Impairment of the glymphatic system may contribute to atypical brain development and increased vulnerability to psychiatric conditions such as psychosis. In particular, disrupted glymphatic efficiency may affect neurochemical homeostasis during critical maturational windows, leading to structural and circuit-level alterations. However, its role in early neurodevelopmental trajectories remains largely unexplored. We combined longitudinal diffusion tensor imaging (DTI) in 85 individuals with 22q11.2 deletion syndrome (22q11DS), a neurodevelopmental condition associated with elevated psychosis risk (143 scans), with cross-sectional magnetic resonance spectroscopy in a subset of 39 individuals with 22q11DS. Glymphatic function was estimated indirectly using the DTI analysis along the perivascular space (ALPS) index, a diffusion-based proxy derived from manual and automated region of interest placement. Excitation/inhibition ratio was assessed in the right hippocampus via cerebrospinal fluid-corrected combined glutamate-glutamine signal (Glx) and GABA (gamma-aminobutyric acid) levels. The ALPS index was significantly reduced in individuals with 22q11DS compared with control participants (p = .017), especially in the right hemisphere. Individuals with positive psychotic symptoms (PPS+) showed a divergent developmental trajectory, failing to exhibit the age-related ALPS increase seen in PPS- individuals (group × age interaction: p = .009). In a subset with spectroscopy data (n = 39), lower ALPS index predicted higher Glx/GABA ratio in the right hippocampus (p = .002). These findings provide in vivo evidence that glymphatic-related dysfunction, as indexed by the DTI-ALPS proxy, emerges early and follows atypical developmental trajectories in individuals at risk for psychosis. An impaired ALPS index is also associated with excitatory/inhibitory imbalance. This dysfunction may represent a novel pathway contributing to psychosis vulnerability and a potential target for early intervention.

Cancer arises from the accumulation of genetic alterations, including chromosomal translocations and deletions. Faulty repair of DNA double-strand breaks can give rise to such chromosomal rearrangements. In this study, we focus on diverse translocations that share a common partner, BCL6 on chromosome 3, which are implicated in diffuse large B-cell lymphoma (DLBCL). Analysis of patient breakpoints identified several breakpoint clusters within BCL6, of which Cluster III is the focus of this work. Here, we investigate the role of non-B DNA structures in imparting chromosomal fragility. In silico analyses, gel shift assays, and circular dichroism confirmed G-quadruplex (G4) formation at BCL6 Cluster III. Mutation studies revealed multiple G4 conformations utilizing distinct G-stretches, including GNG motifs. Disrupting G4-forming sequences in this region enhanced plasmid propagation in E. coli, indicating structure-dependent replication stalling. Sodium bisulfite modification assays detected single-stranded character here, both in plasmids and chromosomal DNA, suggesting additional fragility hotspots within Cluster III. Ex vivo assays showed that the G4 structure blocks transcription as a roadblock. Together, these data demonstrate that G4 folding in BCL6 Cluster III generates partially single-stranded regions, rendering the locus prone to breakage and translocation.

Abstract Background 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder and represents one of the strongest known genetic risk factors for psychosis. Social cognition (SC) deficits are a core feature of schizophrenia and are strongly associated with functional outcomes. In individuals with 22q11.2DS and psychotic symptoms, SC impairments may emerge early; however, direct comparisons between patients with 22q11.2DS with psychotic symptoms and those with schizophrenia remain limited. Methods In this case–control study, we investigated 21 patients with 22q11.2DS and active psychotic symptoms and 21 outpatients with schizophrenia and active psychotic symptoms recruited from the outpatient clinics of Sant’Andrea Hospital, Rome. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive and social cognitive functioning were evaluated using the Cognitive Assessment Interview (CAI). Results Patients with schizophrenia showed significantly higher severity of positive, general, cognitive, excitement, and depression symptoms (all p<.05). In contrast, patients with 22q11.2DS exhibited more pronounced SC impairment (U = 81.00, p<.001). In the 22q11.2DS group, SC was associated with multiple cognitive and clinical domains, including working memory, attention/vigilance, processing speed, reasoning/problem solving, and PANSS total score. Correlation analyses further revealed stronger associations between negative symptoms and cognitive domains in 22q11.2DS group compared with schizophrenia group. Conclusions In this study, patients with 22q11.2DS and patients with schizophrenia showed partially distinct profiles of psychopathology and social cognition. While schizophrenia was characterized by greater overall symptom severity, 22q11.2DS was associated with more pronounced social cognitive impairment.

When tumor suppressor genes are lost through chromosomal deletion, deletion of adjacent genes can generate therapeutic vulnerabilities. MTAP is frequently co-deleted with the Chr9p21 tumor suppressor gene CDKN2A, creating synthetic lethal dependency on PRMT5. Telomeric to MTAP lies FOCAD, whose loss induces dependency on the HBS1L/PELO ribosome-rescue complex for translational maintenance. FOCAD is deleted in ~1/3 of MTAP-deleted cancers. We screened an IMiD-focused diversity library and identified a weak hit that bound cereblon, promoted HBS1L-CRBN-compound complex formation, and induced E3-ligase-dependent HBS1L ubiquitination and degradation. Guided by cryo-EM structures and proteome selectivity we developed TNG961, a potent, selective HBS1L degrader that disrupts the HBS1L/PELO complex, inducing translational arrest, unfolded protein response activation, and growth inhibition in FOCAD-negative models. Oral administration of TNG961 regresses FOCAD-negative xenografts, including PRMT5 inhibitor-refractory models, establishing HBS1L degradation as a strategy to exploit FOCAD loss and supporting clinical evaluation of TNG961 as a first-in-class precision oncology therapeutic.

Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization of the unique and shared neuroanatomical signatures of these schizotypy dimensions is lacking. Leveraging 3D brain MRI data from 2730 unmedicated healthy individuals, we identified neuroanatomical profiles of positive and negative schizotypy and systematically compared them with disorder-specific, microarchitectural, neurotransmitter-level, and connectome measures. Positive and negative schizotypy were associated with distinct cortical signatures, of predominantly thinner frontal and thicker paralimbic cortical areas, respectively. These cortical signatures of positive and negative schizotypy were differentially linked to brain-wide cortical patterns of schizophrenia-spectrum (clinical high-risk for psychosis, schizophrenia) and neurodevelopmental conditions (ADHD, autism spectrum disorder and 22q11.2 deletion syndrome). Additionally, the positive and negative schizotypy-related cortical profiles mapped onto different local attributes of gene expression, cortical myelination, D1, and histamine receptor distributions. Network models further showed that positive and negative schizotypy cortical signatures were spatially associated with cortical hubs, suggesting that highly interconnected regions are more vulnerable to the morphological differences associated with both schizotypy dimensions. Finally, predominantly sensorimotor-to-association and paralimbic areas emerged as epicenters with connectivity profiles significantly linked to the schizotypy-related cortical patterns. Collectively, this study identified cortical signatures of positive and negative schizotypy traits that are embedded along multiple scales of cortical organization and neuropsychiatric pathologies. Our work yields novel insights into how neurobiology and brain architecture may guide neuroanatomical vulnerability and resilience to psychopathology in the general population.

Chromosome 9p deletions are frequently detected in postnatal cases presenting with diverse neurological symptoms. However, limited prenatal reports of these chromosomal disorders poses a challenge for genetic counseling during pregnancy. A pregnant woman underwent amniocentesis for cytogenetic analysis and a chromosomal microarray analysis (CMA) because of imaging findings indicating subependymal cysts. The prenatal phenotypes were reviewed on the basis of previous reports. The fetal karyotype was 46,XN,del(9)(p22). The CMA showed a 16.65-Mb deletion in the 9p24.3p22.2 region. After genetic counseling, the couple chose to terminate the pregnancy. Fetal growth restriction and a single umbilical artery are common ultrasound findings detected in 9p deletions. The prenatal genotype-phenotype of 9p deletion syndrome is complicated because of phenotypic diversity and incomplete penetrance. To offer better genetic counseling for such cases, ultrasonographic, cytogenetic, and molecular genetic results should be combined.

Amniotic fluid exosomes (AF-Exos) are pivotal carriers of biological information during fetal development; however, their role in 22q11.2 Deletion Syndrome (22q11.2DS) remains unclear. To elucidate the molecular mechanisms underlying fetal anomalies in 22q11.2DS, this study performed a comprehensive multiomics analysis of AF-Exos obtained from 22q11.2DS fetuses (n = 5) and matched controls (n = 5). While exosomal morphology and size distribution remained unaltered, integrated lipidomic and proteomic profiling revealed profound molecular remodeling. Lipidomics analysis revealed a specific suppression of diacylglycerols, triacylglycerols, and ceramides, accompanied by a shift in carbon chain length distribution. Concurrently, data-independent acquisition proteomics identified 329 differentially expressed proteins, highlighting a significant downregulation of PI4KA and widespread perturbations in pathways governing cardiovascular morphogenesis, angiogenesis, and SNARE-mediated vesicular transport. Integrated network analysis revealed strong correlations between the depletion of key lipids and reduced abundance of PI4KA and SNARE complex components, suggesting a potential interplay between lipid metabolism and vesicle trafficking. These findings, extending beyond the primary genetic driver TBX1, point to distinct alterations in lipid signaling and exosomal transport machinery in 22q11.2DS, suggesting a novel parallel pathogenic mechanism. This study provides a novel multiomics resource for understanding 22q11.2DS pathogenesis and generates valuable hypothesis-driven candidates for future mechanistic investigation.

