Buffering Mechanism in Aortic Arch Artery Formation and Congenital Heart Disease.

BACKGROUND: The resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease arising from defective morphogenesis of pharyngeal arch arteries (PAAs) and their derivatives. OBJECTIVE: To uncover mechanisms underlying the robustness of PAA morphogenesis. METHODS AND RESULTS: The second heart field (SHF) gives rise to the PAA endothelium. Here, we show that the number of SHF-derived endothelial cells (ECs) is regulated by VEGFR2 (vascular endothelial growth factor receptor 2) and Tbx1. Remarkably, when the SHF-derived EC number is decreased, PAA development can be rescued by the compensatory endothelium. Blocking such compensatory response leads to embryonic demise. To determine the source of compensating ECs and mechanisms regulating their recruitment, we investigated 3-dimensional EC connectivity, EC fate, and gene expression. Our studies demonstrate that the expression of VEGFR2 by the SHF is required for the differentiation of SHF-derived cells into PAA ECs. The deletion of 1 VEGFR2 allele (VEGFR2SHF-HET) reduces SHF contribution to the PAA endothelium, while the deletion of both alleles (VEGFR2SHF-KO) abolishes it. The decrease in SHF-derived ECs in VEGFR2SHF-HET and VEGFR2SHF-KO embryos is complemented by the recruitment of ECs from the nearby veins. Compensatory ECs contribute to PAA derivatives, giving rise to the endothelium of the aortic arch and the ductus in VEGFR2SHF-KO mutants. Blocking the compensatory response in VEGFR2SHF-KO mutants results in embryonic lethality shortly after mid-gestation. The compensatory ECs are absent in Tbx1± embryos, a model for 22q11 deletion syndrome, leading to unpredictable arch artery morphogenesis and congenital heart disease. Tbx1 regulates the recruitment of the compensatory endothelium in an SHF-noncell-autonomous manner. CONCLUSIONS: Our studies uncover a novel buffering mechanism underlying the resiliency of PAA development and remodeling.

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

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

Out of Line or Altered States? Neural Progenitors as a Target in a Polygenic Neurodevelopmental Disorder.

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

Preoperative Imaging in Patients with 22q11 Deletion Syndrome Undergoing Velopharyngeal Surgery.

OBJECTIVE: To evaluate the utility of preoperative imaging before velopharyngeal dysfunction (VPD) surgery in children with 22q11 Deletion Syndrome (22qDS) in evaluating internal carotid artery (ICA) medialization. DATA SOURCES: PubMed, Scopus, and CINAHL. REVIEW METHODS: Following PRISMA guidelines, a systematic review was performed. Studies of children with 22qDS who underwent preoperative imaging (MRA or CTA) to identify ICA anomalies were included. High-risk medialized ICAs were defined as either submucosal, retropharyngeal, Pfeiffer Grade III-IV, or <3 mm from the pharyngeal mucosa. Meta-analyses of proportions were performed. RESULTS: Eleven studies met inclusion criteria, comprising 398 patients with 22qDS (weighted mean age 7.6 years). In 372 patients with imaging, the rate of ICA medialization on imaging was 47.1% (95%CI 29.2-65.5), of which 46.3% (95%CI 27.4-65.8) were determined high risk. Operative plans were modified in 19.4% (95%CI 5.7-38.8) of 254 surgeries due to medialized ICA. In studies attempting to use nasopharyngoscopy pulsations to identify medialization for 214 patients, the true-positive rate was 53.9% (95%CI 27.5-79.2) and the false-positive rate was 16.2% (95%CI 7.9-26.8). Nine of eleven studies (81.8%) recommended universal preoperative imaging of the ICAs in children with 22qDS undergoing VPD surgery. No cases of perioperative bleeding secondary to ICA injury were identified. CONCLUSION: Although most studies endorse routine preoperative imaging to assess for ICA medialization in children with 22qDS undergoing VPD surgery, only a minority of these cases led to surgical modification. Additional studies are needed to compare outcomes in children with and without preoperative imaging given the low rates of ICA injury in the literature. LEVEL OF EVIDENCE: N/A Laryngoscope, 2023.

Risk of thyroid neoplasms in patients with 22q11.2 deletion and DiGeorge-like syndromes: an insight for follow-up.

