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Pathogenic variants in the splicing factor SF1 lead to a new neurodevelopmental disorder.

ABSTRACT: Pathogenic variants in the splicing factor SF1 lead to a new neurodevelopmental disorder.

PROVIDER: PRJNA1216233 | ENA |

REPOSITORIES: ENA

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Pathogenic variants in the splicing factor SF1 lead to a new neurodevelopmental disorder.

Project description:Alternative splicing is highly prevalent in the brain, orchestrating key processes like neurogenesis and synaptogenesis, which are critical for generating the nervous system's complexity and plasticity. Dysregulation of splicing mechanisms has been increasingly implicated in neurodevelopmental disorders. Splicing factor 1 (SF1) is integral to pre-mRNA processing, facilitating early spliceosome assembly at the 3′ splice site and contributing to the regulation of alternative splicing. Here, we report a newly identified neurodevelopmental disorder associated with de novo heterozygous variants in SF1, characterized by intellectual disability, dysmorphic features, and structural brain anomalies in 15 affected individuals. Functional studies in neural progenitor cells demonstrate that SF1 inhibition alters alternative splicing programs, with pronounced effects on genes involved in neuronal differentiation, synaptic transmission, and axonal guidance, processes fundamental to brain development. These findings establish SF1-related dysfunction as a novel spliceosomopathy and highlight its critical importance in neurodevelopment and human disease.

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Bi-allelic SNAPC4 variants lead to altered global splicing and a neurodevelopmental disorder

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Biallelic UNC5C variants cause a recessive neurodevelopmental disorder with brain anomalies

Project description:Precise axon guidance is fundamental to neural circuit formation, yet the full spectrum of neurodevelopmental disorders arising from disruptions in this process remains undefined. Here, we describe a multi-ethnic cohort of eight patients from five independent families presenting with a neurodevelopmental disorder characterized by structural brain anomalies, distal limb contractures, developmental delay, intellectual disability, and additional variable features. All affected individuals carry biallelic deleterious variants in UNC5C, a gene encoding a conserved netrin receptor essential for axon guidance and neuronal migration. To investigate the functional consequences of these variants, we performed structural analyses, which indicated that the identified variants disrupt key functional domains, including the immunoglobulin-like (Ig), thrombospondin-1 type repeats (TSP), ZU5, UPA, and death domains. We then introduced disease-associated mutations into conserved residues of the Caenorhabditis elegans unc-5 orthologue using CRISPR/Cas9 genome editing and assessed phenotypic outcomes in vivo. Cell-type-specific rescue experiments revealed the observed motor defects are primarily neurogenic in origin. Consistent with the clinical features observed in patients, C. elegans carrying the corresponding human mutations exhibited defects in axon guidance, locomotion, and behaviour, supporting disruption of UNC-5–mediated signalling pathways. Together, our findings establish biallelic pathogenic variants in UNC5C as the cause of a previously unrecognized autosomal recessive neurodevelopmental disorder with structural brain anomalies and distal limb contractures. Our combined approach of human genetics and in vivo modelling defines a critical role for UNC5C in human neurodevelopment and expands the spectrum of disorders arising from disrupted axon guidance machinery.

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Biallelic UNC5C variants cause a recessive neurodevelopmental disorder with brain anomalies

Project description:Biallelic UNC5C variants cause a recessive neurodevelopmental disorder with brain anomalies

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Epigenome analysis of control and neurodevelopmental disorder lymphoblastoid cell lines

Project description:Genome wide DNA methylation profiling of control and neurodevelopmental disorder lymphoblastoid cell lines (LCL). The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in LCLs. Samples included 19 control, 18 Rett syndrome, 17 autism and 6 generalized epilepsy LCL samples. Six technical replicates were also included in the analysis. Bisulphite converted DNA from the 60 samples and 5 technical replicates were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2

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Project description:Associated with dataset "A CRISPR screen in human iPSC-derived neurons reveals convergent transcriptomic effects of neurodevelopmental disorder genes"

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Biallelic inactivating variants in the chromatin remodeler DMAP1 cause a syndromic neurodevelopmental disorder

Project description:Chromatin remodeling is a dynamic epigenetic process that alters chromatin structure to gauge gene accessibility, enabling precise spatiotemporal gene expression, with disruptions often underlying neurodevelopmental disorders (NDDs), although the mechanistic underpinning remains incompletely understood. Despite essential roles in chromatin remodeling processes such as DNA methylation, and histone acetylation and deposition, DMAP1 has not been implicated in human disease. We identified 20 individuals from 16 families with a syndromic NDD carrying homozygous or compound heterozygous variants in DMAP1. Neural-specific knockdown of its Drosophila ortholog, dDMAP1, caused pupal lethality, structural defects in the mushroom body (MB), decreased dendrite length, abnormal social behavior and mechanical-induced seizures. Wildtype human DMAP1 could largely compensate for the loss of dDMAP1 in knockdown flies, whereas patient variants failed to restore or differentially rescued the phenotypes, confirming their pathogenicity with differing severity. Transcriptome profiling of dDMAP1 knockdown fly brains nominated Cbl and SF1 as downstream targets. Their overexpression rescued the aforementioned lethality and MB defects. Finally, a DNA methylation episignature was identified, leading to the molecular diagnosis of an additional patient. Our findings demonstrate that biallelic inactivating variants in DMAP1 cause a novel syndromic NDD, expanding the short list of recessive disease-causing genes within the epigenetic machinery.

2026-04-02 | GSE326696 | GEO

Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features.

Project description: Not available

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Rare germline heterozygous missense variants of the BRCA1-Associated Protein 1 gene, BAP1, heterozygous missense variants cause a syndromic neurodevelopmental disorder

Project description:Nuclear deubiquitinase BAP1 (BRCA1-Associated Protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor gene whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a NDD or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic neurodevelopmental disorder (NDD). Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired in matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

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