PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors

Nature Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Language: Английский

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Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 17, 2023

Abstract To elucidate the pathogenesis of vein Galen malformations (VOGMs), most common and severe congenital brain arteriovenous malformations, we performed an integrated analysis 310 VOGM proband-family exomes 336,326 human cerebrovasculature single-cell transcriptomes. We found Ras suppressor p120 RasGAP ( RASA1 ) harbored a genome-wide significant burden loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10 −7 ). Rare, damaging transmitted were enriched in Ephrin receptor-B4 EPHB4 (17.5-fold, 1.22 −5 ), which cooperates with to regulate vascular development. Additional probands had ACVRL1 , NOTCH1 ITGB1 PTPN11 . also identified multi-generational pedigree. Integrative genomic defined developing endothelial cells as likely spatio-temporal locus pathophysiology. Mice expressing VOGM-specific kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis impaired hierarchical development arterial-capillary-venous networks, but only presence “second-hit” allele. These results illuminate arterio-venous pathobiology have implications for patients their families.

Language: Английский

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TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus

Brain, Journal Year: 2024, Volume and Issue: 147(12), P. 4292 - 4305

Published: June 2, 2024

Congenital hydrocephalus, characterized by cerebral ventriculomegaly, is one of the most common reasons for paediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate congenital hydrocephalus risk gene; however, TRIM71 variants not been systematically examined in large patient cohort or conclusively linked with an OMIM syndrome. Through cross-sectional analysis largest assembled patients including neurosurgically-treated (totalling 2697 parent-proband trios and 8091 total exomes), we identified 13 protein-altering de novo (DNVs) unrelated children exhibiting variable developmental delay, dysmorphic features other structural defects, corpus callosum dysgenesis white matter hypoplasia. Eight were found to harbour arginine variants, two recurrent missense DNVs, at homologous positions RPXGV motifs different NHL domains. Seven rare, damaging, unphased transmitted uncertain significance also identified. NHL-domain exhibited impaired binding canonical target CDKN1A; failed direct subcellular localization processing bodies. Single-cell transcriptomic human embryos revealed expression early first-trimester neural stem cells brain. These data show essential morphogenesis that mutations cause novel neurodevelopmental syndrome term 'TRIM71-associated disorders (TADD)', featuring defects.

Language: Английский

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A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus

Brain, Journal Year: 2023, Volume and Issue: 147(4), P. 1553 - 1570

Published: Dec. 20, 2023

Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of BRG1-associated factor (BAF) chromatin remodelling complex, as candidate congenital hydrocephalus gene. However, SMARCC1 variants not been systematically examined large patient cohort or conclusively linked with human syndrome. Moreover, hydrocephalus-associated functionally validated mechanistically studied vivo. Here, we aimed to assess prevalence an expanded cohort, describe associated clinical and radiographic phenotypes, impact Smarcc1 depletion novel Xenopus tropicalis model hydrocephalus. To do this, performed genetic association study using whole-exome sequencing from consisting 2697 total ventriculomegalic trios, including patients neurosurgically-treated hydrocephalus, that 8091 exomes collected over 7 years (2016-23). A comparison control consisted 1798 unaffected siblings autism spectrum their parents were sourced Simons Simplex Collection. Enrichment on protein structure assessed identified variants. Effects fetal transcriptome RNA-sequencing knockdowns generated optical coherence tomography imaging, situ hybridization immunofluorescence. surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo localized highly conserved residues key functional domains. Patients exhibited aqueductal stenosis; corpus callosum abnormalities, developmental delay, cardiac defects also common. recapitulated both stenosis rescued wild-type but patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant Smarcc1-variant similarly altered expression genes midgestational neurogenesis, transcription factors NEUROD2 MAB21L2. These results suggest cause BAFopathy term 'SMARCC1-associated dysgenesis syndrome', variable presence stenosis, delay variety structural defects. data underscore importance BAF complex for morphogenesis provide evidence 'neural stem cell' paradigm pathogenesis. highlight utility trio-based identifying pathogenic sporadic disorders may be valuable adjunct management patients.

