Transcriptome analysis of intellectual disability patients with mutation in transcription factor genes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE108887 | GEO | 2021/01/08
REPOSITORIES: GEO
Similar Datasets
Project description:Nonsense-mediated mRNA decay (NMD) functions to degrade transcripts bearing premature stop codon (PTC) and is a crucial regulator of gene expression. NMD and the UPF3B gene have been implicated as the cause of various forms of intellectual disability (ID) and other neurological symptoms. Here, we reports three patients with global developmental delay carrying hemizygous deletions of the UPF2 gene, another important member of the NMD pathway and direct interacting partner of UPF3B. Using RNA-SEQ on lymphoblastoid cells from UPF2 deletion patients, we identified 1009 differently expressed genes (DEGs). 38% of these DEGs overlapped with DEGs identified in UPF3B patients. More importantly, 95% of all DEGs in either UPF2 or UPF3B patients share the same trend of de-regulation. This demonstrates that the transcriptome deregulation in these two patient groups is similar and that UPF2 should be considered as a new candidate gene for ID in man. We expanded our inq`uiries and performed a comprehensive search for copy number variations (CNVs) encompassing all NMD genes in cohorts of ID patients and controls. We found that UPF2, UPF3A, Y14, SMG6 and EIF4A3 are frequently deleted and/or duplicated in ID patients. These CNVs are likely to be the root of the problems or to act as predisposing factors. Our results suggest that dosage imbalance of NMD factors is associated with ID and further emphasize the importance of NMD in normal learning and memory processes.
2012-12-31 | E-GEOD-35420 | biostudies-arrayexpress
Project description:Intellectual disability (ID) is a clinically important disease and a most prevalent neurodevelopmental disorder. The etiology and pathogenesis of ID are poorly recognized. Exome sequencing revealed a homozygous missense mutation in the POLR3B gene in a consanguineous family with three Intellectual disability with craniofacal anomalies patients. POLR3B gene encoding the second largest subunit of RNA polymerase III. To explore how genetic variants alter cell expression in ID patients, RNA sequencing on blood samples was performed and to obtain insights into the biological pathways influenced by POLR3B mutation, we applied our RNA-Seq data to several gene ontology programs such as ToppGene, Enrichr, KEGG. We detected a significant decrease expression of several spliceosomal RNAs, ribosomal proteins and transcription factors in our ID patients. We hypothesize that POLR3B mutation dysregulates the expression of some important transcription factors, ribosomal and spliceosomal genes and impairments in protein synthesis and splicing mediated in part by transcription factors such as FOXC2, GATA1, .. contribute to impaired neuronal function and concurrence of intellectual disability and craniofacial anomalies in our patients. Our study highlights the emerging role of spliceosome and ribosomal proteins in intellectual disability.
2022-04-27 | GSE184234 | GEO
Project description:Intellectual disability is a common condition that carries lifelong severe medical and developmental consequences. The causes of intellectual disability (ID) remain unknown for the majority of patients due to the extensive clinical and genetic heterogeneity of this disorder. De novo mutations may play an important role in ID as most individuals with ID present as isolated cases without family history and/or clear syndromic indication. In addition, the involvement of such mutations have recently been demonstrated in a small number of individuals with ID. Here we evaluate the diagnostic potential and role of de novo mutations in a cohort of 100 patients with ID of unknown cause using family-based exome sequencing. Single end short-read (50 bp) SOLiD 4 sequencing data for 300 individuals, constituting 100 patient-parent trios. For more details please read; http://www.nejm.org/doi/full/10.1056/NEJMoa1206524. Dataset is created by RUNMC (Radboud University, Nijmegen Medical Center), partner of Geuvadis consortium (http://www.geuvadis.org).
2013-11-06 | E-GEUV-5 | biostudies-arrayexpress
Project description:Objective: Intellectual disability (ID) is often sporadic, and its complex etiology can make clinical diagnosis difficult. The aims of this study were to detect genomic copy number variations (CNVs) in Chinese patients with ID, and to analyze the correlation between pathogenic CNVs and clinical phenotypes. Methods: After excluding cases of ID caused by chromosomal aneuploidy, metabolic dysfunction, or environmental factors, we enrolled 60 patients with moderate to severe ID. We performed karyotype and single-nucleotide polymorphism (SNP) array analyses for all patients. Finally, we analyzed the relationship between CNVs and phenotype using CNV databases and genotype-phenotype comparisons. Results: Karyotype analysis showed chromosomal terminal abnormalities in five patients and balanced translocations in two patients. Using SNP array analysis for 60 patients, we detected 87 CNVs in 45 patients, which included 16 pathogenic CNVs in 12 patients with a diagnostic yield of 20.0% (12/60). In one patient, we observed 14 regions of homozygosity > 10 Mb to 266 Mb. We detected a large deletion at 16q22.2 or 3q24q25 in each of two patients, in regions that have not previously been associated with specific syndromes. One case carried a 210-kb deletion at 1q21, including only one coding gene, LPPR4, which may be a candidate gene for the ID phenotype. Conclusions: Use of the genome-wide array screening method can improve the detection rate of CNVs, reveal chromosomal abnormalities that have not been well characterized by cytology, and provide a new way to locate genes for patients with the ID phenotype. However, interpretation of CNVs remains a major challenge, which is why we believe that publicly shared data on CNVs and phenotypes can create a rich database of information.
