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Changes in gene regulatory elements play critical roles in human phenotypic divergence. However, identifying the base-pair changes responsible for the distinctive morphology of Homo sapiens remains challenging. Here, we report a noncoding single-nucleotide polymorphism (SNP), rs41298798, as a potential causal variant contributing to the morphology of the skull base and vertebral structures found in Homo sapiens. Screening for differentially regulated genes between Homo sapiens and extinct relatives revealed 13 candidate genes associated with basicranial development, with TBX1 , implicated in DiGeorge syndrome, playing a pivotal role. Epigenetic markers and in silico analyses prioritized rs41298798 within a TBX1 intron for functional validation. CRISPR editing revealed that the 41-base-pair region surrounding rs41298798 modulates gene expression at 22q11.21. The derived allele of rs41298798 acts as an allele-specific enhancer mediated by E2F1, resulting in increased TBX1 expression levels compared to the ancestral allele. Tbx1 -knockout mice exhibited skull base and vertebral abnormalities similar to those seen in DiGeorge syndrome. Phenotypic differences associated with TBX1 deficiency are observed between Homo sapiens and Neanderthals (Homo neanderthalensis). In conclusion, the regulatory divergence of TBX1 contributes to the formation of skull base and vertebral structures found in Homo sapiens. [Display omitted] Changes in gene regulatory elements are crucial for human phenotypic divergence. However, identifying the changes responsible for the distinct morphology of Homo sapiens remains challenging. Here, we report a noncoding SNP, rs41298798, in TBX1 as a potential causal variant contributing to the basicranial morphology found in Homo sapiens. [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]

The 22q11.2 deletion syndrome (22q11.2DS) is associated with a heterogeneous neurocognitive phenotype, which includes psychiatric disorders. However, few studies have investigated the influence of socioeconomic variables on intellectual variability. The aim of this study was to investigate the cognitive profile of 25 patients, aged 7 to 32 years, with a typical ≈3 Mb 22q11.2 deletion, considering intellectual, adaptive, and neuropsychological functioning. Univariate linear regression analysis explored the influence of socioeconomic variables on intellectual quotient (IQ) and global adaptive behavior. Associations with relevant clinical conditions such as seizures, recurrent infections, and heart diseases were also considered. Results showed IQ scores ranging from 42 to 104. Communication, executive functions, attention, and visuoconstructive skills were the most impaired in the sample. The study found effects of access to quality education, family socioeconomic status (SES), and caregiver education level on IQ. Conversely, age at diagnosis and language delay were associated with outcomes in adaptive behavior. This characterization may be useful for better understanding the influence of social-environmental factors on the development of patients with 22q11.2 deletion syndrome, as well as for intervention processes aimed at improving their quality of life. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion 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.The objective is to investigate salivary total α‐synuclein levels in 22q11.2DS patients with and without parkinsonian motor signs.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.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.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]

Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo epithelial–mesenchymal transition (EMT) and upon key developmental gene deregulation, fetuses and neonates are prone to exhibit diverse manifestations depending on the affected area. These conditions are generally rare and often have a genetic basis, with many following Mendelian inheritance patterns, thus making them perfect candidates for precision medicine. Examples include cranial NCPs, like Goldenhar syndrome and Axenfeld–Rieger syndrome; cardiac–vagal NCPs, such as DiGeorge syndrome; truncal NCPs, like congenital central hypoventilation syndrome and Waardenburg syndrome; and enteric NCPs, such as Hirschsprung disease. Additionally, NCCs' migratory and differentiating nature makes their derivatives prone to tumors, with various cancer types categorized based on their NCC origin. Representative examples include schwannomas and pheochromocytomas. This review summarizes current knowledge of diseases arising from defects in NCCs' specification and highlights the potential of precision medicine to remedy a clinical phenotype by targeting the genotype, particularly important given that those affected are primarily infants and young children. [ABSTRACT FROM AUTHOR]

22q11.2 deletion is the most prominent risk factor for schizophrenia (SZ). The aim of the present study was to identify unique transcriptome profile for 22q11.2 deletion syndrome (DS)-related SZ-spectrum disorder (SZ-SD). We performed RNA-Seq screening in lymphoblasts collected from 20 individuals with 22q11.2DS (10 men and 10 women, four of each sex with SZ-SD and six with no psychotic disorders (Np)). Sex effect in RNA-Seq descriptive analysis led to separating the analyses between men and women. In women, only one differentially expressed gene (DEG), HLA-DQA2, was associated with SZ-SD. In men, 48 DEGs (adjp < 0.05) were found to be associated with SZ-SD. Ingenuity pathway analysis of top 85 DEGs (p < 4.66E − 04) indicated significant enrichment for immune-inflammatory response (IIR) and neuro-inflammatory signalling pathways. Additionally, NFATC2, IFNG, IFN-alpha, STAT1 and IL-4 were identified as upstream regulators. Co-expression network analysis revealed the contribution of endoplasmic reticulum protein processing and N-Glycan biosynthesis. These findings indicate dysregulation of IIR and post-translational protein modification processes in individuals with 22q11.2DS-related SZ-SD. Candidate pathways and upstream regulators may serve as novel biomarkers and treatment targets for SZ. Future transcriptome studies, including larger samples and proteomic analysis, are needed to substantiate our findings. [ABSTRACT FROM AUTHOR]

