Novel compound heterozygous missense variants in TOE1 gene associated with pontocerebellar hypoplasia type 7

Gene. 2023 Apr 30:862:147250. doi: 10.1016/j.gene.2023.147250. Epub 2023 Feb 2.


Background: Pontocerebellar hypoplasia type 7(PCH7)is a neurodegenerative disease related to autosomal recessive variants in the target of EGR1 (TOE1)gene. Biallelic mutation in the TOE1 gene causes global developmental delay, cognitive and psychomotor impairment, hypotonia, breathing abnormalities, and gonadal abnormalities. This study examined the clinical and genetic features of a 2-year-old patient carrying novel compound heterozygous variants in the TOE1 gene, mutations of previously reported 14 PCH7 patients were reviewed.

Methods: Clinical data of the 2-year-old patient were captured. Trio- whole exome sequencing (Trio-WES) was performed to identify pathogenic variants. Sanger sequencing was further used to verify the variants. In silico analysis was performed to explain the pathogenicity.

Results: Herein, we described the clinical features of the 2-year-old patient diagnosed with PCH7 caused by mutations in the TOE1gene. The kid was presenting with global development delay and gonadal abnormalities. Brain imaging revealed hypoplasia of the cerebellum and pons with ambiguous genitalia. Trio-WES revealed novel compound heterozygous missense variants in TOE1gene (c.911C > T p.S304L, c.161C > T p.A54V). Multiple in silico tools predicted the deleterious effects of the mutations.

Conclusion: The novel compound heterozygous missense mutation in the TOE1 gene identified in the proband broadened the genotypic and phenotypic spectrum of disorders associated with PCH7. