Variants in ZFX Cause an X-linked Neurodevelopmental Disorder with Recurrent Facial Gestalt
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PROVIDER: PRJNA904808 | ENA |
REPOSITORIES: ENA
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Project description:Pathogenic variants in multiple X-linked genes have been implicated in syndromic and non- syndromic intellectual disability disorders. The gene ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not previously been reported in association with disease. Here, we present clinical and molecular characterization of 18 patients with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven frameshift variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum and ear abnormalities. Hyperparathyroidism was found in 4 families with missense variants and enrichment of different types of tumors was also observed. In molecular studies, variants in the DNA-binding domain demonstrated differential expression of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, supporting the pathogenicity of predicted loss- of-function frameshift variants. Our clinical and experimental data support that variants in ZFX cause a novel X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.
2023-11-30 | GSE218689 | GEO
Project description:Pathogenic variants in multiple X-linked genes have been implicated in syndromic and non- syndromic intellectual disability disorders. The gene ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not previously been reported in association with disease. Here, we present clinical and molecular characterization of 18 patients with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven frameshift variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum and ear abnormalities. Hyperparathyroidism was found in 4 families with missense variants and enrichment of different types of tumors was also observed. In molecular studies, variants in the DNA-binding domain demonstrated differential expression of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, supporting the pathogenicity of predicted loss- of-function frameshift variants. Our clinical and experimental data support that variants in ZFX cause a novel X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.
2023-11-30 | GSE218688 | GEO
Project description:Variants in ZFX Cause an X-linked Neurodevelopmental Disorder with Recurrent Facial Gestalt
| PRJNA904810 | ENA
Project description:Variants in ZFX Cause an X-linked Neurodevelopmental Disorder with Recurrent Facial Gestalt
| PRJNA904805 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-11-30 | GSE218691 | GEO
Project description:We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Clinical and genetic data from affected individuals with neurological disorders were matched across families from five global sites. Here, we report five recessive CSPG4 (NM_001897) missense variants [three homozygous: c.A1370G (p.Asp457Gly), c.2627G>A (p.Arg876His) and c.3247C>A (p.Gln1083Lys), and two compound heterozygote: c.A1370G and c.5156A>G (p.Asp457Gly and p.Gln1719Arg) and c.658A>G and c.1220_1221delinsTG (p.(Thr220Ala and p.Pro407Leu)] by next-generation sequencing of five unrelated families with seven affected subjects. All subjects share a novel neurodevelopmental syndrome characterized by severe intellectual disability, global developmental delay, delayed ability to walk, speech and language delay, distinctive facial features, along with varying degrees of neurological impairment, including hypotonia, cerebellar hypoplasia, and/or seizures. All CSPG4 variants were predicted to be damaging using in silico tools, and three-dimensional molecular modeling suggested significant alterations in protein stability, compromising inter- and intra-molecular interactions. The impact on neurological and craniofacial development was analyzed in CRISPR/Cas9-mediated zebrafish models. CSPG4 variants affected notochord development, neuronal function, and cerebellar structure along with a disorganized head scaffold with anomalous skeletal and cartilage components. Two individuals metabolomics and crispant transcriptomics revealed significant perturbation of metabolites, extracellular matrix (ECM) regulating pathways, and genes previously described to cause mental retardation, dwarfism, and facial anomalies in humans. Our study links novel, rare, damaging variants of the ECM gene CSPG4 to a novel recessive Mendelian neurodevelopmental disorder in humans and supports the role of CSPG4 in early development.
2023-07-01 | GSE229401 | GEO
Project description:Biallelic variants in CSPG4 cause a novel neurodevelopmental disorder with intellectual disability, global developmental delay and facial anomalies
| PRJNA954363 | ENA
Project description:Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia
| PRJNA951710 | ENA
Project description:The ZFX transcriptional activator binds to CpG island promoters, with a major peak at ~200-250bp downstream from transcription start sites. Because ZFX binds within the transcribed region, we investigated whether it regulates transcriptional elongation. We used GRO-seq to show that loss or reduction of ZFX increased the pause ratio at ZFX-regulated promoters. To further investigate the mechanisms by which ZFX regulates transcription, we determined regions of the protein needed for transactivation and for recruitment to the chromatin. Interestingly, although ZFX has 13 grouped zinc fingers, deletion of the first 11 fingers produces a protein that can still bind to chromatin and activate transcription. We next used TurboID-MS to detect ZFX-interacting proteins, identifying ZNF593, proteins that interact with the N-terminal transactivation domain (e.g. histone modifying proteins), and proteins that interact with ZFX when it is bound to the chromatin (e.g. TAFs and other histone modifying proteins). Our studies support a model in which ZFX enhances elongation at target promoters by recruiting H4 acetylation complexes and reducing pausing.
2024-08-09 | PXD044709 | Pride
Project description:Integrator (INT) is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. INT has at least 14 subunits, but INT germline mutations causing human disease have not been reported. We identified mutations in the Integrator Complex Subunit 8 gene (INTS8) causing a rare neurodevelopmental syndrome. In patient cells we identified significant disturbance of gene expression and RNA processing. Also, we show that injection of ints8 oligonucleotide morpholinos into zebrafish embryos leads to prominent underdevelopment of the head demonstrating the evolutionary conserved requirement of INTS8 in brain development. RNA sequencing was carried out using RNA samples from fibroblasts from two individuals with germline bi-allelic INTS8 mutations and from two healthy individuals
2017-05-17 | E-GEOD-76878 | biostudies-arrayexpress