Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1080482 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28091774.fastq.gz | Fastqsanger.gz | |||
| SRR28091775.fastq.gz | Fastqsanger.gz | |||
| SRR28091776.fastq.gz | Fastqsanger.gz | |||
| SRR28091777.fastq.gz | Fastqsanger.gz | |||
| SRR28091778.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype
| PRJNA895326 | ENA
Project description:Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator gene ZMYM3, located on the X chromosome. Most (n=24) individuals were males, 17 of which have a maternally inherited variant and four of which have de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n=26) are missense, including six with variants that have arisen independently at the same codon at least two times. Four unrelated probands were identified with inherited variation at Arg441 (Arg441Trp or Arg441Gln), a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation at Arg1294 (Arg1294Cys). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one mutant, Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to support a conclusive causative role for variation in ZMYM3 in disease, the totality of the evidence, including 27 affected individuals, recurrent variation affecting at least two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects strongly support ZMYM3 as a novel NDD gene.
2022-10-31 | GSE216752 | GEO
Project description:Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator gene ZMYM3, located on the X chromosome. Most (n=24) individuals were males, 17 of which have a maternally inherited variant and four of which have de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n=26) are missense, including six with variants that have arisen independently at the same codon at least two times. Four unrelated probands were identified with inherited variation at Arg441 (Arg441Trp or Arg441Gln), a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation at Arg1294 (Arg1294Cys). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one mutant, Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. Similarly, RNA-seq comparing mutant cells to reference revealed numerous expression changes. Such changes were not seen in edited cells harboring a likely benign variant, Arg688His. While we are unable to perform statistical evaluations to support a conclusive causative role for variation in ZMYM3 in disease, the totality of the evidence, including 27 affected individuals, recurrent variation affecting at least two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects strongly support ZMYM3 as a novel NDD gene.
2024-03-02 | GSE259222 | GEO
Project description:Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.
| S-EPMC9943726 | biostudies-literature
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:Fetal brain anomalies identified by prenatal ultrasound and/or magnetic resonance imaging represent a considerable healthcare burden with ~1-2/1,000 live births. To identify underlying etiology, trio prenatal exome sequencing or genome sequencing (ES/GS) has emerged as a comprehensive diagnostic paradigm with a reported diagnostic rate up to ~32%. Here, we report five unrelated families with six affected cases that presented neuroanatomical, craniofacial, and skeletal anomalies, all harboring rare, biallelic deleterious variants in SNAPIN, encoding SNARE-associated protein. SNAPIN is a ubiquitously expressed component of the autophagy-lysosomal pathway that catalyzes retrograde axonal transport and synaptic transmission. To investigate the role of SNAPIN in brain development, we generated zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes. Two independent, genetically stable snapin mutants exhibited pre-adulthood lethality, reduced overall length, disproportionately smaller head size, and altered brain morphology. Transcriptomic profiling of snapin mutant zebrafish heads revealed an early and progressive transcriptomic shift marked by autophagy activation with concomitant downregulation of structural and neurodevelopmental genes. Assessment of brain cellular ultrastructure with electron microscopy and LC3-II immunoblotting revealed retrograde vesicle transport defects, with accumulation of late endosomes and autophagosomes. Together, these findings support SNAPIN as a likely causal gene for a severe neurodevelopmental syndrome and expand the growing list of autophagy-lysosome pathway regulators essential for human brain development.
2025-08-14 | GSE298994 | GEO
Project description:Fetal brain anomalies identified by prenatal ultrasound and/or magnetic resonance imaging represent a considerable healthcare burden with ~1-2/1,000 live births. To identify underlying etiology, trio prenatal exome sequencing or genome sequencing (ES/GS) has emerged as a comprehensive diagnostic paradigm with a reported diagnostic rate up to ~32%. Here, we report five unrelated families with six affected cases that presented neuroanatomical, craniofacial, and skeletal anomalies, all harboring rare, biallelic deleterious variants in SNAPIN, encoding SNARE-associated protein. SNAPIN is a ubiquitously expressed component of the autophagy-lysosomal pathway that catalyzes retrograde axonal transport and synaptic transmission. To investigate the role of SNAPIN in brain development, we generated zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes. Two independent, genetically stable snapin mutants exhibited pre-adulthood lethality, reduced overall length, disproportionately smaller head size, and altered brain morphology. Transcriptomic profiling of snapin mutant zebrafish heads revealed an early and progressive transcriptomic shift marked by autophagy activation with concomitant downregulation of structural and neurodevelopmental genes. Assessment of brain cellular ultrastructure with electron microscopy and LC3-II immunoblotting revealed retrograde vesicle transport defects, with accumulation of late endosomes and autophagosomes. Together, these findings support SNAPIN as a likely causal gene for a severe neurodevelopmental syndrome and expand the growing list of autophagy-lysosome pathway regulators essential for human brain development.
2025-08-14 | GSE298991 | GEO
Project description:Biallelic deleterious variants in SNAPIN, a retrograde dynein adaptor, cause a prenatal-onset neurodevelopmental disorder [1]
| PRJNA1272071 | ENA
Project description:Biallelic deleterious variants in SNAPIN, a retrograde dynein adaptor, cause a prenatal-onset neurodevelopmental disorder [2]
| PRJNA1272074 | ENA
Project description:Biallelic variants in CSPG4 cause a novel neurodevelopmental disorder with intellectual disability, global developmental delay and facial anomalies
| PRJNA954363 | ENA