Language: Английский

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Genomic approaches to improve the clinical diagnosis and management of patients with congenital hydrocephalus

Journal of Neurosurgery Pediatrics, Journal Year: 2022, Volume and Issue: 29(2), P. 168 - 177

Published: Feb. 1, 2022

Congenital hydrocephalus (CH), characterized by incomplete clearance of CSF and subsequent enlargement brain ventricles, is the most common congenital disorder. The lack curative strategies for CH reflects a poor understanding underlying pathogenesis. Herein, authors present an overview recent findings in pathogenesis from human genetic studies discuss implications these treatment CH. Findings omics data have potential to reclassify according molecular nomenclature that may increase precision counseling, outcome prognostication, stratification. Beyond immediate patient benefits, genomic also inform future clinical trials catalyze development nonsurgical, molecularly targeted therapies. Therefore, advocate further application sequencing practice neurosurgical community as diagnostic adjunct evaluation management patients diagnosed with

Language: Английский

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Familial and syndromic forms of arachnoid cyst implicate genetic factors in disease pathogenesis

Cerebral Cortex, Journal Year: 2022, Volume and Issue: 33(6), P. 3012 - 3025

Published: July 18, 2022

Arachnoid cysts (ACs) are the most common space-occupying lesions in human brain and present significant challenges for clinical management. While cases of ACs sporadic, nearly 40 familial forms have been reported. Moreover, seen with increased frequency multiple Mendelian syndromes, including Chudley-McCullough syndrome, acrocallosal autosomal recessive primary ciliary dyskinesia. These findings suggest that genetic factors contribute to AC pathogenesis. However, traditional linkage segregation approaches limited their ability identify causative genes because disease is genetically heterogeneous often presents asymptomatically sporadically. Here, we comprehensively review theories pathogenesis, evidence formation, discuss a different approach genomics could help elucidate this perplexing lesion shed light on associated neurodevelopmental phenotypes subset these patients.

Language: Английский

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A novelSMARCC1-mutant BAFopathy implicates epigenetic dysregulation of neural progenitors in hydrocephalus

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 20, 2023

Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery. A few familial forms of congenital hydrocephalus (CH) have been identified, but cause sporadic cases CH remains elusive. Recent studies implicated

Language: Английский

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Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 19, 2023

SUMMARY Expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles (ventriculomegaly) is quintessential feature congenital hydrocephalus (CH) but also seen in autism spectrum disorder (ASD) and several neuropsychiatric diseases. PTEN frequently mutated ASD; here, we show a bona fide risk gene for development ventriculomegaly, including neurosurgically-treated CH. Pten -mutant associated with aqueductal stenosis due to hyperproliferation periventricular Nkx2.1 + neural precursors (NPCs) CSF hypersecretion from inflammation-dependent choroid plexus hyperplasia. The hydrocephalic cortex exhibits ASD-like network dysfunction impaired activity NPC-derived inhibitory interneurons. Raptor deletion or post-natal Everolimus corrects rescues cortical deficits, increases survival by antagonizing mTORC1-dependent cell pathology. These results implicate dual impact mutation on dynamics networks via dysregulation NPCs their interneuron descendants. data identify non-surgical treatment target have implications other developmental brain disorders. HIGHLIGHTS de novo mutations are ventriculomegaly (CH). medial ganglionic eminence inflammation-induced mTORC1 inhibition early rapamycin everolimus ameliorates

Language: Английский

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Statistical methods for assessing the effects of de novo variants on birth defects

Human Genomics, Journal Year: 2024, Volume and Issue: 18(1)

Published: March 14, 2024

Abstract With the development of next-generation sequencing technology, de novo variants (DNVs) with deleterious effects can be identified and investigated for their on birth defects such as congenital heart disease (CHD). However, statistical power is still limited studies because small sample size due to high cost recruiting samples low occurrence DNVs. DNV analysis further complicated by genetic heterogeneity across diseased individuals. Therefore, it critical jointly analyze DNVs other types genomic/biological information improve identify genes associated defects. In this review, we discuss general workflow, recent developments in methods, future directions analysis.

Language: Английский

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De novo Variants Disrupt an LDB1-Regulated Transcriptional Network in Congenital Ventriculomegaly

Published: Jan. 1, 2024

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. In largest-assembled CV cohort (>2,697 parent-proband trios), we identified an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15). Seven unrelated patients with ventriculomegaly, developmental delay, dysmorphic features harbored loss-of-function DNVs that truncate LDB1's carboxy-terminal LIM interaction domain, which regulates assembly homeodomain-containing transcriptional modulators. Integrative multiomic analyses suggest a key regulator ventricular neuroprogenitors binding LIM-homeodomain proteins including SMARCC1 ARID1B. Consistent this, LIM-homeodomain-containing genes carry disproportionate burden protein-damaging our cohort, 5.83 10-9) ARID1B 1.80 10-17) surpassing significance thresholds. These data identify LBD1 as novel neurodevelopmental disorder gene LDB1-regulated program essential for human brain morphogenesis.

Language: Английский

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