2019-06-15 | GSE83414 | GEO
Project description:Characterization of methylation changes related do KDM5C c.807delC (p.V271X) Mutations in KDM5C (lysine (K)-specific demethylase 5C) were associated to up to 3% of the X-linked ID cases. Males carrying KDM5C mutations present reduced activity of the KDM5C protein, increasing H3K4 tri-methylation, which ultimately leads to up-regulation of KDM5C target genes. Whole-exome sequencingi n one of three brothers with intellectual disability followed by confirmation by Sanger sequencing in the family identified a frameshift mutation in the KDM5C exon 7 that devoid of the JmjC catalytic domain from the protein. Two other brothers also presenting intellectual disability as well as in their clinically normal mother, who had completely skewed X-inactivation also had the mutation. An empirical Bayesian analysis of methylation levels between cases and controls identified 399 differentially methylated positions, 288 hypomethylated and 111 hypermethylated.Among the genes associated with the hypomethylated CpGs were FBXL5 and CACYBP, both involved in the ubiquitination pathway.
2018-11-30 | GSE108423 | GEO
Project description:Nonsense-mediated mRNA decay (NMD) functions to degrade transcripts bearing premature stop codon (PTC) and is a crucial regulator of gene expression. NMD and the UPF3B gene have been implicated as the cause of various forms of intellectual disability (ID) and other neurological symptoms. Here, we reports three patients with global developmental delay carrying hemizygous deletions of the UPF2 gene, another important member of the NMD pathway and direct interacting partner of UPF3B.
2012-12-31 | GSE35420 | GEO
Project description:We analyzed the DNA methylation of peripheral blood samples from 81 individuals with intellectual disability (ID) and compared this methylation pattern to 19 normal controls using the HumanMethylation450 BeadChip and bisulfite pyrosequencing for validiation. We could not show a global methylation pattern that separates the patients from the normal controls. But we detected in an individual approach DNA methylation changes in the genes COLEC11, SHANK2, GLI2 and KCNQ2, known to be associated with ID, in at least one patient. DNA methylation analysis of imprinted genes revealed patients with aberrant methylation pattern at the imprinted genes PPIEL, IGF2R, MEG3 and MCTS2/HM13. Our results suggest that imprinting disorders are under-diagnosed in ID patients moreover point to DNA methylation changes as potential alternative means to deregulated genes involved in the pathogenesis of ID.
2015-06-03 | GSE64380 | GEO
Project description:Based on a transcriptomic and functional approach, we performed ex-vivo studies on fibroblasts originated from a patient with Intellectual Disability and Autism Spectrum Disorders (ID-ASD) carrying a nonsense de novo mutation in CSDE1. The aim is to decipher the CSDE1-dependent biological pathways involved in the pathophysiology of ID-ASD. We identified the Wnt/β-catenin pathway and cell adhesion as two deregulated cellular pathways deregulated in the ID-ASD patient.
2023-12-09 | GSE162954 | GEO
Project description:The Wiskott-Aldrich Syndrome Protein (WASP) family is known for its participation in cytoskeleton reorganization (Marchand et al., 2001 and Jia et al., 2010). In 2007, the human subtelomeric MGC52000 genes were renamed as Wiskott-Aldrich Syndrome Protein and SCAR Homolog (WASH). Human WASH proteins are part of the WASP protein family and colocalize with actin in cells and promote Arp2/3-dependent actin polymerization in vitro (Linardopoulou et al., 2007). WASH multiprotein complex consists of seven subunits: notable to mention Strumpelin and Was Protein Family Homolog (WASH)-interacting protein (SWIP), which is encoded by KIAA1033/WASHC4 gene, FAM21 and Arp2/3. The Arp2/3 dependent actin polymerization from G-actin to F-actin is an important step in regulation of the cytoskeleton, enabling multiple endosomal transport processes (Kelleher et al., 1995 and Derivery et al., 2010). Linardopoulou and colleagues have also shown in an animal model (Drosophila), that the single WASH ortholog is essential for viability (Linardopoulou et al., 2007), strengthening the concept, that WASHC4 plays a crucial role in muscle cell integrity and function. A link between autosomal recessive intellectual disability (ARID) and mutations in the KIAA1033/WASHC4 gene was first recognized in 2011 by Ropers and colleagues. Very recently, Assoum and colleagues reported three additional patients (from two unrelated families) with syndromic ID. Two of them being sisters (8 and 6 years), both presenting with learning disabilities, macrocephaly, dysmorphic features, skeletal anomalies and subependymal heterotopic nodules due to a compound heterozygous mutation of the KIAA1033/WASHC4 gene (p.[Gln442*] and p.[Asp1048Gly]). In this study, we precisely describe the clinical phenotype of the two siblings and provide additional information (histological and proteomic data) derived from the muscle biopsy of the elder sibling to confirm the pathogenicity of the reported variant and establish the function of WASHC4 as relevant for muscle homeostasis. Which, as far as the authors know, has not yet been described in literature.
2021-10-14 | PXD024222 | Pride
Project description:We designed a microarray to test at exonic resolution for genomic imbalance for genes representative of all known chromosomal microdeletion/microduplication syndromes, all known causative genes for ID, all known genes encoding glutamate receptors and their known encoding proteins and all known genes encoding proteins with epigenetic regulatory function. We found 36 de novo copy number variants affecting 35 children in this study.
2012-07-24 | GSE39533 | GEO