Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus

Nat Med. 2020 Nov;26(11):1754-1765. doi: 10.1038/s41591-020-1090-2. Epub 2020 Oct 19.


Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

Publication types

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

MeSH terms

  • Brain / diagnostic imaging
  • Brain / pathology
  • Cerebral Ventricles / diagnostic imaging
  • Cerebral Ventricles / metabolism*
  • Cerebral Ventricles / pathology
  • Exome / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Hydrocephalus / cerebrospinal fluid
  • Hydrocephalus / diagnostic imaging
  • Hydrocephalus / genetics*
  • Hydrocephalus / pathology
  • Male
  • Mutation / genetics
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Neurogenesis / genetics*
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Transcription Factors / genetics
  • Tripartite Motif Proteins / genetics
  • Ubiquitin-Protein Ligases / genetics
  • Whole Exome Sequencing


  • SMARCC1 protein, human
  • Transcription Factors
  • Tripartite Motif Proteins
  • TRIM71 protein, human
  • Ubiquitin-Protein Ligases