Consequences of the 16p11.2 microdeletion on transcription in developing human GABAergic neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB46758 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR6395390.fastq.gz | Fastqsanger.gz | |||
| ERR6395391.fastq.gz | Fastqsanger.gz | |||
| ERR6395386.fastq.gz | Fastqsanger.gz | |||
| ERR6395387.fastq.gz | Fastqsanger.gz | |||
| ERR6395388.fastq.gz | Fastqsanger.gz |
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Project description:The study presents three cases of patients with deletions within 16p11.2 regions. Every child had characteristic craniofacial dysmorphic features and hand or feet abnormalities. The first proband had additionally obesity, epilepsy, moderate intellectual disability, aphasia, motor delay, hyperinsulinism and café au lait spots. The second proband suffered from cardiac, pulmonary and hematological problems. The third proband had motor delay, bronchial asthma and umbilical hernia. Although each patient presented characteristic features of the syndrome, children differed in clinical pictures among themselves. The genetic diagnosis of the 16p11.2 deletion syndrome was made in children at different age, based on the multiplex ligation probe-dependent amplification (MLPA) analysis and/or microarrays methods. This study highlights the impact of the size of deleted regions, as they may affect the clinical picture of patients with 16p11.2 microdeletion syndrome. Reported cases indicates the key role of the interdisciplinary approach in 16p11.2 microdeletion syndrome diagnostics, as the care of patients with this deletion is based on regular health assessment and adjustment of the nervous system development therapy
2020-10-07 | GSE159129 | GEO
Project description:Clinical and molecular characterization of patients with 16p11.2 microdeletion syndrome
| PRJNA667734 | ENA
Project description:Background: Chromosomal 16p11.2 deletions and duplications are genomic disorders which are characterized by neurobehavioral abnormalities, obesity, congenital abnormalities and so on. However, the prenatal phenotypes of 16p11.2 copy number variations (CNVs) are still not well described till now. This study aimed to provide an elaborate summary of intrauterine phenotypic features for such genomic disorders. Methods: Twenty prenatal amniotic fluid samples diagnosed with 16p11.2 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed in parallel. The pregnancy outcomes and health conditions after birth for all cases were followed up. Meanwhile, we made a pooled analysis on the prenatal phenotypes for the published cases carrying 16p11.2 CNVs. Results: 20 fetuses (20/20884, 0.10%) with 16p11.2 CNVs were identified: five 16p11.2 BP2-BP3 deletion, ten 16p11.2 BP4-BP5 deletion and five 16p11.2 BP4-BP5 duplication. Abnormal ultrasound findings were recorded in ten participants with 16p11.2 deletions.Various degrees of intrauterine phenotypic features, ranging from normal to abnormal, were observed. No ultrasound abnormalities were observed for all 16p11.2 duplication cases during the pregnancy period. For 16p11.2 deletions, eleven cases terminated their pregnancies. For 16p11.2 duplications, four cases gave birth to healthy neonates except one was lost to follow up. Conclusions: Diverse prenatal phenotypes were presented in 16p11.2 CNVs, ranging from normal to abnormal. For 16p11.2 BP4-BP5 deletion, the most common structural and non-structural abnormalities were the abnormality of the vertebral column or rib and thickened nuchal translucency, respectively. 16p11.2 BP2-BP3 deletion might be closely associated with fetal growth restriction and single umbilical artery. No representative ultrasound findings for 16p11.2 duplication were observed till now. Considering the variable expressivity and incomplete penetrance of 16p11.2 CNVs, long term follow up after birth should be carried out for these cases. We identified 20 fetuses carrying the 16p11.2 microdeletions and microduplications using chromosomal microarray analysis. And diverse prenatal phenotypes and the critical genes involved in the deleted/duplicated regions were described in this study.
2024-04-29 | GSE265911 | GEO
Project description:Prenatal phenotypes and pregnancy outcomes of fetuses with 16p11.2 microdeletion/microduplication
| PRJNA1104671 | ENA
Project description:The human 16p11.2 gene locus is a hot spot for copy number variations, which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity, or motor impairment. Electrophysiological recordings of 16p11.2dp/+ mice found deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2dp/+ mice ameliorated the social and cognitive deficits and reversed GABAergic synaptic impairment and neuronal hyperexcitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.
2020-07-27 | GSE155131 | GEO
Project description:The 600kb BP4-BP5 16p11.2 CNV (copy number variant) is associated with neuroanatomical, neurocognitive and metabolic disorders. These recurrent rearrangements are associated with reciprocal phenotypes such as obesity and underweight, macro- and microcephaly, as well as autism spectrum disorder (ASD) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal CNVs in 16p11.2. The genome-wide transcript perturbations correlated with clinical endophenotypes of the CNV and were enriched for genes associated with ASD. We uncovered a significant correlation between copy number changes and expression levels of genes mutated in ciliopathies. Transcriptome profiles of lymphoblastoid cell lines of 50 16p11.2 deletion carriers, 31 16p11.2 duplication carriers and 17 controls.