Inactivation of the sco2730/2731 copper chaperone-transporter system in Streptomyces coelicolor and its orthologs in Streptomyces venezuelae, together with chromosomal end deletion, greatly enhances secondary metabolism.

22q11.2 deletion syndrome (22q11DS) is associated with a variety of complications, including mental illness, intellectual disability, and physical disorders. Due to the overlap of these conditions, there is often a mismatch in existing healthcare frameworks, leading to unmet support needs. However, little is known about how patients and their caregivers perceive these issues. This study aims to automate thematic analysis (TA) and topic classification via natural language processing (NLP) techniques to extract medical needs from qualitative data provided by patients’ caregivers. A web-based survey was conducted targeting caregivers of individuals with 22q11DS in Japan. 125 caregivers participated in the study and their responses were analyzed to identify medical challenges and unmet needs. TA and NLP-based thematic extraction was implemented on free-text responses related to medical concerns. To ensure privacy, the analysis was conducted offline using the open-source large language model (Cohere Command R Plus). Ethical considerations were addressed following the Declaration of Helsinki, with approval from the Ethics Committee of the University of Tokyo Graduate School of Medicine and Faculty of Medicine. NLP unveiled medical challenges and unmet needs of individuals with 22q11DS: a child-centered approach, comprehensive support across medical and welfare services, and support for caregivers through social and community networks. A comparison with manual TA confirmed that most themes were consistent. Given the limited size of our dataset, the implications of this study should be regarded as preliminary. Nevertheless, our findings suggest that NLP may serve as a useful exploratory approach to complement manual TA when analyzing larger free-text datasets on medical needs in future research. NLP should not be viewed as a replacement for manual TA, but rather as a supportive method that offers additional perspectives and potential patterns.

Contiguous gene deletion syndromes (CGDSs) can be inherited or the result of microdeletions (eg, resulting from crossing-over errors) in gene-rich chromosome regions. Molecular mechanisms leading to chromosome loss in hotspot areas, such as errors in chromosome crossing-over events, can explain phenotypic presentations in CGDSs. Accurate interpretation of laboratory results in the context of clinical presentation can guide genetic testing that supports a timely diagnosis so that quicker interventions can improve clinical outcomes. Treatment of genetic disorders not only requires timely and accurate treatment, however, but also necessitates management and education of family members who care for the patient. Xp21.3-p21.2 deletion syndrome is a CGDS that has been documented in more than 100 male patients; it presents with primary adrenal insufficiency in the neonatal period. Here, we report the largest Xp21.3-p21.2 CGDS series to date. Initial presentation was incorrectly diagnosed as adrenal insufficiency only, despite excessively elevated creatinine kinase and triglycerides, which could have expedited the correct diagnosis of Xp21.3p21.1 CGDS by guiding whole genome or targeted sequencing.

The 22q11.2 deletion syndrome: Genetic mechanisms, clinical manifestations, and therapeutic strategies.

ABL2 rearrangements represent a subtype of acute lymphoblastic leukaemia (ALL) associated with poor prognosis and survival. This study reports a high-risk T-cell ALL (T-ALL) case with a novel TPR::ABL2 gene fusion resulting from a chromosomal deletion. Overexpression of TPR::ABL2 in Ba/F3 cells promoted cytokine-independent growth, demonstrating its oncogenic nature. Both primary patient and Ba/F3 cells carrying TPR::ABL2 exhibited kinase activation and sensitivity to tyrosine kinase inhibitors (TKIs). This study expands the repertoire of ABL2 fusions identified in ALL and supports the incorporation of TKIs into T-ALL treatment regimens to improve outcomes for this subtype.

Late Diagnosis of 22q11.2 Deletion Syndrome in a 33-year-old Woman Presenting With Symptomatic Hypocalcemia

An enhanced transformer model for detecting 1p36 deletion syndrome.

Metabolic engineering of Pseudomonas putida KT2440 for valorization of terephthalic acid to produce catechol and muconic acid.

