.003), primarily driven by negative symptoms. Five a priori selected cognitive functions conjointly predicted the beta clusters with an accuracy of 63.6% (p = 0.034). The two beta clusters displayed higher and lower DMN connectivity, respectively, compared to healthy controls. In conclusion, the functional connectivity within the DMN provides a novel, data-driven means to stratify patients into clinically relevant clusters. The results support the notion of biological subgroups in schizophrenia and endorse the application of data-driven methods to recognize pathophysiological patterns at earliest stage of this syndrome. [ABSTRACT FROM AUTHOR]

Introduction: While stigma toward autistic individuals has been well documented, less is known about how autism is perceived relative to other stigmatized disabilities. As a highly stigmatized condition with similar social cognitive features to autism, schizophrenia may offer a useful comparison for stigma. Previous studies have found that autistic people may be perceived more favorably than those with schizophrenia, but little is known about the underlying volitional thoughts that contribute to differences in how these conditions are perceived. Methods: The present study utilizes a mixed-methods approach, allowing for a detailed understanding of how young adults perceive different diagnostic labels. 533 college undergraduates completed questionnaires reflecting their perceptions of one of eight diagnostic labels: four related to autism (autism, autistic, autism spectrum disorder, or Asperger's), two related to schizophrenia (schizophrenia or schizophrenic), and two related to an unspecified clinical condition (clinical diagnosis or clinical disorder). Participants also completed an open-ended question regarding their thoughts about, and exposure to, these labels. Responses were compared across broader diagnostic categories (autism, schizophrenia, general clinical condition), with thematic analysis used to assess the broader themes occurring within the open-ended text. Results: While perceptions did not differ significantly for person-first and identity-first language within labels, several differences were apparent across labels. Specifically, quantitative results indicated greater prejudice towards autism and schizophrenia than the generic clinical condition, with schizophrenia associated with more perceived fear and danger, as well as an increased preference for social distance, compared to autism. Patterns in initial codes differed across diagnostic labels, with greater variation in responses about autism than responses about schizophrenia or the general clinical condition. While participants described a range of attitudes toward autism (patronizing, exclusionary, and accepting) and schizophrenia (fear, prejudice, and empathy), they refrained from describing their attitudes toward the general clinical label, highlighting the centrality of a cohesive group identity for the development of stigma. Finally, participants reported a number of misconceptions about autism and schizophrenia, with many believing features such as savant syndrome to be core characteristics of the conditions. Conclusion: These findings offer a more detailed account of how non-autistic individuals view autism and may therefore aid in the development of targeted programs to improve attitudes toward autism. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Schizophrenia is associated with altered energy metabolism, but the cause and potential impact of these metabolic changes remain unknown. 22q11.2 deletion syndrome (22q11.2DS) represents a genetic risk factor for schizophrenia, which is associated with the loss of several genes involved in mitochondrial physiology. Here we examine how the haploinsufficiency of these genes could contribute to the emergence of schizophrenia in 22q11.2DS. Study Design We characterize changes in neuronal mitochondrial function caused by haploinsufficiency of mitochondria-associated genes within the 22q11.2 region (PRODH, MRPL40, TANGO2, ZDHHC8, SLC25A1, TXNRD2 , UFD1, and DGCR8). For that purpose, we combine data from 22q11.2DS carriers and schizophrenia patients, in vivo (animal models) and in vitro (induced pluripotent stem cells, IPSCs) studies. We also review the current knowledge about seven non-coding microRNA molecules located in the 22q11.2 region that may be indirectly involved in energy metabolism by acting as regulatory factors. Study Results We found that the haploinsufficiency of genes of interest is mainly associated with increased oxidative stress, altered energy metabolism, and calcium homeostasis in animal models. Studies on IPSCs from 22q11.2DS carriers corroborate findings of deficits in the brain energy metabolism, implying a causal role between impaired mitochondrial function and the development of schizophrenia in 22q11.2DS. Conclusions The haploinsufficiency of genes within the 22q11.2 region leads to multifaceted mitochondrial dysfunction with consequences to neuronal function, viability, and wiring. Overlap between in vitro and in vivo studies implies a causal role between impaired mitochondrial function and the development of schizophrenia in 22q11.2DS. [ABSTRACT FROM AUTHOR]

This case report explores clinical treatment efficacy in a Cantonese-speaking child with 22q11.2 Deletion Syndrome where diagnosis and management of velopharyngeal dysfunction can be considered late. All treatment sessions were undertaken via telepractice during the peak of the COVID-19 pandemic in Hong Kong. A hybrid of specialized cleft palate speech treatment techniques and traditional treatment approaches in Speech Sound Disorders were utilized. Treatment intensity components including dose, dose form, session duration, and total intervention duration were documented. [ABSTRACT FROM AUTHOR]