Introduction: The chromosome 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with a wide range of brain-related phenotypes including schizophrenia spectrum disorders (SCZ), autism spectrum disorders (ASD), anxiety disorders and attention deficit disorders (ADHD). The typically deleted region in 22q11.2DS contains multiple genes which haploinsufficiency has the potential of altering the protein and the metabolic profiles. Objectives: Alteration in metabolic processes and downstream protein pathways during the early brain development may help to explain the increased prevalence of the observed neurodevelopmental phenotypes in 22q11.2DS. However, relatively little is known about the correlation of dysregulated protein/metabolite expression and neurobehavioral impairments in individuals who developed them over time. Methods: In this study, we performed untargeted metabolic and proteomic analysis in plasma samples derived from 30 subjects including 16 participants with 22q11.2DS and 14 healthy controls (TD) enrolled in a longitudinal study, aiming to identify a metabolic and protein signature informing about the underlying mechanisms involved in disease development and progression. The metabolic and proteomic profiles were also compared between the participants with 22q11.2DS with and without various comorbidities, such as medical involvement, psychiatric conditions, and autism spectrum disorder (ASD) to detect potential changes among multiple specimens, collected overtime, with the aim to understand the basic underlying mechanisms involved in disease development and progression. Results: We observed a large number of statistically significant differences in metabolites between the two groups. Among them, the levels of taurine and arachidonic acid were significantly lower in 22q11.2DS compared to the TD group. In addition, we identified 16 proteins that showed significant changes in expression levels (adjusted P < 0.05) in 22q11.2DS as compared to TD, including those involved in 70 pathways such as gene expression, the PI3K-Akt signaling pathway and the complement system. Within participants with 22q11.2DS, no significant changes in those with and without medical or psychiatric conditions were observed. Conclusion: To our knowledge, this is the first report on plasma metabolic and proteomic profiling and on the identification of unique biomarkers in 22q11.2DS. These findings may suggest the potential role of the identified metabolites and proteins as biomarkers for the onset of comorbid conditions in 22q11.2DS. Ultimately, the altered protein pathways in 22q11.2DS may provide insights of the biological mechanisms underlying the neurodevelopmental phenotype and may provide missing molecular outcome measures in future clinical trials to assess early-diagnosis treatment and the efficacy of response to targeted treatment. [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]

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]

22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus, pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings. [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]

22q11.2 Deletion Syndrome (22q11.2DS), the most common chromosomal microdeletion, presents as a heterogeneous phenotype characterized by an array of anatomical, behavioral, and cognitive abnormalities. Individuals with 22q11.2DS exhibit extensive cognitive deficits, both in overall intellectual capacity and focal challenges in executive functioning, attentional control, perceptual abilities, motor skills, verbal processing, as well as socioemotional operations. Heterogeneity is an intrinsic factor of the deletion's clinical manifestation in these cognitive domains. Structural imaging has identified significant changes in volume, thickness, and surface area. These alterations are closely linked and display region-specific variations with an overall increase in abnormalities following a rostral-caudal gradient. Despite the extensive literature developing around the neurocognitive and neuroanatomical profiles associated with 22q11.2DS, comparatively little research has addressed specific structure–function relationships between aberrant morphological features and deficient cognitive processes. The current review attempts to categorize these limited findings alongside comparisons to populations with phenotypic and structural similarities in order to answer to what degree structural findings can explain the characteristic neurocognitive deficits seen in individuals with 22q11.2DS. In integrating findings from structural neuroimaging and cognitive assessments, this review seeks to characterize structural changes associated with the broad neurocognitive challenges faced by individuals with 22q11.2DS. [ABSTRACT FROM AUTHOR]

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]

Long noncoding RNAs (lncRNAs) are major components of cellular transcripts that are emerging as important players in various biological pathways. Due to their specific expression and functional diversity in a variety of cancers, lncRNAs have promising applications in cancer diagnosis, prognosis, and therapy. Studies have shown that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) with high specificity and accuracy has the potential to become biomarkers in cancers. LncRNA DGCR5 can be noninvasively extracted from body fluids, tissues, and cells, and can be used as independent or auxiliary biomarkers to improve the accuracy of diagnosis or prognosis. Now, the underlying mechanisms of lncRNAs such as DGCR5 were explored as therapeutic targets, which have been investigated in clinical trials of several cancers. The DGCR5 lacks an appropriate animal model, which is necessary to gain greater knowledge of their functions. While some studies on the uses of DGCR5 have been carried out, the small sample size makes them unreliable. In this review, we presented a compilation of recent publications addressing the potential of lncRNA DGCR5 that could be considered as biomarkers or therapeutic targets, with the hopes of providing promised implications for future cancer therapy. Significant statement: Long noncoding RNAs (lncRNAs) in the development and management of cancer have been the focus of many studies in recent years. LncRNAs have an enormous amount of potential for cancer diagnosis, prognosis, and treatment because of their highly specific expression and variety of activities. The research and development of DiGeorge syndrome critical region gene 5 (DGCR5) biomarkers is given novel possibilities by bioinformatics and computational tools. In this review, we presented a compilation of recent publications addressing the potential of lncRNA DGCR5 that could be considered as biomarkers or therapeutic targets, with the hopes of providing promised implications for future cancer therapy. [ABSTRACT FROM AUTHOR]

Summary: The thymus is the primary site of T‐cell development, enabling generation, and selection of a diverse repertoire of T cells that recognize non‐self, whilst remaining tolerant to self‐ antigens. Severe congenital disorders of thymic development (athymia) can be fatal if left untreated due to infections, and thymic tissue implantation is the only cure. While newborn screening for severe combined immune deficiency has allowed improved detection at birth of congenital athymia, thymic disorders acquired later in life are still underrecognized and assessing the quality of thymic function in such conditions remains a challenge. The thymus is sensitive to injury elicited from a variety of endogenous and exogenous factors, and its self‐renewal capacity decreases with age. Secondary and age‐related forms of thymic dysfunction may lead to an increased risk of infections, malignancy, and autoimmunity. Promising results have been obtained in preclinical models and clinical trials upon administration of soluble factors promoting thymic regeneration, but to date no therapy is approved for clinical use. In this review we provide a background on thymus development, function, and age‐related involution. We discuss disease mechanisms, diagnostic, and therapeutic approaches for primary and secondary thymic defects. [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]

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]

The DGCR8 gene, encoding a critical miRNA processing protein, maps within the hemizygous region in patients with 22q11.2 deletion syndrome. Most patients have malformations of the cardiac outflow tract that is derived in part from the anterior second heart field (aSHF) mesoderm. To understand the function of Dgcr8 in the aSHF, we inactivated it in mice using Mef2c-AHF-Cre. Inactivation resulted in a fully penetrant persistent truncus arteriosus and a hypoplastic right ventricle leading to lethality by E14.5. To understand the molecular mechanism for this phenotype, we performed gene expression profiling of the aSHF and the cardiac outflow tract with right ventricle in conditional null versus normal mouse littermates at stage E9.5 prior to morphology changes. We identified dysregulation of mRNA gene expression, of which some are relevant to cardiogenesis. Many pri-miRNA genes were strongly increased in expression in mutant embryos along with reduced expression of mature miRNA genes. We further examined the individual, mature miRNAs that were decreased in expression along with pri-miRNAs that were accumulated that could be direct effects due to loss of Dgcr8. Among these genes, were miR-1a, miR-133a, miR-134, miR143 and miR145a, which have known functions in heart development. These early mRNA and miRNA changes may in part, explain the first steps that lead to the resulting phenotype in Dgcr8 aSHF conditional mutant embryos. [Display omitted] • The DGCR8 gene encodes a miRNA processing protein. • DGCR8 is in the chromosome 22q11.2 region deleted in patients with 22q11.2DS. • Inactivation in the anterior second heart field results in severe heart defects. • Inactivation of Dgcr8 in mice causes dysregulation of cardiac gene expression. • miRNAs important for cardiac development are decreased in expression. The DGCR8 gene encodes a subunit of a protein complex that processes miRNAs and it is in the hemizygously deleted region on chromosome 22 in patients with 22q11.2 deletion syndrome (22q11.2DS). To understand the specific functions of Dgcr8 in mouse heart development, we inactivated it in the anterior second heart field. We found severe heart malformations, dysregulation of mRNA expression, increased expression of pri-miRNAs with decreased expression of mature miRNAs related to heart development. This work contributes to our understanding of DGCR8 functions in heart development in mammals. [ABSTRACT FROM AUTHOR]

Introduction: Persistent tympanic membrane perforation is a known complication of pressure-equalizing (PE) tube insertion. Conductive hearing loss and otorrhea can necessitate surgical repair of these perforations. Long-term tympanostomy tube placement can increase the risk of these complications. Patients with velocardiofacial syndrome (VCFS) typically require prolonged PE tube placement and are thought to have higher risk of requiring additional otologic interventions after PE tube placement. To date, no work has established rates of post-PE tube complications requiring myringoplasty or tympanoplasty in patients with VCFS. Methods: A retrospective case review including all patients with VCFS at a single large children's hospital between the years 2000 and 2020 was performed. Number of PE tube insertions required and additional otologic interventions performed were the primary endpoints assessed. Results: Of 212 total patients with VCFS, 66 (31%) underwent PE tube placement. Of these children, 46 (70%) required 2 or more sets of PE tubes. A total of 53 patients (80.3%) required no otologic interventions apart from PE tube insertions. Of the 13 patients (19.7%) requiring additional otologic surgery, 6 (9.5%) underwent myringoplasty, and 9 patients (13.6%) required tympanoplasty. There was no significant difference in tympanoplasty (P > 1), myringoplasty (P > 1), or other surgical intervention rates (P =.7464) between VCFS patients with any type of cleft palate versus those with anatomically normal palates. Conclusion: This work suggests that most VCFS patients that require tubes, require at least 2 sets of PE tubes, and that the rate of post-PE tube complications requiring further otologic surgery is an order of magnitude higher than the rate established at this institution. Counseling for PE tube placement in VCFS patients may require specific dialogue regarding the substantially increased risk of complications and effort to build appropriate expectations for surgical outcomes regardless of palatal status. [ABSTRACT FROM AUTHOR]

Aim: Rheumatoid arthritis (RA) inflicts chronic joint inflammation, leading to cartilage damage and potential disability. This study delves into the impact of fat mass and obesity‐associated protein (FTO) on the invasion and migration of fibroblast‐like synoviocytes (FLSs) in RA, aiming to identify a novel target for RA treatment. Methods: RA‐FLSs and control‐FLSs from RA patients and healthy controls were isolated and cultured. An FTO overexpression vector was constructed and transfected into RA‐FLSs, with subsequent measurement of FTO, miR‐126‐5p, and FOXO3 expression levels using quantitative real‐time polymerase chain reaction or western blot assays. The proliferation, invasion, and migration capabilities of RA‐FLSs were assessed. The total m6A modification of cellular mRNA was quantified. The interaction between m6A and DiGeorge syndrome critical region 8 (DGCR8) on pri‐miR‐126‐5p was evaluated using methylated RNA immunoprecipitation. The binding relationship between miR‐126‐5p and FOXO3 3′UTR sequence was verified. Results: FTO was downregulated in RA‐FLSs. FTO overexpression inhibited the invasion and migration of RA‐FLSs. FTO reduced the m6A modification level of pri‐miR‐126‐5p in RA‐FLSs, inhibiting miR‐126‐5p expression by reducing the binding of DGCR8 to pri‐miR‐126‐5p. miR‐126‐5p targeted and inhibited FOXO3 expression. Overexpression of miR‐126‐5p or FOXO3 knockdown could partially reverse FTO overexpression's inhibitory effect on the invasion and migration of RA‐FLSs. Conclusion: FTO overexpression curtailed miR‐126‐5p by diminishing the m6A modification level of pri‐miR‐126‐5p, subsequently enhancing FOXO3 expression and restraining the invasion and migration of RA‐FLSs. [ABSTRACT FROM AUTHOR]

