De novo Variants Disrupt an LDB1-Regulated Transcriptional Network in Congenital Ventriculomegaly DOI
Garrett Allington, Neel Mehta, Evan Dennis

et al.

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

The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact DOI Creative Commons
Andrew T. Hale, Hunter Boudreau, Rishi K. Devulapalli

et al.

Fluids and Barriers of the CNS, Journal Year: 2024, Volume and Issue: 21(1)

Published: March 4, 2024

Hydrocephalus (HC) is a heterogenous disease characterized by alterations in cerebrospinal fluid (CSF) dynamics that may cause increased intracranial pressure. HC component of wide array genetic syndromes as well secondary consequence brain injury (intraventricular hemorrhage (IVH), infection, etc.) can present across the age spectrum, highlighting phenotypic heterogeneity disease. Surgical treatments include ventricular shunting and endoscopic third ventriculostomy with or without choroid plexus cauterization, both which are prone to failure, no effective pharmacologic for have been developed. Thus, there an urgent need understand architecture molecular pathogenesis HC. Without this knowledge, development preventive, diagnostic, therapeutic measures impeded. However, genetics extraordinarily complex, based on studies varying size, scope, rigor. This review serves provide comprehensive overview genes, pathways, mechanisms, global impact contributing all etiologies humans.

Language: Английский

Citations

9
Congenital hydrocephalus: a review of recent advances in genetic etiology and molecular mechanisms DOI Creative Commons
Xiuyun Liu,

Xin Song,

Marek Czosnyka

et al.

Military Medical Research, Journal Year: 2024, Volume and Issue: 11(1)

Published: Aug. 12, 2024

Abstract The global prevalence rate for congenital hydrocephalus (CH) is approximately one out of every five hundred births with multifaceted predisposing factors at play. Genetic influences stand as a major contributor to CH pathogenesis, and epidemiological evidence suggests their involvement in up 40% all cases observed globally. Knowledge about an individual’s genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise etiology has only been pinpointed fewer than 5% human instances. More occurrences are required comprehensive gene sequencing aimed uncovering additional potential loci. A deeper comprehension its underlying genetics may offer invaluable insights into molecular cellular basis this brain disorder. This review provides summary pertinent genes identified through technologies humans, addition 4 currently associated (two X-linked L1CAM AP1S2 , two autosomal recessive MPDZ CCDC88C ). Others predominantly participate aqueduct abnormalities, ciliary movement, nervous system development. prospective CH-related revealed animal model gene-editing techniques further outlined, focusing mainly on pathways, namely cilia synthesis ion channels transportation, Reissner’s fiber (RF) synthesis, cell apoptosis, neurogenesis. Notably, proper functioning motile significant impulsion cerebrospinal fluid (CSF) circulation within ventricles mutations cilia-related constitute primary cause condition. So far, limited number CH-associated have humans. integration genotype phenotype disease diagnosis represents new trend medical field. Animal models provide pathogenesis contribute our understanding association related complications, such renal cysts, scoliosis, cardiomyopathy, these also play role development diseases. Genes discovered animals present targets treatments but require validation future studies.

Language: Английский

Citations

7
Biomechanical instability of the brain–CSF interface in hydrocephalus DOI
Phan Q. Duy, Neel H. Mehta, Kristopher T. Kahle

et al.

Brain, Journal Year: 2024, Volume and Issue: 147(10), P. 3274 - 3285

Published: May 27, 2024

Hydrocephalus, characterized by progressive expansion of the CSF-filled ventricles (ventriculomegaly), is most common reason for brain surgery. 'Communicating' (i.e. non-obstructive) hydrocephalus classically attributed to a primary derangement in CSF homeostasis, such as choroid plexus-dependent hypersecretion, impaired cilia-mediated flow currents, or decreased reabsorption via arachnoid granulations other pathways. Emerging data suggest that abnormal biomechanical properties parenchyma are an under-appreciated driver ventriculomegaly multiple forms communicating across lifespan. We discuss recent evidence from human and animal studies suggests neurodevelopment congenital hydrocephalus, neurodegeneration elderly normal pressure and, all age groups, inflammation-related neural injury post-infectious post-haemorrhagic can result loss stiffness viscoelasticity parenchyma. Abnormal biomechanics create barrier alterations at brain-CSF interface pathologically facilitates secondary enlargement ventricles, even low intracranial pressures. This 'brain-centric' paradigm has implications diagnosis, treatment study womb tomb.

Language: Английский

Citations

4
SWI/SNF Complex Connects Signaling and Epigenetic State in Cells of Nervous System DOI
Victor Chmykhalo, Roman V. Deev, Artemy T. Tokarev

et al.

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: July 13, 2024

Language: Английский

Citations

4
Chromatin remodeling in tissue stem cell fate determination DOI Creative Commons

Xinyang Li,

Gaoxiang Zhu,

Bing Zhao

et al.

Cell Regeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Sept. 30, 2024

Abstract Tissue stem cells (TSCs), which reside in specialized tissues, constitute the major cell sources for tissue homeostasis and regeneration, contribution of transcriptional or epigenetic regulation distinct biological processes TSCs has been discussed past few decades. Meanwhile, ATP-dependent chromatin remodelers use energy from ATP hydrolysis to remodel nucleosomes, thereby affecting dynamics gene expression programs each type. However, role fate determination is less well understood. In this review, we systematically discuss recent advances control by hematopoietic cells, intestinal epithelial neural skin their highlight importance essential homeostasis, development, regeneration. Moreover, exploration molecular cellular mechanisms crucial advancing our understanding maintenance discovery novel therapeutic targets.

Language: Английский

Citations

4
Precision medicine in the pediatric and neonatal intensive care units through genomics DOI
Phan Q. Duy,

Benjamin Dylik,

Engin Deniz

et al.

Current Opinion in Pediatrics, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

Purpose of review Genome-wide sequencing technologies have revolutionized the understanding human disorders and advanced precision medicine, especially for pediatric disorders. Here, we discuss utility genomic in advancing care children admitted to neonatal intensive units. Recent findings Rapid molecular diagnosis permitted by medicine has yielded clinically actionable that influence decision-making facilitate timely therapeutic interventions. Identifying a genetic association provides causal anchor disease biology at single nucleotide resolution, revealing hidden biological heterogeneity may be obscured traditional imaging, laboratory, pathological workup. The importance is further highlighted promise gene therapy correct underlying perturbation, as evidenced recent emergence FDA-approved therapies childhood conditions. Summary We predict whole-genome sequencing, conjunction with other omic technologies, will become critical diagnostic adjuncts clinical workup critically ill children.

Language: Английский

Citations

0
De novo Variants Disrupt an LDB1-Regulated Transcriptional Network in Congenital Ventriculomegaly DOI
Garrett Allington, Neel Mehta, Evan Dennis

et al.

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

Citations

0