Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Nat Genet. 2020 Oct;52(10):1046-1056. doi: 10.1038/s41588-020-0695-1. Epub 2020 Sep 28.


In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Publication types

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

MeSH terms

  • Animals
  • Cerebral Palsy / genetics*
  • Cerebral Palsy / pathology
  • Cyclin D / genetics
  • Cytoskeleton / genetics
  • Drosophila / genetics
  • Exome / genetics
  • Exome Sequencing
  • Extracellular Matrix / genetics
  • F-Box Proteins / genetics*
  • Female
  • Focal Adhesions / genetics
  • Genetic Predisposition to Disease
  • Genome, Human / genetics
  • Humans
  • Male
  • Mutation / genetics
  • Neurites / metabolism
  • Neurites / pathology
  • Risk Factors
  • Sequence Analysis, DNA
  • Signal Transduction / genetics
  • Tubulin / genetics*
  • Tumor Suppressor Proteins / genetics*
  • beta Catenin / genetics*
  • rhoB GTP-Binding Protein / genetics


  • CTNNB1 protein, human
  • Cyclin D
  • F-Box Proteins
  • FBXO31 protein, human
  • RHOB protein, human
  • TUBA1A protein, human
  • Tubulin
  • Tumor Suppressor Proteins
  • beta Catenin
  • rhoB GTP-Binding Protein