Introduction: The chromosome 22q11.2 deletion syndrome comprises phenotypically similar diseases characterized by abnormal development of the third and fourth branchial arches, resulting in variable combinations of congenital heart defects, dysmorphisms, hypocalcemia, palatal dysfunction, developmental or neuropsychiatric disorders, and impairment of the immune system due to thymic dysfunction. Other genetic syndromes, often called DiGeorge-like, share clinical and immunological features with 22q11.2 deletion syndrome. This syndrome has been rarely associated with malignancies, mainly hematological but also hepatic, renal, and cerebral. Rarely, malignancies in the head and neck region have been described, although no aggregate of data on the development of thyroid neoplasms in patients with this clinical phenotype has been conducted so far. Materials and methods: To characterize this possible association, a multicenter survey was made. Thus, we present a case series of five pediatric patients with 22q11.2 deletion syndrome or DiGeorge-like syndrome who were occasionally found with confirmed or highly suspected neoplasms of the thyroid gland during their follow-up. In three cases, malignancies were histologically confirmed, but their outcome was good due to an early recognition of suspicious nodules and precocious surgery. Conclusions: This study underlines for clinicians the higher risk of neoplasms in the head and neck district for patients affected by these syndromes. It also emphasizes the importance of a prolonged clinical and ultrasound follow-up for patients with this clinical and immunological phenotype.

Bridging the Communication Gap Between People With Cognitive Impairments and Their Caregivers Using mHealth Apps: User-Centered Design and Evaluation Study With People With 22q11 Deletion Syndrome.

BACKGROUND: In families with children with cognitive impairments, both parents and children experience tension and have questions because of a lack of communication and adequate information. Therefore, there is a great need to develop tools that can help bridge the communication gap between patients and caregivers by stimulating conversations and providing psychoeducational tools. mHealth apps show great potential in this context. OBJECTIVE: The objective of this research is to discover the specific ways young people with cognitive impairments and their families interact with mHealth apps in the context of bridging the communication gap. This newly discovered information leads to potentially more impactful mHealth interventions in the future. Therefore, this paper documents the design and development of a mHealth app for a specific group of people with cognitive impairments-people with 22q11 deletion syndrome (22q11 DS)-and their caregivers, as well as key learnings from the evaluation of this app. METHODS: An iterative, user-centered design approach is used to design and develop the app. Design and evaluation happens in 2 phases. During the design phase, feedback is gathered from 2 medical experts and 3 human computer interaction (HCI) experts using a low-fidelity paper prototype. During the evaluation phase, feedback is gathered from 8 families with a child with 22q11 DS using a fully working proof of concept. This phase consists of a semistructured interview, a 2-4-week trial period, and a concluding semistructured interview. RESULTS: The evaluation results of the fully working proof of concept led to design recommendations related to four different topics: (1) overcoming usage barriers, (2) stimulating conversation through a mHealth app, (3) providing information, and (4) bringing continual added value. Results are presented according to six different categories obtained in a thematic analysis: (1) feedback about the app "as is," (2) difficulties, (3) comparison between physical and digital tool, (4) extensions, (5) intention, and (6) other. CONCLUSIONS: In this research, the need for apps that help bridge the communication gap between a person with cognitive impairment and their caregiver is confirmed. All participating families express their gratitude and mention the added value for other families. Therefore, it is highly encouraged for clinics and institutions to take action and develop an app to be used in practice. Furthermore, considerations when developing for people with 22q11 DS, or more broadly, people with cognitive impairments, are proposed. First, one should keep design principles in mind to overcome usage barriers. Next, recognition is a key concept when stimulating conversations through mobile apps. Third, information should be provided by a trusted source, and more than just clinical information can be considered valuable. Finally, having the possibility of using a digital tool that can be personalized brings continual added value.

Social cognition and real-life functioning in patient samples with 22q11.2 deletion syndrome with or without psychosis, compared to a large sample of patients with schizophrenia only and healthy controls.

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.