Background: Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation. Objectives: Objectives of this study were to characterize the natural history, immune phenotype, and biomarkers in pDGS with AIC. Methods: Data on clinical presentation, disease severity, immunological phenotype, treatment selection, and response for patients with pDGS with AIC were collected via retrospective chart review. Flow cytometric analysis was done to assess T and B cell subsets, including biomarkers of immune dysregulation. Results: Twenty-nine patients with the diagnosis of pDGS and AIC were identified from 5 international institutions. Nineteen (62%) patients developed Evan's syndrome (ES) during their clinical course and twenty (69%) had antibody deficiency syndrome. These patients demonstrated expansion in T follicular helper cells, CD19hiCD21lo B cells, and double negative cells and reduction in CD4 naïve T cells and regulatory T cells. First-line treatment for 17/29 (59%) included corticosteroids and/or high-dose immunoglobulin replacement therapy. Other overlapping therapies included eltrombopag, rituximab, and T cell immunomodulators. Conclusions: AIC in pDGS is often refractory to conventional AIC treatment paradigms. Biomarkers may have utility for correlation with disease state and potentially even response to therapy. Immunomodulating therapies could be initiated early based on early immune phenotyping and biomarkers before the disease develops or significantly worsens. [ABSTRACT FROM AUTHOR]

The condition known as 22q11.2 deletion syndrome (MIM #188400) is a rare disease with a highly variable clinical presentation including more than 180 features; specific guidelines for screening individuals have been used to support clinical suspicion before confirmatory tests by Brazil's Craniofacial Project. Of the 2568 patients listed in the Brazilian Database on Craniofacial Anomalies, 43 individuals negative for the 22q11.2 deletion syndrome were further investigated through whole-exome sequencing. Three patients (6.7%) presented with heterozygous pathogenic variants in the KMT2A gene, including a novel variant (c.6158+1del) and two that had been previously reported (c.173dup and c.3241C>T); reverse phenotyping concluded that all three patients presented features of Wiedemann–Steiner syndrome, such as neurodevelopmental disorders and dysmorphic facial features (n = 3), hyperactivity and anxiety (n = 2), thick eyebrows and lower-limb hypertrichosis (n = 2), congenital heart disease (n = 1), short stature (n = 1), and velopharyngeal insufficiency (n = 2). Overlapping features between 22q11.2 deletion syndrome and Wiedemann–Steiner syndrome comprised neuropsychiatric disorders and dysmorphic characteristics involving the eyes and nose region; velopharyngeal insufficiency was seen in two patients and is an unreported finding in WDSTS. Therefore, we suggest that both conditions should be included in each other's differential diagnoses. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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]

In this Letter to the Editor, we present a case of 22q11.2 deletion syndrome that was diagnosed in an adolescent girl after the onset of acute catatonic symptoms. We discuss the challenges in diagnosing catatonia in children and patients with comorbid neurodevelopmental disorders (NDDs), especially in the setting of recent traumatic exposure. We then review treatment strategies in this patient population and conclude with our recommendations regarding genetic workup in acute catatonia. The patient and guardians have reviewed this article and provided informed consent for its publication. In addition, the authors used the CARE guidelines and checklist in writing this report (Supplement 1, available online). [ABSTRACT FROM AUTHOR]

Concurrent microduplication and microdeletion of the chromosome 22q11.2 region are a rarely reported phenomenon. We describe a case of germline 22q11.21 microduplication syndrome with concurrent mosaic 22q11.2 deletion in a pregnant patient, identified by chromosomal microarray and FISH after noninvasive prenatal genetic screening (cfDNA) results discordant with family history. The patient was referred to maternal-fetal medicine (MFM) at 14 weeks' gestation secondary to an SNP-based cfDNA result of a suspected maternal 22q11.2 deletion and a fetal risk of 1 in 2 for 22q11.2 deletion syndrome. The patient reported a similar cfDNA result in a previous pregnancy; however postnatal chromosomal microarray on that child identified an atypical 22q11.21 microduplication. We report the maternal chromosomal microarray findings of a germline 726 kb 22q11.21 duplication and a mosaic 1.33 Mb 22q11.2 deletion and highlight the copy number variant data generated by cfDNA in this unique case. This family adds to the limited literature of concurrent 22q11.2 microduplication and microdeletion carriers. [ABSTRACT FROM AUTHOR]

• 22q11.2 deletion syndrome is associated with a high prevalence of schizophrenia. • Inflammation and oxidative stress (OS) involve in schizophrenia's pathophysiology. • The relationship between OS, schizophrenia and 22q11.2DS has not been studied. • Individuals with 22q11.2DS had higher OS levels, compared to healthy controls. • PBMCs of individuals with 22q11.2DS were less resilient to the induction of OS. 22q11.2 Deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. This condition is associated with a wide range of symptoms including immune and neuropsychiatric disorders. Notably, psychotic disorders including schizophrenia have a prevalence of ∼ 30%. A growing body of evidence indicates that neuroinflammation and oxidative stress (OS) play a role in the pathophysiology of schizophrenia. In this study, we aim to assess the interaction between 22q11.2DS, OS and schizophrenia. Blood samples were collected from 125 participants (including individuals with 22q11.2DS [n = 73] and healthy controls [n = 52]) from two sites: Sheba Medical Center in Israel, and University Hospital Gasthuisberg in Belgium. Baseline OS levels were evaluated by measuring Myeloperoxidase (MPO) activity. A sub-sample of the Israeli sample (n = 50) was further analyzed to examine survival of Peripheral Blood Mononuclear Cells (PBMCs) following induction of OS using vitamin K3. The levels of MPO were significantly higher in all individuals with 22q11.2DS, compared to healthy controls (0.346 ± 0.256 vs. 0.252 ± 0.238, p =.004). In addition, when comparing to healthy controls, the PBMCs of individuals with 22q11.2DS were less resilient to induced OS, specifically the group diagnosed with psychotic disorder (0.233 ± 0.206 for the 22q11.2DS individuals with psychotic disorders, 0.678 ± 1.162 for the 22q11.2DS individuals without psychotic disorders, and 1.428 ± 1.359 for the healthy controls, p =.003, η2 = 0.207). Our results suggest that dysregulation of OS mechanisms may play a role in the pathophysiology of the 22q11.2DS phenotype. The 22q11.2DS individuals with psychotic disorders were more sensitive to induction of OS, but did not present significantly different levels of OS at baseline. These results may be due to the effect of antipsychotic treatment administered to this sup-group. By elucidating novel molecular pathways, early identification of biochemical risk markers for 22q11.2DS and psychotic disorders can be detected. This can ultimately pave the way to the design of early and more precise interventions of individuals with 22q11.2DS. [ABSTRACT FROM AUTHOR]

