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

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

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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  • 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