De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus

Charuta Gavankar Furey, Jungmin Choi, Sheng Chih Jin, Xue Zeng, Andrew T. Timberlake, Carol Nelson-Williams, M. Shahid Mansuri, Qiongshi Lu, Daniel Duran, Shreyas Panchagnula, August Allocco, Jason K. Karimy, Arjun Khanna, Jonathan R. Gaillard, Tyrone DeSpenza, Prince Antwi, Erin Loring, William E. Butler, Edward R. Smith, Benjamin C. WarfJennifer M. Strahle, David D. Limbrick, Phillip B. Storm, Gregory Heuer, Eric Jackson, Bermans J. Iskandar, James M. Johnston, Irina Tikhonova, Christopher Castaldi, Francesc López-Giráldez, Robert D. Bjornson, James R. Knight, Kaya Bilguvar, Shrikant Mane, Seth L. Alper, Shozeb Haider, Bulent Guclu, Yasar Bayri, Yener Sahin, Michael L.J. Apuzzo, Charles C. Duncan, Michael L. DiLuna, Murat Günel, Richard P. Lifton, Kristopher T. Kahle

Research output: Contribution to journalArticle

Abstract

Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10−7), SMARCC1 (p = 8.15 × 10−10), and PTCH1 (p = 1.06 × 10−6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10−4). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications. Congenital hydrocephalus (CH) is a major cause of childhood morbidity and mortality, affecting 1 in 1,000 live births and representing up to 3% of all pediatric hospital charges. Using data from the largest CH exome sequencing study to date, Furey et al. identify four genes (TRIM71, SMARCC1, PTCH1, and SHH) not previously implicated in CH. Remarkably, all four genes regulate ventricular zone neural stem cell fate and, together, explain ∼10% of CH cases. These findings implicate impaired neurogenesis in pathogenesis of a significant number of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.

Original languageEnglish (US)
Pages (from-to)302-314.e4
JournalNeuron
Volume99
Issue number2
DOIs
StatePublished - Jul 25 2018

Fingerprint

Neural Stem Cells
Hydrocephalus
Mutation
Genes
Exome
Cerebrospinal Fluid
Neurogenesis
Morbidity
Hospital Charges
Neural Tube
Pediatric Hospitals
Live Birth
Homeostasis
Ligands
Mortality
Brain

Keywords

  • aqueductal stenosis
  • congenital hydrocephalus
  • de novo variants
  • gene discovery
  • neural stem cell
  • PTCH1
  • SHH
  • SMARCC1
  • TRIM71
  • whole-exome sequencing

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Furey, C. G., Choi, J., Jin, S. C., Zeng, X., Timberlake, A. T., Nelson-Williams, C., ... Kahle, K. T. (2018). De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus. Neuron, 99(2), 302-314.e4. https://doi.org/10.1016/j.neuron.2018.06.019

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus. / Furey, Charuta Gavankar; Choi, Jungmin; Jin, Sheng Chih; Zeng, Xue; Timberlake, Andrew T.; Nelson-Williams, Carol; Mansuri, M. Shahid; Lu, Qiongshi; Duran, Daniel; Panchagnula, Shreyas; Allocco, August; Karimy, Jason K.; Khanna, Arjun; Gaillard, Jonathan R.; DeSpenza, Tyrone; Antwi, Prince; Loring, Erin; Butler, William E.; Smith, Edward R.; Warf, Benjamin C.; Strahle, Jennifer M.; Limbrick, David D.; Storm, Phillip B.; Heuer, Gregory; Jackson, Eric; Iskandar, Bermans J.; Johnston, James M.; Tikhonova, Irina; Castaldi, Christopher; López-Giráldez, Francesc; Bjornson, Robert D.; Knight, James R.; Bilguvar, Kaya; Mane, Shrikant; Alper, Seth L.; Haider, Shozeb; Guclu, Bulent; Bayri, Yasar; Sahin, Yener; Apuzzo, Michael L.J.; Duncan, Charles C.; DiLuna, Michael L.; Günel, Murat; Lifton, Richard P.; Kahle, Kristopher T.

In: Neuron, Vol. 99, No. 2, 25.07.2018, p. 302-314.e4.