Endocrine Abnormalities and Growth Characterization in Colombian Pediatric Patients with 22q11 Deletion Syndrome

Objective: Several endocrine manifestations have been described in patients with 22q11 deletion syndrome, including growth retardation, hypoparathyroidism, and thyroid disorders. This study aimed to characterize these abnormalities in a Colombian retrospective cohort of children with this condition. Methods: A retrospective study comprising a cohort of children with 22q11 deletion syndrome in Medellín, Colombia followed up between 2011 and 2017 was conducted. Results: Thirty-seven patients with a confirmed diagnosis of 22q11 deletion syndrome were included. 37.8% had some endocrinopathy, the most frequent being hypoparathyroidism (21.6%), followed by hypothyroidism (13.5%), hyperthyroidism (2.7%) and growth hormone deficiency (2.7%). There was wide heterogeneity in the clinical presentation, with late onset of severe hypocalcemia associated with seizure or precipitated in postoperative cardiac surgery, which highlights the importance of continuous follow-up as indicated by the guidelines. Short stature was mainly related to nutritional factors. Growth monitoring is required with the use of syndrome-specific charts and careful monitoring of the growth rate. Conclusion: As previously reported, a significant proportion of patients with endocrine abnormalities were found in this cohort. This highlights that it is essential to carry out an adequate multidisciplinary follow-up, based on the specific clinical guidelines, in order to avoid serious complications such as convulsions due to hypocalcemia. It is important to track size with curves specific to the syndrome and analyze the growth rate.

Late-Onset 22q11.2 Deletion Syndrome With Mild Cardiac Phenotype: A Unique Adult Presentation Diagnosed at 45 Years of Age.

This case report presents a detailed exploration of an adult-onset 22q11 deletion syndrome, a rare genetic disorder typically diagnosed in children. The report highlights the diagnostic challenges posed by this atypical presentation, emphasizing the need for clinicians to consider such conditions in differential diagnoses, especially in adults. This case is remarkable for its late onset and mild symptoms, which significantly deviated from the common pediatric presentation, including hypocalcemia due to hypoparathyroidism and a fenestrated atrial septal defect without significant hemodynamic implications. The importance of recognizing the broad phenotypic variability of the syndrome and the implications for clinical practice are discussed, providing insights into the genetic and phenotypic diversity of the condition. In conclusion, this case illuminates the diverse clinical spectrum of adult-onset 22q11 deletion syndrome, emphasizing its relevance to clinical practice.

Effects of risperidone on psychotic symptoms and cognitive functions in 22q11.2 deletion syndrome: Results from a clinical trial.

Background: Carriers of the 22q11.2 deletion syndrome (22q11DS) have an enhanced risk of developing psychotic disorders. Full-blown psychosis is typically diagnosed by late adolescence/adulthood. However, cognitive decline is already apparent as early as childhood. Recent findings in mice show that antipsychotic medication administered during adolescence has a long-lasting neuroprotective effect. These findings offer promising evidence for implementing preventive treatment in humans at risk for psychosis. Methods: We conducted a 12-week double-blind randomized controlled clinical trial with individuals with 22q11DS. Recruitment difficulties resulted in a final sample size of 13 participants (n = 6 treated with antipsychotics and n = 7 receiving placebo). We examined the response to treatment and assessed its short- and long-term effects on psychotic symptomatology using the Structured Interview for Psychosis-Risk Syndromes (SIPS) and cognitive measures. Results: First, two treated participants discontinued treatment after experiencing adverse events. Second, treated participants showed a short-term improvement in 33.3% of the SIPS items, mainly those targeting negative symptoms. Third, reliable improvements in at least one measure of working memory and attention were respectively found in 83.3 and 66.7% of treated participants. Conclusion: This is the first double-blind study to investigate the potential neuroprotective effect of antipsychotics in humans at risk for psychosis. Our preliminary results suggest that antipsychotic treatment may prevent long-term deterioration in clinical symptoms and cognitive skills. Yet, given the limited sample size, our findings need to be replicated in larger samples. To do so, future studies may rather adopt open-label or retrospective designs to ensure sufficient power. Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT04639960].

Comunicación en personas con el síndrome de deleción de 22q11: voz y habla / Communication in people with 22q11 deletion syndrome: Voice and speech

Antecedentes y objetivos: En la actualidad hay pocos estudios que definan el perfil psicolingüístico de las personas con el síndrome de deleción de 22q11 (S22q11) con el castellano y/o el catalán como lengua materna. El objetivo de este estudio fue definir las características de la voz y el habla de las personas con el S22q11. Método: Se realizó un estudio con una muestra de 30 sujetos de entre 5 y 21 años (12.14±4.20) con S22q11. Se administraron cuestionarios ad hoc a los padres y se evaluó la voz, la ejecución de praxias bucofonatorias, la discriminación auditiva y el habla de los participantes. Resultados: Más de la mitad de los participantes tenían una voz más aguda de lo esperado por sexo y edad, y la mitad mostraba signos de hipofonía, a pesar de que los resultados de intensidad máxima mostraban que podrían utilizar una mayor intensidad. En cuanto al habla, los participantes más jóvenes presentaban un retraso en la adquisición de fonemas (excepto consonantes nasales) en comparación con su grupo normativo, y la mayoría hizo uso del sonido compensatorio ʔ. Los participantes mayores de 8 años producían correctamente los fonemas de adquisición tardía, aunque persistieron dificultades específicas de articulación. Conclusiones: Los participantes mostraron características específicas de voz y habla.(AU)