Background: The 22q11.2 deletion (22q11Del) is among the strongest known genetic risk factors for psychosis. Stress, a known risk factor for psychosis in the general population, has seldom been studied in 22q11Del. We investigated how lifetime stressors related to symptomatic outcomes in patients with 22q11Del. We also explored this association in individuals with 22q11.2 duplications (22q11Dup), which may be potentially protective against psychosis. Method: One hundred individuals (46 with 22q11Del, 30 with 22q11Dup, and 24 healthy controls; M age = 17.30 years±10.15) were included. Logistic models were used to examine cross-sectional associations between lifetime acute and chronic stressors (severity and count) and the presence (score ⩾3) of positive, negative, and general symptoms, assessed via the Structured Interview for Psychosis-risk Syndromes (SIPS). Results: The 22q11Dup group reported the greatest number and severity of acute lifetime stressors, but did not differ from 22q11Del in chronic stressor count or severity. Lifetime chronic and acute stressors were uniquely associated with positive symptoms in 22q11Del (chronic count: odds ratio [OR] = 2.35, p = 0.02; chronic severity: OR = 1.88, p = 0.03; acute count: OR = 1.78, p = 0.03), but not with negative or general symptoms (p s > 0.05). Conclusion: Findings suggest that stress may play a role in psychotic symptoms in 22q1Del, while the 22q11Dup CNV appears protective against psychotic symptoms despite higher rates of stressors. Interventions that mitigate effects of stressors in 22qDel may reduce the odds of psychosis in this group. Prospective longitudinal research is needed to replicate these findings. [ABSTRACT FROM AUTHOR]

Background: 22q11.2 Deletion Syndrome (22q11DS) is a genetic disorder characterized by the deletion of adjacent genes at a location specified as q11.2 of chromosome 22, resulting in an array of clinical phenotypes including autistic spectrum disorder, schizophrenia, congenital heart defects, and immune deficiency. Many characteristics of the disorder are known, such as the phenotypic variability of the disease and the biological processes associated with it; however, the exact and systemic molecular mechanisms between the deleted area and its resulting clinical phenotypic expression, for example that of neuropsychiatric diseases, are not yet fully understood. Results: Using previously published transcriptomics data (GEO:GSE59216), we constructed two datasets: one set compares 22q11DS patients experiencing neuropsychiatric diseases versus healthy controls, and the other set 22q11DS patients without neuropsychiatric diseases versus healthy controls. We modified and applied the pathway interaction method, originally proposed by Kelder et al. (2011), on a network created using the WikiPathways pathway repository and the STRING protein-protein interaction database. We identified genes and biological processes that were exclusively associated with the development of neuropsychiatric diseases among the 22q11DS patients. Compared with the 22q11DS patients without neuropsychiatric diseases, patients experiencing neuropsychiatric diseases showed significant overrepresentation of regulated genes involving the natural killer cell function and the PI3K/Akt signalling pathway, with affected genes being closely associated with downregulation of CRK like proto-oncogene adaptor protein. Both the pathway interaction and the pathway overrepresentation analysis observed the disruption of the same biological processes, even though the exact lists of genes collected by the two methods were different. Conclusions: Using the pathway interaction method, we were able to detect a molecular network that could possibly explain the development of neuropsychiatric diseases among the 22q11DS patients. This way, our method was able to complement the pathway overrepresentation analysis, by filling the knowledge gaps on how the affected pathways are linked to the original deletion on chromosome 22. We expect our pathway interaction method could be used for problems with similar contexts, where complex genetic mechanisms need to be identified to explain the resulting phenotypic plasticity. [ABSTRACT FROM AUTHOR]

Objective: 22q11.2 Deletion Syndrome (22q11DS) results in physical, cognitive, and behavioral issues. Although it is the most common microdeletion syndrome, there remains a high prevalence of delayed diagnosis. Its heterogeneous phenotypic presentation lead to differing considerations for early diagnostic identification. If initial symptomatology includes behavioral and cognitive disturbance, it is likely for such individuals to be referred first for neuropsychological testing before genetic testing. This case will expand upon diagnostic identification of 22q11DS. Method: A 12-year-old, 5-years educated, white female was seen for tele-neuropsychological evaluation due to COVID-19 restrictions in December 2020. Patient's mother reported concern regarding sudden and worsening behavioral changes including hallucinations, unusual affects, odd beliefs, academic decline, illegible handwriting, attention and memory issues, and behavioral problems in school to the point of removal. Results: Overall performance on the Meyers Neuropsychological Battery was severely impaired. See uploaded image file for specific test findings. Speech, affect, and behavior were notable during examination. Diagnoses included schizophrenia (provisional) and specific learning disorder with reading impairment (historical). Immediate neurology consultation was recommended. Later EEG, brain MRI, and CSF were unremarkable. Acute metabolic etiology was ruled out. Subsequent genetic testing revealed 22q11DS. Conclusions: Diagnostic identification of 22q11DS and resulting access to care management heavily depends on initial symptom presentation. In this specific case, the COVID-19 lockdown created barrier to sufficient services. This case expands upon knowledge of the cognitive profile of 22q11DS and calls upon increased awareness. Targeted improvement of neurocognition potentially protects against cognitive decline related to psychotic symptoms, and thus neuropsychologists play a vital role in referral to such resources. [ABSTRACT FROM AUTHOR]

Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) exhibit impaired ability to process and understand emotions in others. We measured structural connectivity in children and adolescents with 22q11.2DS (n = 28) and healthy controls (n = 29). Compared to controls, those with 22q11.2DS had poorer social skills and more difficulty recognizing facial emotions. Children with 22q11.2DS also had higher fractional anisotropic diffusion in right amygdala to fusiform gyrus white matter pathways. Right amygdala to fusiform gyrus fractional anisotropy values partially mediated the relationship between 22q11.2DS and social skills, as well as the relationship between 22q11.2DS and emotion recognition accuracy. These findings provide insight into the neural origins of social skills deficits seen in 22q11.2DS and may serve as a biomarker for risk of future psychiatric problems. [ABSTRACT FROM AUTHOR]

Abnormal neurotransmitter levels have been reported in individuals at high risk for schizophrenia, leading to a shift in the excitatory/inhibitory balance. However, it is unclear whether these alterations predate the onset of clinically relevant symptoms. Our aim was to explore in vivo measures of excitatory/inhibitory balance in 22q11.2 deletion carriers, a population at genetic risk for psychosis. Glx (glutamate+glutamine) and GABA+ (gamma-aminobutyric acid with macromolecules and homocarnosine) concentrations were estimated in the anterior cingulate cortex, superior temporal cortex, and hippocampus using the Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and the Gannet toolbox in 52 deletion carriers and 42 control participants. T1-weighted images were acquired longitudinally and processed with FreeSurfer version 6 to extract hippocampal volume. Subgroup analyses were conducted in deletion carriers with psychotic symptoms. While no differences were found in the anterior cingulate cortex, deletion carriers had higher levels of Glx in the hippocampus and superior temporal cortex and lower levels of GABA+ in the hippocampus than control participants. We additionally found a higher Glx concentration in the hippocampus of deletion carriers with psychotic symptoms. Finally, more pronounced hippocampal atrophy was significantly associated with increased Glx levels in deletion carriers. We provide evidence for an excitatory/inhibitory imbalance in temporal brain structures of deletion carriers, with a further hippocampal Glx increase in individuals with psychotic symptoms that was associated with hippocampal atrophy. These results are in line with theories proposing abnormally enhanced glutamate levels as a mechanistic explanation for hippocampal atrophy via excitotoxicity. Our results highlight a central role of glutamate in the hippocampus of individuals at genetic risk for schizophrenia. [ABSTRACT FROM AUTHOR]

TANGO2 deficiency disorder is a rare genetic disease caused by biallelic defects in TANGO2 gene. We report the clinical phenotype of two children with TANGO2 deficiency disorder. Patient 1 is a female child presenting with developmental delay and microcephaly during the second year of life, who evolved with severe cognitive impairment, facial dysmorphisms, spastic paraparesis, and atonic seizures. At age 13 years, she was hospitalized due to an episode of rhabdomyolysis complicated with cardiac arrhythmia and hypothyroidism. Patient 2 is a female child with dysmorphic facial features, cleft palate, and developmental delay who was diagnosed with DiGeorge syndrome. At age three years, she presented with an acute episode of severe rhabdomyolysis in the context of human herpesvirus 6 infection. After the resolution of this acute episode, she maintained recurrent muscle weakness with axial hypotonia and progressive spasticity of the lower extremities. In both patients, diagnosis of TANGO2 deficiency disorder was only confirmed after an acute metabolic crisis. A high index of suspicion for TANGO2 deficiency disorder is needed in patients with developmental delay or other neurological symptoms and episodic rhabdomyolysis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Cognitive and motor functions are modulated by dopaminergic signalling, which is shaped by several genetic factors. The biological effects of single genetic variants might differ depending on epistatic interactions that can be functionally multi‐directional and non‐linear. Experimental Approach: We performed behavioural and neurochemical assessments in genetically modified mice and behavioural assessments and genetic screening in human patients with 22q11.2 deletion syndrome (22q11.2DS). Key Results: Here, we confirm a genetic interaction between the Comt (catechol‐O‐methyltransferase, human orthologue: COMT) and Dtnbp1 (dystrobrevin binding protein 1, alias dysbindin, human orthologue: DTNBP1) genes that modulate cortical and striatal dopaminergic signalling in a manner not predictable by the effects of each single gene. In mice, Comt‐by‐Dtnbp1 concomitant reduction leads to a hypoactive mesocortical and a hyperactive mesostriatal dopamine pathway, associated with specific cognitive abnormalities. Like mice, in subjects with the 22q11.2DS (characterized by COMT hemideletion and dopamine alterations), COMT‐by‐DTNBP1 concomitant reduction was associated with analogous cognitive disturbances. We then developed an easy and inexpensive colourimetric kit for the genetic screening of common COMT and DTNBP1 functional genetic variants for clinical application. Conclusions and Implications: These findings illustrate an epistatic interaction of two dopamine‐related genes and their functional effects, supporting the need to address genetic interaction mechanisms at the base of complex behavioural traits. [ABSTRACT FROM AUTHOR]

