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

Neuron. 2018 Jul 25;99(2):302-314.e4. doi: 10.1016/j.neuron.2018.06.019. Epub 2018 Jul 5.

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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cohort Studies
  • Exome / genetics
  • Female
  • Humans
  • Hydrocephalus / diagnosis*
  • Hydrocephalus / genetics*
  • Male
  • Mutation / genetics*
  • Neural Stem Cells / pathology
  • Neural Stem Cells / physiology*
  • Patched-1 Receptor / genetics
  • Pedigree
  • Transcription Factors / genetics
  • Whole Exome Sequencing / methods

Substances

  • PTCH1 protein, human
  • Patched-1 Receptor
  • SMARCC1 protein, human
  • Transcription Factors