Two siblings with a novel variant of EXOSC3 extended phenotypic spectrum of pontocerebellar hypoplasia 1B to an exceptionally mild form

BMJ Case Rep. 2021 Jan 18;14(1):e236732. doi: 10.1136/bcr-2020-236732.


Pontocerebellar hypoplasia type 1B (PCH1B) describes an autosomal recessive neurological condition that involves hypoplasia or atrophy of the cerebellum and pons, resulting in neurocognitive impairments. Although there is phenotypic variability, this is often an infantile lethal condition, and most cases have been described to be congenital and neurodegenerative. PCH1B is caused by mutations in the gene EXOSC3, which encodes exosome component 3, a subunit of the human RNA exosome complex. A range of pathogenic variants with some correlation to phenotype have been reported. The most commonly reported pathogenic variant in EXOSC3 is c.395A>C, p.(Asp132Ala); homozygosity for this variant has been proposed to lead to milder phenotypes than compound heterozygosity. In this case, we report two siblings with extraordinarily mild presentations of PCH1B who are compound heterozygous for variants in EXOSC3 c.155delC and c.80T>G. These patients drastically expand the phenotypic variability of PCH1B and raise questions about genotype-phenotype associations.

Keywords: brain stem / cerebellum; movement disorders (other than Parkinsons); neuro genetics.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Cerebellar Diseases / diagnosis*
  • Cerebellar Diseases / genetics*
  • Exosome Multienzyme Ribonuclease Complex / genetics*
  • Female
  • Genetic Markers
  • Heterozygote
  • Humans
  • Mutation*
  • Pedigree
  • Phenotype*
  • RNA-Binding Proteins / genetics*
  • Severity of Illness Index
  • Siblings
  • Young Adult


  • EXOSC3 protein, human
  • Genetic Markers
  • RNA-Binding Proteins
  • Exosome Multienzyme Ribonuclease Complex

Supplementary concepts

  • Pontocerebellar Hypoplasia