The article describes a case of respiratory distress and hypocalcemia in a 2-week-old boy, leading to the diagnosis of DiGeorge syndrome, emphasizing the importance of considering a wide range of differentials for electrolyte imbalances in infants. Topics include differential diagnosis of hypocalcemia in newborns, phenotypic features and diagnostic workup of DiGeorge syndrome, and the necessity of a multidisciplinary approach in managing associated abnormalities.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Ventricular dysfunction and cardiac arrhythmias are well-documented complications in patients with repaired TOF. Whether intrinsic abnormalities exist in TOF cardiomyocytes is unknown. We establish human induced pluripotent stem cells (hiPSCs) from TOF patients with and without DiGeorge (DG) syndrome, the latter being the most commonly associated syndromal association of TOF. TOF-DG hiPSC-derived cardiomyocytes (hiPSC-CMs) show impaired ventricular specification, downregulated cardiac gene expression and upregulated neural gene expression. Transcriptomic profiling of the in vitro cardiac progenitors reveals early bifurcation, as marked by ectopic RGS13 expression, in the trajectory of TOF-DG-hiPSC cardiac differentiation. Functional assessments further reveal increased arrhythmogenicity in TOF-DG-hiPSC-CMs. These findings are found only in the TOF-DG but not TOF-with no DG (ND) patient-derived hiPSC-CMs and cardiac progenitors (CPs), which have implications on the worse clinical outcomes of TOF-DG patients. Using hiPSC, the authors report impaired ventricular specification, altered cardiac gene expression and ectopic neuronal gene expression in tetralogy of Fallot with DiGeorge syndrome cardiomyocytes (TOF-DG-hiPSC-CMs) and increased arrhythmogenicity in cardiac anisotropic sheet derived from TOF-DG-hiPSC-CMs. [ABSTRACT FROM AUTHOR]

Objective: 22q11.2 deletion syndrome (22q11.2 DS) is the most common chromosomal microdeletion disorder. Associated problems in 22q11.2 DS may include cardiac abnormalities, immune dysfunction, facial dysmorphism, with endocrine, genitourinary and gastrointestinal problems, and developmental delay. The aim of this study was to evaluate and present all endocrinological findings of patients with 22q11.2 DS from a single center. Methods: All participants had confirmed 22q11.2 DS by fluorescence in situ hybridization with hypoparathyroidism. Data were retrieved by retrospective review of patient records. Results: A total of 17 patients were reviewed. On physical examination, all patients had similar dysmorphic features. The median age at diagnosis was 45 days (1 day-13 years). Most cases (64.7%, 11/17) were diagnosed with hypoparathyroidism incidentally after routine tests. At the time of diagnosis, mean calcium was 7.04±0.80 mg/dL, phosphorus was 6.2±1.1 mg/dL, and median parathyroid hormone (PTH) was 11.5 (3.7-47.6) ng/L. Transient hypoparathyroidism was detected in five cases (29.4%). There was no significant difference between patients with permanent or transient hypoparathyroidism regarding gender, age at diagnosis, calcium, phosphorus, and PTH levels. However, vitamin D levels were significantly lower in the transient group (p=0.036). During follow-up, short stature, obesity, and type 2 diabetes mellitus were absent. Thyroid autoantibodies were detected in two patients with normal thyroid function tests. Despite there being no pathological short stature, final stature was shorter than the general population (mean height standard deviation score: -0.94±0.83). Conclusion: Hypocalcemia may be detected during acute illness in some cases where hypocalcemia appears at later ages. There was no significant difference between permanent and transient hypoparathyroidism cases in terms of PTH level. Recognition of the more specific facial findings is important to trigger investigation of genetic variants, additional anomalies, and for follow-up. [ABSTRACT FROM AUTHOR]

Background: Most individuals with 22q11.2 deletion syndrome (22q11DS) have multi‐system and lifelong needs requiring substantial support. Their primary caregivers are usually family members who dedicate lifelong time and effort to their role. The pressures of their roles can negatively impact caregivers' psychosocial well‐being, suggesting a need for additional support for this community who currently have no specialised interventions available. Method: This online study surveyed 103 caregivers of family members with 22q11DS to determine the barriers to accessing support that they faced, the kind of support they would value and whether an online intervention could meet their needs. Results: The caregivers indicated that a brief online intervention focused on teaching practical skills and connecting them with a peer network of support would be most valuable. Conclusions: Future studies are planned that will build on these results by designing and testing online interventions tailored to this community. [ABSTRACT FROM AUTHOR]

Patients with the 22q11.2 deletion syndrome (DS) show an increased risk of developing a psychotic illness lifetime. 22q11.2DS may represent a reliable model for studying the neurobiological underpinnings of schizophrenia. The study of social inference abilities in a genetic condition at high risk for psychosis, like 22q11.2DS, may shed light on the relationships between neurocognitive processes and patients' daily general functioning. The study sample consisted of 1736 participants, divided into four groups: 22q11.2DS patients with diagnosis of psychotic disorder (DEL SCZ, N = 20); 22q11.2DS subjects with no diagnosis of psychosis (DEL, N = 43); patients diagnosed with schizophrenia without 22q11.2DS (SCZ, N = 893); and healthy controls (HC, N = 780). Social cognition was assessed through The Awareness of Social Inference Test (TASIT) and general functioning through the Specific Levels of Functioning (SLoF) scale. We analysed data through regression analysis. The SCZ and DEL groups had similar levels of global functioning; they both had significantly lower SLoF Total scores than HC (p <.001); the DEL SCZ group showed significantly lower scores compared to the other groups (SCZ, p =.004; DEL, p =.003; HC, p <.001). A significant deficit in social cognition was observed in the three clinical groups. In the DEL SCZ and SCZ groups, TASIT scores significantly predicted global functioning (p <.05). Our findings of social cognition deficit in psychosis‐prone patients point to the possible future adoption of rehabilitation programmes, like Social Skills Training and Cognitive Remediation, during premorbid stages of psychosis. [ABSTRACT FROM AUTHOR]

