Transcriptional analysis of T cells derived from individuals with neurodevelopmental disorder carrying de novo heterozygous PSMC3 variants.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228675 | GEO | 2024/03/30
REPOSITORIES: GEO
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Project description:Gene expression profiling on T cells to investigate the effects of PSMD11 loss-of-function variants on the immune system using the Nanostring nCounter® Human AutoImmune Profiling Panel.
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Project description:GATA zinc finger domain containing 2A (GATAD2A) is a subunit of the nucleosome remodeling and deacetylase (NuRD) complex. NuRD is known to regulate gene expression during neural development and other processes. The NuRD complex modulates chromatin status through histone deacetylation and ATP-dependent chromatin remodeling activities. Several neurodevelopmental disorders (NDDs) have been previously linked to variants in other components of NuRD's chromatin remodeling subcomplex (NuRDopathies). We identified five individuals with features of an NDD that possessed de novo autosomal dominant variants in GATAD2A. Core features in affected individuals include global developmental delay, structural brain defects, and craniofacial dysmorphology. These GATAD2A variants are predicted to affect protein dosage and/or interactions with other NuRD chromatin remodeling subunits. We provide evidence that a GATAD2A missense variant disrupts interactions of GATAD2A with CHD3, CHD4, and CHD5. Our findings expand the list of NuRDopathies and provide evidence that GATAD2A variants are the genetic basis of a previously uncharacterized developmental disorder.
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Project description:BackgroundNext-generation sequencing has been invaluable to delineate the genetic etiology of neurodevelopmental disorders (NDDs) in recent years. BCL11B, encoding Cys2 His2 zinc finger transcription factor, is essential for the development of immune and neural systems.MethodsHerein, we describe a Chinese girl presenting craniofacial abnormalities, developmental delay and intellectual disability with speech impairment. Exomes of genes were enriched with the Agilent SureSelect QXT ALL Human Exon V6 kit and sequenced on Illumina Hiseq 2500 platform.ResultsAfter variants filtering and annotation, we identified a de novo heterozygous 11bp frameshift mutation NM_138576.4: c.2190_2200delGGACGCACGAC (p.Thr730Thrfs*151) in exon 4 of BCL11B, which is expected to escape nonsense-mediated mRNA decay and probably result in a truncated protein with lack of the C-terminal DNA-binding zinc-finger domains.ConclusionThis is the first report of NDD caused by a BCL11B variant in a Chinese population. The mutation identified in this report broadens the knowledge of mutation spectrum of BCL11B and might help in genetic counseling and reducing reproductive risk.
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Project description:Transcriptional analysis of T cells derived from individuals with neurodevelopmental disorder carrying de novo heterozygous PSMD11 variants
| PRJNA1094860 | ENA
Project description:Transcriptional analysis of T cells derived from individuals with neurodevelopmental disorder carrying de novo heterozygous PSMC3 variants.
| PRJNA950994 | ENA
Project description:Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.
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