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Phenotypic complexities of rare heterozygous neurexin-1 deletions

ABSTRACT: Phenotypic complexities of rare heterozygous neurexin-1 deletions

PROVIDER: PRJNA1220127 | ENA |

REPOSITORIES: ENA

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Phenotypic complexities of rare heterozygous neurexin-1 deletions

Project description:Given the large number of genes significantly associated with risk for neuropsychiatric disorders, a critical unanswered question is the extent to which diverse mutations --sometimes impacting the same gene-- will require tailored therapeutic strategies. Here we consider this in the context of rare neuropsychiatric disorder-associated copy number variants (2p16.3) resulting in heterozygous deletions in NRXN1, a pre-synaptic cell adhesion protein that serves as a critical synaptic organizer in the brain. Complex patterns of NRXN1 alternative splicing are fundamental to establishing diverse neurocircuitry, vary between the cell types of the brain, and are differentially impacted by unique (non-recurrent) deletions. We contrast the cell-type-specific impact of patient-specific mutations in NRXN1 using human induced pluripotent stem cells, finding that perturbations in NRXN1 splicing result in divergent cell-type-specific synaptic outcomes. Via distinct loss-of-function (LOF) and gain-of-function (GOF) mechanisms, NRXN1+/- deletions cause decreased synaptic activity in glutamatergic neurons, yet increased synaptic activity in GABAergic neurons. Reciprocal isogenic manipulations causally demonstrate that aberrant splicing drives these changes in synaptic activity. For NRXN1 deletions, and perhaps more broadly, precision medicine will require stratifying patients based on whether their gene mutations act through LOF or GOF mechanisms, in order to achieve individualized restoration of NRXN1 isoform repertoires by increasing wildtype, or ablating mutant isoforms. Given the increasing number of mutations predicted to engender both LOF and GOF mechanisms in brain disorders, our findings add nuance to future considerations of precision medicine.

2025-02-10 | GSE288964 | GEO

Large rare Deletions in Ashkenazi Jewish schizophrenia cases vs controls

Project description:Schizophrenia is a severe psychiatric illness that affects ~1% of the population and has a strong genetic underpinning. Recently, genome wide analysis of copy number variation (CNV) has implicated rare and de novo events as important in schizophrenia. Here we report a genome-wide analysis of 245 schizophrenia cases and 490 controls, all of Ashkenazi Jewish descent. Since many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3–1.6 Mb deletion previously identified in children with intellectual disability (ID) and autism, as increasing evidence suggests an overlap of specific rare CNVs between autism and schizophrenia. By combining our data with prior CNV studies of schizophrenia and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7,545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with schizophrenia (p = 0.02) and an odds ratio estimate of 17 (95% CI: 1.36–1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior schizophrenia family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for schizophrenia susceptibility.

2010-08-06 | GSE23201 | GEO

Large rare Deletions in Ashkenazi Jewish schizophrenia cases vs controls

2010-08-06 | E-GEOD-23201 | biostudies-arrayexpress

Patient-derived hiPSC neurons with heterozygous CNTNAP2 deletions display altered neuronal gene expression and network activity

Project description:We queried the expression of CNTNAP2 in Ngn2-induced neurons from each member of this family trio, hypothesizing that heterozygous intragenic deletions may affect the expression of CNTNAP2.

2017-08-19 | GSE102838 | GEO

Transcription profiling by array of yeast heterozygous diploid deletions strains screened with 20 compounds to identify gene deletions that confer sensitivity to each compound

Project description:The complete pool of barcoded essential heterozygous diploid deletion strains of S. cerevisiae were screened with 20 compounds from the Chembridge NOVACore chemical library to identify gene deletions that confer sensitivity to each compound.

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

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Transcription profiling of yeast homozygous and essential heterozygous diploid deletion strains screened with 3-nitroso-imidazo[1,2-a]pyridines and -pyrimidines to identify gene deletions that confer sensitivity to each compound

Project description:The complete pool of barcoded homozygous and essential heterozygous diploid deletion strains of S. cerevisiae were screened with 3-nitroso-imidazo[1,2-a]pyridines and -pyrimidines to identify gene deletions that confer sensitivity to each compound.

2008-09-19 | E-TABM-560 | biostudies-arrayexpress

Genome-wide single nucleotide polymorphism array analysis unveils the origin of heterozygous androgenetic complete moles

Project description:Heterozygous CHMs have been believed as synonymous with dispermic moles (two sperm origin). The possibility of diploid sperm origin has not been considered. We assessed whether heterozygous CHMs would be of dispermic or diploid sperm origin. In all the cases, centromeric zygosity was random, i.e., mixed status. Theoretically, if the heterozygous CHMs were of diploid sperm origin, the centromeric status will be all homozygous or all heterozygous. Thus, all the analyzed heterozygous CHMs were considered to be of dispermic origin. Three cases showed the trisomy while we did not notice them with STR analysis. Diploid sperm fertilization can be rare during the development of heterozygous androgenetic CHM.

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PIEZO1 loss of function compound heterozygous mutation in the rare congenital human disorder Prune Belly Syndrome

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