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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

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

PROVIDER: PRJNA786928 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17159748_1.fastq.gz	Fastqsanger.gz
	SRR17159748_2.fastq.gz	Fastqsanger.gz
	SRR17159749_1.fastq.gz	Fastqsanger.gz
	SRR17159749_2.fastq.gz	Fastqsanger.gz
	SRR17159750_1.fastq.gz	Fastqsanger.gz

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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.

2021-12-10 | GSE190394 | GEO

Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, 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 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 neurodevelopmental disorder (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 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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NFKB1 Missense Variants

Project description:1 Novel Missense Variants in Patients with Primary Immunodeficiency and Immune dysregulation

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Targeted resequencing in a patient with a syndromic form of neurodevelopmental disorder

Project description:We identified a missense variant in PSMD12 gene, recently associated to an emerging syndromic form of NDD, in a patient with intellectual disability/speech delay, congenital anomalies and facial dysmorphisms. The variant described herein is useful to expand the molecular spectrum of heterozygous PSMD12 mutations and to provide insight into the molecular pathogenesis of this new condition since it is, to the best of our knowledge, the first missense substitution to date reported in medical literature. Finally, our patient is the one with the most detailed dysmorphic characterization and for this reason useful to start defining a typical facial gestalt that addresses the diagnosis.

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De novo heterozygous variants in POLR2A cause a neurodevelopmental syndrome with infantile-onset hypotonia

Project description: ABSTRACT POLR2A encodes RPB1, the largest subunit of the RNA polymerase II (pol II) complex, which is responsible for transcription of all ~21,000 protein-encoding genes. Here we describe the first fifteen patients harboring de novo heterozygous variants in POLR2A. The majority presents with profound infantile onset hypotonia and developmental delay. Missense variants that were expected to exert only mild structural effects, lead to malfunctioning RPB1, thereby inducing a dominant negative effect on pol II function. Intriguingly, these patients presented with a severe clinical phenotype. Conversely, variants expected to result in loss-of-function, leading to reduced availability of RPB1 were better tolerated: these patients exhibited the mildest phenotypes.

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2024-02-08 | GSE224943 | GEO

Heterozygous variants in MGP lead to endoplasmic reticulum stress causing spondyloepiphyseal dysplasia

Project description:Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor of extracellular matrix mineralization. Biallelic loss of function variants in the MGP gene cause Keutel syndrome, an autosomal recessive disorder characterized by widespread calcification of various cartilaginous tissues and skeletal and vascular anomalies. In this study, we report four individuals from two unrelated families with two heterozygous variants in MGP, both altering the Cysteine 19 residue to phenylalanine or tyrosine. These individuals presented with a spondyloepiphyseal skeletal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. We investigated the cellular and molecular effects of one of the heterozygous deleterious variants (C19F) using both cell and genetically modified mouse models. Heterozygous ‘knock-in’ mice expressing C19F MGP recapitulated most of the skeletal anomalies observed in the affected individuals. We demonstrated that the main underlying mechanism leading to the observed skeletal dysplasia is endoplasmic reticulum stress-induced apoptosis of the growth plate chondrocytes. Our findings support that heterozygous variants in MGP altering Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia, a condition distinct from Keutel syndrome both clinically and molecularly.

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Heterozygous variants in POLR1A cause diverse human phenotypes

Project description:Heterozygous pathogenic variants in POLR1A were identified as the cause of Acrofacial Dysostosis, Cincinnati-type in 2015. Craniofacial anomalies reminiscent of Treacher Collins syndrome were the predominant phenotype observed in the first 3 affected individuals. We have subsequently identified 17 additional individuals with 12 unique (11 novel) heterozygous variants in POLR1A and observed numerous additional phenotypes including developmental delay, infantile spasms, and structural cardiac defects. To understand the pathogenesis of this pleiotropy, we created an allelic series of POLR1A using a combination of in vivo (mouse) and in vitro models. We describe distinct spatiotemporal requirements for Polr1a during mouse embryogenesis and identify a requirement for Polr1a for survival of pre migratory and migratory neural crest cells, forebrain precursors, and the second heart field. We used CRISPR/Cas9 to recapitulate two human alleles in mouse, demonstrating pathogenicity of one and likely benign nature of the other. Our work greatly expands the phenotype of human POLR1A-related disorders, provides new evidence of reduced penetrance and variable expression of POLR1A heterozygous variants, and demonstrates a multi-faceted approach to characterize and define pathogenicity of variants.

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