Background and objectives: Currently there are few studies that define the psycholinguistic profile of people with 22q11 deletion syndrome (S22q11) with Spanish and/or Catalan as their mother tongue. The aim of this study was to define the characteristics of the voice and speech of people with S22q11. Method: A study was performed with a sample of 30 subjects aged between 5 and 21 years (12.14±4.20) with S22q11. Ad hoc questionnaires were administered to parents, and participants’ voice, execution of oral praxis, hearing discrimination, and speech were assessed. Results: More than half of the participants had a sharper voice than expected by sex and age, and half showed signs of hypophonia, although the maximum intensity results showed that they could use more intensity. In terms of speech, the younger participants had a delay in the acquisition of phonemes (except nasal consonants) compared to their normative group, and most made use of the compensatory sound ʔ. Participants older than 8 years correctly produced late-acquisition phonemes, although specific articulation difficulties persisted. Conclusions: Participants showed specific voice and speech characteristics.(AU)

Neural substrates of psychosis revealed by altered dependencies between brain activity and white-matter architecture in individuals with 22q11 deletion syndrome.

BACKGROUND: Dysconnectivity has been consistently proposed as a major key mechanism in psychosis. Indeed, disruptions in large-scale structural and functional brain networks have been associated with psychotic symptoms. However, brain activity is largely constrained by underlying white matter pathways and the study of function-structure dependency, compared to conventional unimodal analysis, allows a biologically relevant assessment of neural mechanisms. The 22q11.2 deletion syndrome (22q11DS) constitutes a remarkable opportunity to study the pathophysiological processes of psychosis. METHODS: 58 healthy controls and 57 deletion carriers, aged from 16 to 32 years old,underwent resting-state functional and diffusion-weighted magnetic resonance imaging. Deletion carriers were additionally fully assessed for psychotic symptoms. Firstly, we used a graph signal processing method to combine brain activity and structural connectivity measures to obtain regional structural decoupling indexes (SDIs). We use SDI to assess the differences of functional structural dependency (FSD) across the groups. Subsequently we investigated how alterations in FSDs are associated with the severity of positive psychotic symptoms in participants with 22q11DS. RESULTS: In line with previous findings, participants in both groups showed a spatial gradient of FSD ranging from sensory-motor regions (stronger FSD) to regions involved in higher-order function (weaker FSD). Compared to controls, in participants with 22q11DS, and further in deletion carriers with more severe positive psychotic symptoms, the functional activity was more strongly dependent on the structure in parahippocampal gyrus and subcortical dopaminergic regions, while it was less dependent within the cingulate cortex. This analysis revealed group differences not otherwise detected when assessing the structural and functional nodal measures separately. CONCLUSIONS: Our findings point toward a disrupted modulation of functional activity on the underlying structure, which was further associated to psychopathology for candidate critical regions in 22q11DS. This study provides the first evidence for the clinical relevance of function-structure dependency and its contribution to the emergence of psychosis.

Synaptic Plasticity Dysfunctions in the Pathophysiology of 22q11 Deletion Syndrome: Is There a Role for Astrocytes?

The 22q11 deletion syndrome (DS) is the most common microdeletion syndrome in humans and gives a high probability of developing psychiatric disorders. Synaptic and neuronal malfunctions appear to be at the core of the symptoms presented by patients. In fact, it has long been suggested that the behavioural and cognitive impairments observed in 22q11DS are probably due to alterations in the mechanisms regulating synaptic function and plasticity. Often, synaptic changes are related to structural and functional changes observed in patients with cognitive dysfunctions, therefore suggesting that synaptic plasticity has a crucial role in the pathophysiology of the syndrome. Most interestingly, among the genes deleted in 22q11DS, six encode for mitochondrial proteins that, in mouse models, are highly expressed just after birth, when active synaptogenesis occurs, therefore indicating that mitochondrial processes are strictly related to synapse formation and maintenance of a correct synaptic signalling. Because correct synaptic functioning, not only requires correct neuronal function and metabolism, but also needs the active contribution of astrocytes, we summarize in this review recent studies showing the involvement of synaptic plasticity in the pathophysiology of 22q11DS and we discuss the relevance of mitochondria in these processes and the possible involvement of astrocytes.