Research output: Contribution to journalArticle

Furey, CG, Choi, J, Jin, SC, Zeng, X, Timberlake, AT, Nelson-Williams, C, Mansuri, MS, Lu, Q, Duran, D, Panchagnula, S, Allocco, A, Karimy, JK, Khanna, A, Gaillard, JR, DeSpenza, T, Antwi, P, Loring, E, Butler, WE, Smith, ER, Warf, BC, Strahle, JM, Limbrick, DD, Storm, PB, Heuer, G, Jackson, E, Iskandar, BJ, Johnston, JM, Tikhonova, I, Castaldi, C, López-Giráldez, F, Bjornson, RD, Knight, JR, Bilguvar, K, Mane, S, Alper, SL, Haider, S, Guclu, B, Bayri, Y, Sahin, Y, Apuzzo, MLJ, Duncan, CC, DiLuna, ML, Günel, M, Lifton, RP & Kahle, KT 2018, 'De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus', Neuron, vol. 99, no. 2, pp. 302-314.e4. https://doi.org/10.1016/j.neuron.2018.06.019
Furey CG, Choi J, Jin SC, Zeng X, Timberlake AT, Nelson-Williams C et al. De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus. Neuron. 2018 Jul 25;99(2):302-314.e4. https://doi.org/10.1016/j.neuron.2018.06.019
Furey, Charuta Gavankar ; Choi, Jungmin ; Jin, Sheng Chih ; Zeng, Xue ; Timberlake, Andrew T. ; Nelson-Williams, Carol ; Mansuri, M. Shahid ; Lu, Qiongshi ; Duran, Daniel ; Panchagnula, Shreyas ; Allocco, August ; Karimy, Jason K. ; Khanna, Arjun ; Gaillard, Jonathan R. ; DeSpenza, Tyrone ; Antwi, Prince ; Loring, Erin ; Butler, William E. ; Smith, Edward R. ; Warf, Benjamin C. ; Strahle, Jennifer M. ; Limbrick, David D. ; Storm, Phillip B. ; Heuer, Gregory ; Jackson, Eric ; Iskandar, Bermans J. ; Johnston, James M. ; Tikhonova, Irina ; Castaldi, Christopher ; López-Giráldez, Francesc ; Bjornson, Robert D. ; Knight, James R. ; Bilguvar, Kaya ; Mane, Shrikant ; Alper, Seth L. ; Haider, Shozeb ; Guclu, Bulent ; Bayri, Yasar ; Sahin, Yener ; Apuzzo, Michael L.J. ; Duncan, Charles C. ; DiLuna, Michael L. ; Günel, Murat ; Lifton, Richard P. ; Kahle, Kristopher T. / De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus. In: Neuron. 2018 ; Vol. 99, No. 2. pp. 302-314.e4.
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abstract = "Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10−7), SMARCC1 (p = 8.15 × 10−10), and PTCH1 (p = 1.06 × 10−6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10−4). Together, these probands account for ∼10{\%} of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications. Congenital hydrocephalus (CH) is a major cause of childhood morbidity and mortality, affecting 1 in 1,000 live births and representing up to 3{\%} of all pediatric hospital charges. Using data from the largest CH exome sequencing study to date, Furey et al. identify four genes (TRIM71, SMARCC1, PTCH1, and SHH) not previously implicated in CH. Remarkably, all four genes regulate ventricular zone neural stem cell fate and, together, explain ∼10{\%} of CH cases. These findings implicate impaired neurogenesis in pathogenesis of a significant number of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.",
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AU - Furey, Charuta Gavankar

AU - Choi, Jungmin

AU - Jin, Sheng Chih

AU - Zeng, Xue

AU - Timberlake, Andrew T.

AU - Nelson-Williams, Carol

AU - Mansuri, M. Shahid

AU - Lu, Qiongshi

AU - Duran, Daniel

AU - Panchagnula, Shreyas

AU - Allocco, August

AU - Karimy, Jason K.

AU - Khanna, Arjun

AU - Gaillard, Jonathan R.

AU - DeSpenza, Tyrone

AU - Antwi, Prince

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AU - Butler, William E.

AU - Smith, Edward R.

AU - Warf, Benjamin C.

AU - Strahle, Jennifer M.

AU - Limbrick, David D.

AU - Storm, Phillip B.

AU - Heuer, Gregory

AU - Jackson, Eric

AU - Iskandar, Bermans J.

AU - Johnston, James M.

AU - Tikhonova, Irina

AU - Castaldi, Christopher

AU - López-Giráldez, Francesc

AU - Bjornson, Robert D.

AU - Knight, James R.

AU - Bilguvar, Kaya

AU - Mane, Shrikant

AU - Alper, Seth L.

AU - Haider, Shozeb

AU - Guclu, Bulent

AU - Bayri, Yasar

AU - Sahin, Yener

AU - Apuzzo, Michael L.J.

AU - Duncan, Charles C.

AU - DiLuna, Michael L.

AU - Günel, Murat

AU - Lifton, Richard P.

AU - Kahle, Kristopher T.

PY - 2018/7/25

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N2 - Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10−7), SMARCC1 (p = 8.15 × 10−10), and PTCH1 (p = 1.06 × 10−6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10−4). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications. Congenital hydrocephalus (CH) is a major cause of childhood morbidity and mortality, affecting 1 in 1,000 live births and representing up to 3% of all pediatric hospital charges. Using data from the largest CH exome sequencing study to date, Furey et al. identify four genes (TRIM71, SMARCC1, PTCH1, and SHH) not previously implicated in CH. Remarkably, all four genes regulate ventricular zone neural stem cell fate and, together, explain ∼10% of CH cases. These findings implicate impaired neurogenesis in pathogenesis of a significant number of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.

AB - Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10−7), SMARCC1 (p = 8.15 × 10−10), and PTCH1 (p = 1.06 × 10−6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10−4). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications. Congenital hydrocephalus (CH) is a major cause of childhood morbidity and mortality, affecting 1 in 1,000 live births and representing up to 3% of all pediatric hospital charges. Using data from the largest CH exome sequencing study to date, Furey et al. identify four genes (TRIM71, SMARCC1, PTCH1, and SHH) not previously implicated in CH. Remarkably, all four genes regulate ventricular zone neural stem cell fate and, together, explain ∼10% of CH cases. These findings implicate impaired neurogenesis in pathogenesis of a significant number of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.

KW - aqueductal stenosis

KW - congenital hydrocephalus

KW - de novo variants

KW - gene discovery

KW - neural stem cell

KW - PTCH1

KW - SHH

KW - SMARCC1

KW - TRIM71

KW - whole-exome sequencing

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