Identification of a novel FOXP1 variant in a patient with hypotonia, intellectual disability and severe speech impairment
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB64557 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR11758310_1.fastq.gz | Fastqsanger.gz | |||
| ERR11758310_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
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:A female patient with neurodevelopmental disorder, craniofacial dysmorphisms carrying a novel heterozygous FOXP1 variant, c.1030C>T, p.(Gln344Ter). This variant was not found in the parents, which was consistent with de novo inheritance.
2024-03-01 | E-MTAB-13190 | biostudies-arrayexpress
Project description:Identifying causes of sporadic intellectual disability remains a considerable medical challenge. Here, we demonstrate that null mutations in the NONO gene, a member of the Drosophila Behavior Human Splicing (DBHS) protein family, are a novel cause of X-linked syndromic intellectual disability. Comparing humans to Nono-deficient mice revealed related behavioral and craniofacial anomalies, as well as global transcriptional dysregulation. Nono-deficient mice also showed deregulation of a large number of synaptic transcripts, causing a disorganization of inhibitory synapses, with impaired postsynaptic scaffolding of gephyrin. Alteration of gephyrin clustering could be rescued by over-expression of Gabra2 in NONO-compromised neurons. These findings link NONO to intellectual disability and first highlight the key role of DBHS proteins in functional organization of GABAergic synapses.
2015-09-02 | E-MTAB-2895 | biostudies-arrayexpress
Project description:Identifying causes of sporadic intellectual disability remains a considerable medical challenge. Here, we demonstrate that null mutations in the NONO gene, a member of the Drosophila Behavior Human Splicing (DBHS) protein family, are a novel cause of X-linked syndromic intellectual disability. Comparing humans to Nono-deficient mice revealed related behavioral and craniofacial anomalies, as well as global transcriptional dysregulation. Nono-deficient mice also showed deregulation of a large number of synaptic transcripts, causing a disorganization of inhibitory synapses, with impaired postsynaptic scaffolding of gephyrin. Alteration of gephyrin clustering could be rescued by over-expression of Gabra2 in NONO-compromised neurons. These findings link NONO to intellectual disability and first highlight the key role of DBHS proteins in functional organization of GABAergic synapses.
2015-09-02 | E-MTAB-2894 | biostudies-arrayexpress
Project description:Genetic perturbations of the transcription factor, Forkhead Box P1 (FOXP1), occur in patients with autism spectrum disorder who have an increased risk for comorbidity with intellectual disability. Recent work has begun to reveal an important role for Foxp1 in brain development, but the brain region-specific contribution of Foxp1 to autism and intellectual disability phenotypes has yet to be fully determined. Here, we characterize Foxp1 conditional knockout (Foxp1cKO) mice with loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/CA2 subfields of the hippocampus. Foxp1cKO mice exhibit behavioral phenotypes that are relevant to autism spectrum disorder, including hyperactivity, increased anxiety, and decreased sociability. In addition, Foxp1cKO mice have gross deficits in learning and memory tasks that are relevant to intellectual disability. Using a genome-wide approach, we identified genes differentially expressed in the hippocampus of Foxp1cKO mice that are associated with synaptic function and physiology that could represent molecular networks related to the observed behavioral deficits. Finally, we observed reduced maintenance of long-term potentiation in the CA1 subfield of these animals. Together, these data suggest that expression of Foxp1 in pyramidal neurons of the forebrain is important for regulating gene expression pathways that contribute to specific behaviors relevant to autism and intellectual disability. In particular, Foxp1 regulation of gene expression in the hippocampus appears to be crucial for normal CA1 physiology and spatial learning.
2018-02-13 | GSE97181 | GEO
Project description:Failure of neural stem/progenitor cell (NSPC) activity and subsequently neurogenesis during brain development has been linked to cognitive impairment and intellectual disability. However, it remains unclear if changes in metabolism, recently discovered as a key regulator of somatic stem cell activity, contribute to altered neurogenesis and cognitive deficits in humans. To investigate a link between NSPC-associated lipid metabolism and brain development, we generated mice and human embryonic stem cells (hESCs) mimicking a variant in fatty acid synthase (FASN; R1819W), a metabolic regulator of rodent NSPC activity recently identified in humans with intellectual disability. Mice homozygous for the FASN R1812W variant have impaired hippocampal NSPC activity associated with cognitive impairment due to presumed toxic accumulation of lipids in NSPCs and subsequent lipogenic ER stress. Human NSPCs homozygous for the FASN R1819W variant show reduced rates of proliferation in embryonic 2D cultures and 3D forebrain regionalized organoids, revealing that the functional significance of lipid metabolism for neurogenic proliferation of progenitors is conserved between rodents and humans. By taking a disease modeling approach, using mouse and human tissue genome engineering, our data provide genetic evidence for a link between altered lipid metabolism, NSPC activity and brain function.
2020-03-18 | GSE115851 | GEO
Project description:10 patients with Intellectual Disability diagnosed with a clinically relevant copy number change, selected to assess the dection performance of alternative platforms.
2013-08-01 | GSE46060 | GEO
Project description:10 patients with Intellectual Disability diagnosed with a clinically relevant copy number change, selected to assess the dection performance of alternative platforms. 10 Affymetrix arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples.
2013-08-01 | E-GEOD-46060 | biostudies-arrayexpress
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.
| EGAS00001000287 | EGA
Project description:Mutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. We report a three-generation family segregating mild intellectual disability with an apparently balanced chromosomal translocation t(14;18)(q23.3;q21.2) that we characterized as a complex unbalanced karyotype 46,XY,der(14)del(14)(q23.3q23.3)t(14;18)(q23.3;q21.2)del(18)(q21.2q21.2) del(18)(q21.2q21.2)inv(18)(q21.2q21.2),der(18)t(14 ;18)(q23.3;q21.2) disrupting TCF4. Using whole genome sequencing, transcriptome sequencing, qRT-PCR and nCounter analysis, we characterized the breakpoint junctions from derivative chromosomes and gene expression at the TCF4 locus. Our analyses revealed that family members segregating mild intellectual disability with the complex chromosome aberration had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Increased levels of TCF4 transcript variants originating distal to the translocation breakpoint, not the fusion transcript generated by the derivative chromosome, contributed to this increased. Although validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS is partially rescued by overexpression of short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain. Examination of TCF4 Isoform expression comparison between mutant and control skin fibroblast tissues
2016-05-31 | E-GEOD-77742 | biostudies-arrayexpress