Selective disruption of trigeminal sensory neurogenesis and differentiation in a mouse model of 22q11.2 deletion syndrome.

22q11.2 Deletion Syndrome (22q11DS) is a neurodevelopmental disorder associated with cranial nerve anomalies and disordered oropharyngeal function, including pediatric dysphagia. Using the LgDel 22q11DS mouse model, we investigated whether sensory neuron differentiation in the trigeminal ganglion (CNgV), which is essential for normal orofacial function, is disrupted. We did not detect changes in cranial placode cell translocation or neural crest migration at early stages of LgDel CNgV development. However, as the ganglion coalesces, proportions of placode-derived LgDel CNgV cells increase relative to neural crest cells. In addition, local aggregation of placode-derived cells increases and aggregation of neural crest-derived cells decreases in LgDel CNgV. This change in cell-cell relationships was accompanied by altered proliferation of placode-derived cells at embryonic day (E)9.5, and premature neurogenesis from neural crest-derived precursors, reflected by an increased frequency of asymmetric neurogenic divisions for neural crest-derived precursors by E10.5. These early differences in LgDel CNgV genesis prefigure changes in sensory neuron differentiation and gene expression by postnatal day 8, when early signs of cranial nerve dysfunction associated with pediatric dysphagia are observed in LgDel mice. Apparently, 22q11 deletion destabilizes CNgV sensory neuron genesis and differentiation by increasing variability in cell-cell interaction, proliferation and sensory neuron differentiation. This early developmental divergence and its consequences may contribute to oropharyngeal dysfunction, including suckling, feeding and swallowing disruptions at birth, and additional orofacial sensory/motor deficits throughout life.

A Case for Thalamic Mechanisms of Schizophrenia: Perspective From Modeling 22q11.2 Deletion Syndrome.

Schizophrenia is a severe, chronic psychiatric disorder that devastates the lives of millions of people worldwide. The disease is characterized by a constellation of symptoms, ranging from cognitive deficits, to social withdrawal, to hallucinations. Despite decades of research, our understanding of the neurobiology of the disease, specifically the neural circuits underlying schizophrenia symptoms, is still in the early stages. Consequently, the development of therapies continues to be stagnant, and overall prognosis is poor. The main obstacle to improving the treatment of schizophrenia is its multicausal, polygenic etiology, which is difficult to model. Clinical observations and the emergence of preclinical models of rare but well-defined genomic lesions that confer substantial risk of schizophrenia (e.g., 22q11.2 microdeletion) have highlighted the role of the thalamus in the disease. Here we review the literature on the molecular, cellular, and circuitry findings in schizophrenia and discuss the leading theories in the field, which point to abnormalities within the thalamus as potential pathogenic mechanisms of schizophrenia. We posit that synaptic dysfunction and oscillatory abnormalities in neural circuits involving projections from and within the thalamus, with a focus on the thalamocortical circuits, may underlie the psychotic (and possibly other) symptoms of schizophrenia.

Contribution of Congenital Heart Disorders Associated With Copy Number Variants in Mediating Risk for Brain Developmental Disorders: Evidence From 20-Year Retrospective Cohort Study.

Rare pathogenic copy number variants (CNVs) are genetic rearrangements that have been associated with an increased risk for congenital heart disorders (CHDs). However, the association of CNVs with atypical brain development, leading to neurodevelopmental disorders (NDDs), in the presence of CHDs remains unclear. We attempted to explore this association by establishing the prevalence and burden of CNVs associated with CHD in a Welsh population and by studying the effect of rare CNVs associated with CHDs in mediating the risk of NDDs. Toward this goal, we analyzed data from the Congenital Anomaly Register for Wales (CARIS), referred from hospitals in Wales between 1998 and 2018, which included 1,113 subjects in total. Of these, 785 subjects were included in the study following application of the exclusion criteria, and a total of 28 rare CNVs associated with CHD were analyzed. The findings from this cohort study identified 22q11.2 deletion as the most prominent CNV across the cohort. Our data demonstrates that the survival rate of the cohort after 3 years was 99.9%, and mortality fell significantly between 1 and 2 years and between 2 and 3 years [F (1,27) = 10, p = 0.0027; F (1,27) = 5.8, p = 0.0222]. Importantly, the data set revealed a positive correlation between the incidence of congenital heart disease and the incidence of neurodevelopmental abnormalities in patients with CNVs across the whole cohort [95% CI (0.4062, 0.8449), p < 0.0001, r = 0.6829]. Additionally, we identified significant CNVs that result in the co-morbidity of CHD and NDD and show that septal defects and global developmental delay are major congenital defects. Further research should identify a common molecular mechanism leading to the phenotypic comorbidity of CHDs and NDDs, arising from a common CNV, which can have an implication for improving risk classification and for fetal neuroprotection strategies in the affected children and in precision medicine.