22q11.2 deletion syndrome (22qDS) is a genetic disorder affecting various body systems and associated with behavioral and psychiatric conditions, with no currently approved pharmacological treatments. ZYN002, a transdermal gel containing synthetic cannabidiol, has been demonstrated to be well tolerated, showing potential benefit in related neurodevelopmental disorders. The INSPIRE study evaluated the safety, tolerability, and effectiveness of ZYN002 in children and adolescents with 22qDS. INSPIRE was a phase 2, open-label, multicenter trial comprising a 14-week treatment period (Period 1) followed by an optional 24-week, open-label extension (Period 2) for participants with ≥35% improvement on the Aberrant Behavior Checklist-Community (ABC-C) irritability subscale upon Period 1 completion. Participants aged 4 to <18 years with genetically confirmed 22qDS, Clinical Global Impression-Severity score ≥4, and Pediatric Anxiety Rating Scale-Revised (PARS-R) score ≥10, both at Screening and Visit 2 (Day 1), were enrolled. Weight-based, transdermal ZYN002 administration occurred twice daily. Primary outcomes were safety and tolerability, including the incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included the PARS-R; Anxiety, Depression, and Mood Scale (ADAMS); ABC-C; Clinical Global Impression-Improvement (CGI-I), and Qualitative Caregiver-Reported Behavioral Problems survey. Twenty participants initiated treatment; 17 completed Period 1, and 13 continued into Period 2. ZYN002 was well tolerated; only mild TEAEs were experienced in 35% of participants, and 15% reported treatment-related AEs. Upon Period 1 completion, significant changes from Baseline were observed across all measures: 40.6% PARS-R reduction (P=0.0005); 45.3% ADAMS total score reduction (P=0.0005) with clinically meaningful improvements in all subscales; and significant improvements in all ABC-C subscales, including irritability (36.3%, P=0.0055). On the CGI-I, 75% of participants were rated as “improved” or better relative to Baseline. For the behavioral problems survey, >80% of caregivers reported improvement in ≥1 problem during each period. Anxiety and irritability scores from Baseline through Period 2 maintained a similar reduction to Period 1. In this interventional, open-label trial of pediatric participants with 22qDS, ZYN002 was considered safe and well tolerated, and was associated with reductions in anxiety-related and behavioral symptoms, supporting further investigation of ZYN002 in a phase 3 randomized controlled trial. Clinicaltrials.gov (NCT05149898) registered on October 5, 2021.

EEG power spectral and microstate analyses in the 22q11.2 deletion syndrome: from genetic risk to schizophrenia.

Interhemispheric CA1 projections to the subiculum support spatial cognition and are affected in a mouse model of the 22q11.2 deletion syndrome.

Congenital heart disease (CHD) occurs in over half of individuals with 22q11.2 deletion syndrome (22q11.2DS) and the types of lesions range from mild to severe. To determine the basis of variation in cardiac phenotypes we analyzed demographic data from 3,016 unrelated individuals with 22q11.2DS from centers in the Northeast US, Canada, Europe, South America, Israel and Australia. Most individuals in this cohort had a 3 million base pair hemizygous deletion between low copy repeat, LCR22 A-D (87.2%), while some had nested deletions. We performed multivariable mixed-effects logistic regression and uncovered significant differences between CHD phenotypes and basic demographic features. Individuals with the A-D deletion had a lower risk of persistent truncus arteriosus (OR = 0.37, 95% CI 0.18-0.75) but a higher risk of septal defects (OR = 4.7, 95% CI 1.7-12.8) compared to those with the smaller A-B deletion, suggesting distinct developmental pathways sensitive to 22q11.2 gene dosage. In addition, genome-wide genetic principal components (PCs) were associated with specific CHD subtypes, including reduced risk of pulmonary stenosis or atresia with other heart lesions (PC2; OR = 0.73, 95% CI 0.61-0.87) and increased risk of abnormal origin of the subclavian arteries (PC4; OR = 2.6, 95% CI 1.4-4.9), indicating that background genetic variation modifies heart lesion-specific susceptibility. Together, these results suggest that both deletion size and background genetic variation shape the highly variable cardiac phenotypes in 22q11.2DS.

TREC-NBS identifies patients with inborn errors of immunity (IEI) and syndromic features, but uncertainty remains regarding their immunological management. To address this, syndromic patients detected by TREC-NBS in Germany between August 2019 and April 2024 were systematically analyzed, including phenotype, treatment, and outcomes. National registries were screened, and data were completed by the treating centres. A total of 77 syndromic patients were identified, with 22 different gene defects found in 72 individuals (93.5%). Primary thymic deficiency was present in 64% (49/77), most commonly due to 22q11.2 deletion syndrome (62%). Common clinical features included congenital heart disease (57%), facial/skeletal abnormalities (53%), and neurological symptoms (36%). Definitive treatments were provided promptly in eligible patients, including 6 thymus transplants and 6 hematopoietic stem cell transplants (HSCT). A watch-and-wait approach was applied to the remaining patients, with 34% (22/65) receiving prophylactic treatment. Recovery of CD3 + T-cell counts was limited to a minority. Overall survival was 89%, with a median follow-up of 32 months (range 0.5-60). To conclude, this is the first comprehensive study of syndromic IEI patients identified through TREC-NBS. The findings show that the German healthcare system enables both early prophylactic care and timely access to definitive therapies. Moving forward, interdisciplinary collaboration will be key to developing evidence-based management guidelines for this challenging patient group.