Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus

Jin, Sheng Chih; Dong, Weilai; Kundishora, Adam J.; Panchagnula, Shreyas; Moreno-De-Luca, Andrés; Furey, Charuta G.; Allocco, August; Walker, Rebecca L.; Nelson‐Williams, Carol; Smith, Hannah; Dunbar, Ashley; Conine, Sierra B; Lu, Qiongshi; Zeng, Xue; Sierant, Michael C.; Knight, James; Sullivan, William; Duy, Phan Q.; DeSpenza, Tyrone; Reeves, Benjamin C.; Karimy, Jason K.; Marlier, Arnaud; Castaldi, Christopher; Tikhonova, Irina; Li, Boyang; Pena, H.P.; Broach, James R.; Kabachelor, Edith Mbabazi; Ssenyonga, Peter; Hehnly, Christine; Li, Ge; Keren, Boris; Timberlake, Andrew T.; Goto, June; Mangano, Francesco T.; Johnston, James M.; Butler, William E.; Warf, Benjamin C.; Smith, Edward; Schiff, Steven J.; Limbrick, David D.; Heuer, Gregory G.; Jackson, Eric M.; Iskandar, Bermans J.; Mane, Shrikant; Haider, Shozeb; Güçlü, Bülent; Bayri, Yaşar; Şahin, Yener; Duncan, Charles C.; Apuzzo, Michael L.J.; DiLuna, Michael L.; Hoffman, Ellen J.; Šestan, Nenad; Ment, Laura R.; Alper, Seth L.; Bilgüvar, Kaya; Geschwind, Daniel H.; Günel, Murat; Lifton, Richard P.; Kahle, Kristopher T.

doi:10.1038/s41591-020-1090-2

Cited by 109 publications

(140 citation statements)

References 78 publications

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“…The ependymal damage was shown to result from cleavage of cell adhesion proteins 60,61 . Indeed, many forms of human congenital hydrocephalus result from genetic alterations of proteins involved in cell-cell junctional integrity including N-cadherin, connexin, and L1CAM 62 , that are critical for the differentiation of the ventricular and subventricular zones neural stem cells into mature ependyma 63 . In addition, a recent exome sequencing of 381 human congenital hydrocephalus infants identified a predominance of de novo mutations in genes associated with neural stem differentiation 64 .…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, many forms of human congenital hydrocephalus result from genetic alterations of proteins involved in cell-cell junctional integrity including N-cadherin, connexin, and L1CAM 62 , that are critical for the differentiation of the ventricular and subventricular zones neural stem cells into mature ependyma 63 . In addition, a recent exome sequencing of 381 human congenital hydrocephalus infants identified a predominance of de novo mutations in genes associated with neural stem differentiation 64 . Experimentally, a series of studies on hyh mice 49,51,65-67 that develop perinatal aqueductal stenosis also support the concept of a defect in cell junction complexes as an underlying cause of hydrocephalus.…”

Section: Discussionmentioning

confidence: 99%

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Central nervous system immune response in postinfectious hydrocephalus

Isaacs

Morton

Movassagh

et al. 2020

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Inflammation following neonatal infection is a dominant cause of childhood hydrocephalus in the developing world. Understanding this complex inflammatory response is critical for the development of preventive therapies. In 100 African hydrocephalic infants ≤3 months of age, with and without a history of infection, we elucidated the biological pathways that account for this inflammatory response. We integrated proteomics and RNA sequencing in cerebrospinal fluid, identifying gene pathways involving neutrophil, interleukin (4, 12, and 13) and interferon activity associated with this condition. These findings are required to develop strategies to reduce the risk of hydrocephalus during treatment of infection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Central nervous system immune response in postinfectious hydrocephalus

Isaacs

Morton

Movassagh

et al. 2020

Preprint

Self Cite

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“…Such ependymal damage was shown to result from cleavage of cell adhesion proteins (McAllister et al, 2017;Castaneyra-Ruiz et al, 2018). Indeed, many forms of human congenital hydrocephalus result from genetic alterations of proteins involved in cell-cell junctional integrity including N-cadherin, connexin, and L1CAM (Guerra et al, 2015b), which are critical for the differentiation of the ventricular and subventricular zone neural stem cells into mature ependyma (Jin et al, 2020). In addition, a recent exome sequencing of 381 infants with congenital hydrocephalus identified a predominance of de novo mutations in genes associated with neural stem cell differentiation (Jin et al, 2020).…”

