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

Neuron (Cambridge, Mass.), 2018-07, Vol.99 (2), p.302-314.e4 [Peer Reviewed Journal]

2018 Elsevier Inc. ;Copyright © 2018 Elsevier Inc. All rights reserved. ;2018. Elsevier Inc. ;ISSN: 0896-6273 ;EISSN: 1097-4199 ;DOI: 10.1016/j.neuron.2018.06.019 ;PMID: 29983323

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Title:
De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus
Author: 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 M. ; 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.
Subjects: aqueductal stenosis ; Autism ; Cell fate ; Cerebrospinal fluid ; Cohort Studies ; Congenital diseases ; congenital hydrocephalus ; de novo variants ; Exome - genetics ; Female ; gene discovery ; Genes ; Homeostasis ; Humans ; Hydrocephalus ; Hydrocephalus - diagnosis ; Hydrocephalus - genetics ; Male ; Morbidity ; Mutation ; Mutation - genetics ; neural stem cell ; Neural stem cells ; Neural Stem Cells - pathology ; Neural Stem Cells - physiology ; Neural tube ; Neurogenesis ; Patched-1 Receptor - genetics ; Pedigree ; Proteins ; PTCH1 ; SHH ; SMARCC1 ; Transcription Factors - genetics ; TRIM71 ; Ventricle ; Ventricular zone ; Whole Exome Sequencing - methods ; whole-exome sequencing
Is Part Of: Neuron (Cambridge, Mass.), 2018-07, Vol.99 (2), p.302-314.e4
Description: 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. •Exome sequencing identifies novel genetic drivers of congenital hydrocephalus (CH)•De novo and inherited rare variants in four genes explain ∼10% of CH cases•All four CH genes (TRIM71, SMARCC1, PTCH1, and SHH) regulate neural stem cell fate•These data implicate aberrant neurogenesis in the pathogenesis of a subset of CH 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.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0896-6273
EISSN: 1097-4199
DOI: 10.1016/j.neuron.2018.06.019
PMID: 29983323
Source: Cell Press Free Archives
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De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus

2018 Elsevier Inc. ;Copyright © 2018 Elsevier Inc. All rights reserved. ;2018. Elsevier Inc. ;ISSN: 0896-6273 ;EISSN: 1097-4199 ;DOI: 10.1016/j.neuron.2018.06.019 ;PMID: 29983323

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