2015-05-10 | E-GEOD-57802 | biostudies-arrayexpress
Project description:single-cell RNA sequencing data (plate-based CelSeq2) of developing mouse ventral midbrain GABAergic neurons. vmbGABA series contains E16 and P0 VGAT mouse ventral midbrain and E16 and P0 VGAT/PITX3 co-expressing mouse ventral midbrain.
2024-10-08 | GSE268378 | GEO
Project description:Microdeletions and microduplications of the 16p11.2 chromosomal locus are implicated in a collection of neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations of these phenotypes, we generated 65 clones of human induced pluripotent stem cells (hiPSCs) from 13 individuals with 16p11.2 copy number variations (CNVs) and made each clone available by request from the Simons Foundation Autism Research Initiative (SFARI). Here we report on pluripotency, vector silencing, CNV breakpoint location, inter-clonal relatedness, and differentiation capacity for a majority of the available hiPSC clones. Comprehensive demographic and diagnostic data were collected and tabulated to facilitate investigation across a spectrum of pathologies. We demonstrate a customizable bioinformatic strategy for enhanced detection of the effects of episomal reprogramming and use this tool to identify a subset of clones free of off-target effects on neural progenitor gene transcription and phenotypic variation . With cortical neural progenitor cells (NPCs) derived from these hiPSCs, we identified a set of genes modulated by 16p11.2 deletion that precede morphological abnormalities reported at more mature developmental stages. This publicly available resource of 65 human hiPSC clones will serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.
2020-12-03 | GSE144736 | GEO
Project description:Background - Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human iPSC-derived neurons (iNs) has emerged as a promising strategy. Copy number variations (CNV) confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing risk 14.5 fold. Methods - To dissect the contribution of excitatory (iENs) versus GABAergic (iGNs) neurons to SCZ pathophysiology, we induced iNs from CRISPR-Cas9 engineered isogenic and SCZ patient-derived iPSCs, and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures. Results - In iEN/iGN cocultures, we found reduced neuronal network firing rate and synchrony at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for excitatory neurons. Transcriptomic analysis of isogenic 16p11.2 duplication (DUP) iENs revealed pathway dysregulation related to neuroarchitecture and calcium ion binding. Consistent with this, isogenic DUP iENs showed reduced dendrite length and calcium imaging revealed deficits in calcium handling. Analysis of iENs from 16p11.2 duplication-carrying SCZ patients (SCZ) revealed overlapping deficits in network synchrony, dendrite arborization and calcium handling. Conclusions - Our results indicate 16p11.2 duplication-dependent alterations to SCZ neurodevelopment. Calcium ion binding was the only altered transcriptomic gene set shared between isogenic and patient-derived iENs, suggesting a central role of calcium signaling in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers and supports network synchrony and calcium handling as outcomes directly linked to this genetic mutation.
2022-10-13 | GSE215183 | GEO
Project description:Chromosome 16p11.2 reciprocal genomic disorder due to recurrent copy number variants (CNVs) involves intellectual disability, autism spectrum disorder (ASD), and schizophrenia but the responsible mechanisms are not known. To systemically dissect molecular effects, we performed transcriptome profiling of 350 libraries from six tissues (cortex, cerebellum, striatum, liver, brown fat, white fat) in mouse models harboring CNVs of the syntenic 7qF3 region, as well as cellular, transcriptional, and single-cell analyses in 54 isogenic neural stem cell, induced neuron, and cerebral organoid models of CRISPR-engineered 16p11.2 CNVs. Transcriptome-wide differentially expressed genes were largely tissue, cell-type, and dosage specific, though more effects were shared between deletion and duplication and across tissue than expected by chance. The broadest effects were observed in the cerebellum (2163 differentially expressed genes) and the greatest enrichments were associated with synaptic pathways in mouse cerebellum and human induced neurons. Pathway and co-expression analyses identified energy and RNA metabolism as shared processes and enrichment for ASD-associated/loss-of-function constraint/FMRP gene sets. Intriguingly, reciprocal 16p11.2 dosage changes resulted in consistent decrements in neurite and electrophysiological features, while single-cell profiling of organoids showed reciprocal alterations to the proportions of excitatory and inhibitory GABAergic neurons. Both neuronal ratios and gene expression changes in our organoid analyses point most directly to calretinin GABAergic inhibitory neurons and the excitatory/inhibitory balance as targets of disruption in 16p11.2 carriers that may contribute to changes in neurodevelopmental and cognitive function. Collectively, our data indicate the genomic disorder involves disruption of multiple contributing biological processes, with relative impacts that are context-specific.
2022-08-15 | GSE211103 | GEO