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De novo mutations in the genome organizer CTCF cause Intellectual Disability (RNA-Seq)

ABSTRACT: An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46831 | GEO | 2013/06/01

SECONDARY ACCESSION(S): PRJNA202875

REPOSITORIES: GEO

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De novo mutations in the genome organizer CTCF cause Intellectual Disability (RNA-Seq)

Project description:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition. Comparison of lymphocyte gene expression between 3 de novo CTCF mutation patients and 8 controls (4 technical replicates each, no biological replicates).

2013-06-01 | E-GEOD-46831 | biostudies-arrayexpress

De novo mutations in the genome organizer CTCF cause Intellectual Disability (ChIP-Seq)

Project description:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition. ChIP-seq analysis of CTCF genomic binding sites in lymphocytes of a control individual (no replicates).

2013-06-01 | E-GEOD-46832 | biostudies-arrayexpress

De novo mutations in the genome organizer CTCF cause Intellectual Disability (ChIP-Seq)

2013-06-01 | GSE46832 | GEO

Project description:De novo mutations in the genome organizer CTCF cause Intellectual Disability

| PRJNA202441 | ENA

Homo sapiens

Project description:De novo mutations in the genome organizer CTCF cause Intellectual Disability (RNA-Seq)

| PRJNA202875 | ENA

Homo sapiens

Project description:De novo mutations in the genome organizer CTCF cause Intellectual Disability (ChIP-Seq)

| PRJNA202443 | ENA

Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability.

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

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

Project description:De novo mutated ADNP is a most prevalent gene driving syndromic autism with intellectual disability. Using droplet digital PCR and RNA sequencing we identified somatic mutations in ADNP and in other genes in the olfactory bulb and hipocampi of Alzheimer's disease (AD) patients.

2019-11-04 | GSE113524 | GEO

TLK2-associated intellectual disability: report of six novel cases and molecular characterization of p.(Asp551Gly) and p.(Ser617Leu) variants

Project description:Introduction The Tousled-Like Kinases 1 and 2 (TLK1 and TLK2) are involved in many fun-damental processes, including DNA replication, cell cycle checkpoint recovery and chromatin remodelling. Mutations in TLK2 were recently associated with “Mental Retardation Autoso-mal Dominant 57” (MRD57), a neurodevelopmental disorder characterized by a highly varia-ble phenotype, including mild-to-moderate intellectual disability, behavioural abnormalities, facial dysmorphisms, microcephaly, epilepsy and skeletal anomalies. Methods By whole exome sequencing and array-CGH analysis, we identified three independ-ent MRD57 cases. Two were de novo, including a likely pathogenic variant (c.1652A>G; p.(Asp551Gly)) and a 39-kb deletion encompassing TLK2, and one was familial with three sib-lings who inherited a nonsense change from an affected mother (c.1423G>T; p.(Glu475Ter)). Using spatial proteomics (BioID) and single gel electrophoresis, we investigated the proximity interaction landscape of TLK2 and analysed the effects of our missense variant and of another de novo variant reported in the Autism Sequencing Consortium Database (c.1850C>T; p.(Ser617Leu)) on TLK2 interactions, localization and activity. Results Identified clinical phenotypes were in accordance with previously reported cases. Our molecular results demonstrated that TLK2 activity is strongly impaired by both missense mu-tations and we identified proximal interactions between TLK2 and other factors implicated in neurological disorders, including CHD7, CHD8, BRD4, NACC1 and others. Moreover, we demonstrated a more relaxed state of chromatin in lymphoblastoid cells harbouring the p.(Asp551Gly) variant compared to control cells, which confers susceptibility to DNA damage. Conclusion Our study identified novel TLK2-patients carrying pathogenic variants and pro-vides new insights into their potential role in intellectual disability.

2021-05-13 | PXD019450 | Pride

De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway

Project description:Main purpose of the project is to delineate the consequences of de novo variants identified in patients manifesting intellectual disability-craniodigital syndrome. To this end, we investigated the effects of mutated CK2β by performing phosphor proteome profiling of patient derived LCLs along with the age and gender matched control.

2022-05-04 | PXD029983 | Pride

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