22q11.2 deletion syndrome (22qDS) has been associated with varying levels of social impairments, and with atypical visual scanning of faces. The present study explored whether self-reported sensitivity to eye contact might be related to these phenomena. Individuals with confirmed 22qDS were interviewed about their experience and possible discomfort with eye contact. In cases where individuals expresesed discomfort, they were subsequently asked about coping mechanisms used to deal with this discomfort. In addition to self-reported eye contact discomfort, gaze to emotional faces was examined using eye tracking. In the subgroup of individuals who reported discomfort during eye contact, eye tracking results revealed a lower amount of gaze in the eyes of neutral faces, as well as the absence of the typical left visual field (LVF) bias, indicative of alterations in hemispheric lateralization. This subgroup also scored lower on a measure of everyday functioning. Our results show that, by simply asking individuals with this social and communicative disorder about eye gaze discomfort, we may better understand the specific challenges that they experience. Moreover, information gained from such first-person reports together with eye-tracking measures further informs about the integrity of their face processing system, as well as about the nature and degree of impairment in this population. [ABSTRACT FROM AUTHOR]

A meta‐analysis on seven large case series (>1000 cases) of chromosome microarray analysis (CMA) on products of conceptions (POC) evaluated the diagnostic yields of genomic disorders and syndromic pathogenic copy number variants (pCNVs) from a collection of 35,130 POC cases. CMA detected chromosomal abnormalities and pCNVs in approximately 50% and 2.5% of cases, respectively. The genomic disorders and syndromic pCNVs accounted for 31% of the detected pCNVs, and their incidences in POC ranged from 1/750 to 1/12,000. The newborn incidences of these genomic disorders and syndromic pCNVs were estimated in a range of 1/4000 to 1/50,000 live births from population genetic studies and diagnostic yields of a large case series of 32,587 pediatric patients. The risk of spontaneous abortion (SAB) for DiGeorge syndrome (DGS), Wolf–Hirschhorn syndrome (WHS), and William–Beuren syndrome (WBS) was 42%, 33%, and 21%, respectively. The estimated overall risk of SAB for major genomic disorders and syndromic pCNVs was approximately 38%, which was significantly lower than the 94% overall risk of SAB for chromosomal abnormalities. Further classification on levels of risk of SAB to high (>75%), intermediate (51%–75%), and low (26%–50%) for known chromosomal abnormalities, genomic disorders, and syndromic pCNVs could provide evidence‐based interpretation in prenatal diagnosis and genetic counseling. [ABSTRACT FROM AUTHOR]

This study examined the associations of parents' expressed emotion (EE) and parenting stress, with behavioral problems of children with 22q11.2 deletion syndrome, idiopathic autism (iASD) and typically developing (TD) children. Parents of children aged 3–8 years completed the five-minute-speech-sample (FMSS), parental stress index and children behavioral checklist. Parents' FMSS-EE-criticism was higher among parents of children with 22q11DS and iASD compared to parents of TD children. FMSS-EE scores predicted children's behavioral problems, above and beyond parenting stress. The associations between FMSS-EE, parenting stress and children's behavioral problems were consistent across 22q11DS, iASD and TD children. These findings highlight the need for targeting parents' EE and parenting stress as integral elements in the screening and prevention of behavioral problems of young children with 22q11DS and iASD. [ABSTRACT FROM AUTHOR]

The thymus is an organ that plays a critical role in the production of T-cells, which are important for immune functions. Serious consequences can arise if thymic homeostasis is not properly regulated. Therefore, it is necessary to fully understand the thymic environment that induces and supports T-cell development. The most severe thymic defects causing thymic aplasia, as well as disorders affecting the development and function of thymic stromal cells, result in immunodeficiency and autoimmunity. Thymic transplantation can save the lives of athymic patients with severe T-cell lymphopenia and provide the necessary immune reconstitution to prevent infectious complications. Early diagnosis and prophylactic treatments will reduce the frequency of infections in affected individuals as the use of neonatal screening programs for T-cell deficiencies becomes more widespread. [ABSTRACT FROM AUTHOR]

Background: Dendritic spines are the sites of excitatory synapses on pyramidal neurons, and their development is crucial for neural circuits and brain functions. The spine shape, size, or number alterations are associated with neurological disorders, including schizophrenia. DiGeorge syndrome critical region gene 2 (DGCR2) is one of the deleted genes within the 22q11.2 deletion syndrome (22q11DS), which is a high risk for developing schizophrenia. DGCR2 expression was reduced in schizophrenics. However, the pathophysiological mechanism of DGCR2 in schizophrenia or 22q11DS is still unclear. Results: Here, we report that DGCR2 expression was increased during the neurodevelopmental period and enriched in the postsynaptic densities (PSDs). DGCR2-deficient hippocampal neurons formed fewer spines. In agreement, glutamatergic transmission and synaptic plasticity were decreased in the hippocampus of DGCR2-deficient mice. Further molecular studies showed that the extracellular domain (ECD) of DGCR2 is responsible for its transcellular interaction with cell adhesion molecule Neurexin1 (NRXN1) and spine development. Consequently, abnormal behaviors, like anxiety, were observed in DGCR2-deficient mice. Conclusions: These observations indicate that DGCR2 is a novel cell adhesion molecule required for spine development and synaptic plasticity, and its deficiency induces abnormal behaviors in mice. This study provides a potential pathophysiological mechanism of DGCR2 in 22q11DS and related mental disorders. [ABSTRACT FROM AUTHOR]