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. Warf; Jennifer M. Strahle; David D. Limbrick; Phillip B. Storm; Gregory Heuer; Eric M. 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

doi:10.1016/j.neuron.2018.06.019

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 M. 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

School of Medicine

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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 language	English (US)
Pages (from-to)	302-314.e4
Journal	Neuron
Volume	99
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2018.06.019
State	Published - Jul 25 2018

Keywords

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

ASJC Scopus subject areas

General Neuroscience

Access to Document

10.1016/j.neuron.2018.06.019

Cite this

Furey, C. G., Choi, J., Jin, S. C., Zeng, X., Timberlake, A. T., Nelson-Williams, C., Mansuri, M. S., Lu, Q., Duran, D., Panchagnula, S., Allocco, A., Karimy, J. K., Khanna, A., Gaillard, J. R., DeSpenza, T., Antwi, P., Loring, E., Butler, W. E., Smith, E. R., ... 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

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, EM, 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

@article{cc9c727229f64e2b845db0e45369c6f6,

title = "De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus",

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.",

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

author = "Furey, {Charuta Gavankar} and Jungmin Choi and Jin, {Sheng Chih} and Xue Zeng and Timberlake, {Andrew T.} and Carol Nelson-Williams and Mansuri, {M. Shahid} and Qiongshi Lu and Daniel Duran and Shreyas Panchagnula and August Allocco and Karimy, {Jason K.} and Arjun Khanna and Gaillard, {Jonathan R.} and Tyrone DeSpenza and Prince Antwi and Erin Loring and Butler, {William E.} and Smith, {Edward R.} and Warf, {Benjamin C.} and Strahle, {Jennifer M.} and Limbrick, {David D.} and Storm, {Phillip B.} and Gregory Heuer and Jackson, {Eric M.} and Iskandar, {Bermans J.} and Johnston, {James M.} and Irina Tikhonova and Christopher Castaldi and Francesc L{\'o}pez-Gir{\'a}ldez and Bjornson, {Robert D.} and Knight, {James R.} and Kaya Bilguvar and Shrikant Mane and Alper, {Seth L.} and Shozeb Haider and Bulent Guclu and Yasar Bayri and Yener Sahin and Apuzzo, {Michael L.J.} and Duncan, {Charles C.} and DiLuna, {Michael L.} and Murat G{\"u}nel and Lifton, {Richard P.} and Kahle, {Kristopher T.}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = jul,

day = "25",

doi = "10.1016/j.neuron.2018.06.019",

language = "English (US)",

volume = "99",

pages = "302--314.e4",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus

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

AU - Loring, Erin

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 M.

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

Y1 - 2018/7/25

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 - PTCH1

KW - SHH

KW - SMARCC1

KW - TRIM71

KW - aqueductal stenosis

KW - congenital hydrocephalus

KW - de novo variants

KW - gene discovery

KW - neural stem cell

KW - whole-exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85049093144&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049093144&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2018.06.019

DO - 10.1016/j.neuron.2018.06.019

M3 - Article

C2 - 29983323

AN - SCOPUS:85049093144

SN - 0896-6273

VL - 99

SP - 302-314.e4

JO - Neuron

JF - Neuron

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this