Section: Potential Pathologic Overlap With Npihmentioning

confidence: 99%

“…Indeed, many forms of human congenital hydrocephalus result from genetic alterations of proteins involved in cell-cell junctional integrity including N-cadherin, connexin, and L1CAM (Guerra et al, 2015b), which are critical for the differentiation of the ventricular and subventricular zone neural stem cells into mature ependyma (Jin et al, 2020). In addition, a recent exome sequencing of 381 infants with congenital hydrocephalus identified a predominance of de novo mutations in genes associated with neural stem cell differentiation (Jin et al, 2020). Experimentally, a series of studies on hyh mice (Jimenez et al, 2009;Batiz et al, 2005Batiz et al, , 2006Perez-Figares et al, 1998;Wagner et al, 2003) that develop perinatal aqueductal stenosis also support the concept of a defect in cell junction complexes as an underlying cause of hydrocephalus.…”

Section: Potential Pathologic Overlap With Npihmentioning

confidence: 99%

Immune activation during Paenibacillus brain infection in African infants with frequent cytomegalovirus co-infection

et al. 2021

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Summary Inflammation during neonatal brain infections leads to significant secondary sequelae such as hydrocephalus, which often follows neonatal sepsis in the developing world. In 100 African hydrocephalic infants we identified the biological pathways that account for this response. The dominant bacterial pathogen was a Paenibacillus species, with frequent cytomegalovirus co-infection. A proteogenomic strategy was employed to confirm host immune response to Paenibacillus and to define the interplay within the host immune response network. Immune activation emphasized neuroinflammation, oxidative stress reaction, and extracellular matrix organization. The innate immune system response included neutrophil activity, signaling via IL-4, IL-12, IL-13, interferon, and Jak/STAT pathways. Platelet-activating factors and factors involved with microbe recognition such as Class I MHC antigen-presenting complex were also increased. Evidence suggests that dysregulated neuroinflammation propagates inflammatory hydrocephalus, and these pathways are potential targets for adjunctive treatments to reduce the hazards of neuroinflammation and risk of hydrocephalus following neonatal sepsis.

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“…The brain growth and CSF accumulation relationship is critical to characterize because it is impacted in numerous conditions of early childhood where brain growth and fluid accumulation are affected such as infection, hemorrhage, hydrocephalus, and a broad range of congenital disorders 1,2 . Appropriate management of such diseases requires understanding the normal dynamics of brain growth in relationship to fluid accumulation.…”

Section: Introductionmentioning

confidence: 99%

Normal Childhood Brain Growth and a Universal Sex and Anthropomorphic Relationship to Cerebrospinal Fluid

Peterson¹,

Cherukuri²,

Paulson³

et al. 2020

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Brain growth is affected by a broad range of childhood conditions that affect cognitive development, but definitive growth curves for the brain throughout childhood have not been available. We studied the brain volume growth from 1,067 normal MRI scans from 505 normal healthy children from birth through age 18. Brain volume peaked at 10-12 years of age. Males exhibited larger age-adjusted total brain volumes than females, and body size normalization procedures did not eliminate this difference. Other significant gender-based differences were found in cerebrospinal fluid (CSF) accumulation, grey and white matter volumes, and lateralization between left and right temporal lobes and hippocampi. A significant correlation between cognitive scores with brain volume was found in the years leading up to the adolescent brain volume peak. The ratio of brain to CSF volume, however, uncovered a universal age-dependent relationship independent of gender or body size. These findings enable the use of normative growth curves in managing a broad range of childhood disease where cognitive development and brain growth is impaired.

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Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus

Cited by 109 publications

References 78 publications

Central nervous system immune response in postinfectious hydrocephalus

Central nervous system immune response in postinfectious hydrocephalus

Immune activation during Paenibacillus brain infection in African infants with frequent cytomegalovirus co-infection

Normal Childhood Brain Growth and a Universal Sex and Anthropomorphic Relationship to Cerebrospinal Fluid

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