Cardiac Defects and Genetic Syndromes: Old Uncertainties and New Insights.

Recent advances in understanding the genetic causes and anatomic subtypes of cardiac defects have revealed new links between genetic etiology, pathogenetic mechanisms and cardiac phenotypes. Although the same genetic background can result in different cardiac phenotypes, and similar phenotypes can be caused by different genetic causes, researchers' effort to identify specific genotype-phenotype correlations remains crucial. In this review, we report on recent advances in the cardiac pathogenesis of three genetic diseases: Down syndrome, del22q11.2 deletion syndrome and Ellis-Van Creveld syndrome. In these conditions, the frequent and specific association with congenital heart defects and the recent characterization of the underlying molecular events contributing to pathogenesis provide significant examples of genotype-phenotype correlations. Defining these correlations is expected to improve diagnosis and patient stratification, and it has relevant implications for patient management and potential therapeutic options.

Psychiatric phenotypes associated with hyperprolinemia: A systematic review.

Hyperprolinemia Type I and II are genetic metabolic disorders caused by disrupted proline degradation. It has been suggested that hyperprolinemia is associated with increased risk of developmental and mental disorders but detailed information on the psychiatric phenotype in hyperprolinemic patients is limited. Following PRISMA guidelines, we carried out a systematic review to clarify psychiatric phenotypes in patients with hyperprolinemia. We screened 1753 studies and included 35 for analysis, including 20 case reports and 15 case-control and cohort studies. From these studies, a common psychiatric phenotype is observed with a high prevalence of developmental delay, intellectual disability, autism spectrum disorders, and psychosis spectrum disorders. In most cases, a genetic cause of hyperprolinemia was known, these included mutations in the PRODH and ALDH4A1 genes and deletions of chromosome 22q11.2. No evidence for a biochemical phenotype-clinical phenotype correlation was found; that is, no association between higher proline levels and specific psychiatric phenotypes was observed. This suggests that genomic and environmental factors are likely to contribute to clinical outcomes. More studies are needed to clarify whether hyperprolinemia is a primary causal factor underlying the increased risk of developing psychiatric disorders seen in patients with hyperprolinemia, or whether hyperprolinemia and psychiatric disorders are both consequences of a shared underlying mechanism.

GATA 4 Deletions Associated with Congenital Heart Diseases in South Brazil.

The normal development of the heart comprises a highly regulated machinery of genetic events, involving transcriptional factors. Congenital heart disease (CHD), have been associated with chromosomal abnormalities and copy number variants (CNVs). Our goal was to investigate through the multiplex ligation-dependent probe amplification (MLPA) technique, the presence of CNVs in reference genes for normal cardiac development in patients with CHD. GATA4 , NKX2-5 , TBX5 , BMP4 , and CRELD1 genes and 22q11.2 chromosome region were analyzed in 207 children with CHD admitted for the first time in a cardiac intensive care unit from a pediatric hospital. CNVs were detected in seven patients (3.4%): four had a 22q11.2 deletion (22q11DS) (1.9%), two had a GATA4 deletion (1%) and one had a 22q11.2 duplication (0.5%). No patients with CNVs in the NKX2-5 , TBX5 , BMP4 , and CRELD1 genes were identified. GATA4 deletions appear to be present in a significant number of CHD patients, especially those with septal defects, persistent left superior vena cava, pulmonary artery abnormalities, and extracardiac findings. GATA4 screening seems to be more effective when directed to these CHDs. The investigation of CNVs in GATA4 and 22q11 chromosome region in patients with CHD is important to anticipating the diagnosis, and to contributing to family planning.