Expanded PCH1D phenotype linked to EXOSC9 mutation

Eur J Med Genet. 2020 Jan;63(1):103622. doi: 10.1016/j.ejmg.2019.01.012. Epub 2019 Jan 25.


Pontocerebellar Hypoplasia type 1 is a rare heterogeneous neurodegenerative disorder with multiple subtypes linked to dysfunction of the exosome complex. Patients with mutations in exosome subunits exhibit a generally lethal phenotype characterized by cerebellar and pontine hypoplasia in association with spinal motor neuropathy and multiple systemic and neurologic features. Recently, two variants in the novel PCH1 associated protein EXOSC9 p.(Leu14Pro) and p.(Arg161*) have been identified in 4 unrelated patients exhibiting a severe phenotype involving cerebellar hypoplasia, axonal motor neuropathy, hypotonia, feeding difficulties, and respiratory insufficiency (PCH1D). We report clinical and molecular characterization of 2 unrelated patients exhibiting a relatively milder phenotype involving hypotonia, brachycephaly, cerebellar atrophy, psychomotor delay, as well as lactic acidosis and aberrant CNS myelination, resulting from the recurring homozygous missense mutation NM_001034194.1: c.41T>C; p.(Leu14Pro) in the EXOSC9 gene. We review the clinical picture of the EXOSC9-related PCH disorder.

Keywords: EXOSC9; Neurodegenerative; PCH1; PCH1D; Pontocerebellar hypoplasia.

MeSH terms

  • Brain Stem Neoplasms / genetics
  • Brain Stem Neoplasms / pathology
  • Cerebellum / abnormalities*
  • Cerebellum / pathology
  • Child
  • Developmental Disabilities / genetics
  • Developmental Disabilities / pathology
  • Exosome Multienzyme Ribonuclease Complex / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Homozygote
  • Humans
  • Male
  • Mutation / genetics
  • Nervous System Malformations / genetics*
  • Nervous System Malformations / pathology
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / pathology
  • Olivopontocerebellar Atrophies / genetics*
  • Olivopontocerebellar Atrophies / pathology
  • Phenotype
  • RNA-Binding Proteins / genetics*
  • Spinal Nerves / pathology


  • EXOSC9 protein, human
  • RNA-Binding Proteins
  • Exosome Multienzyme Ribonuclease Complex

Supplementary concepts

  • Cerebellar Hypoplasia
  • Pontocerebellar Hypoplasia Type 1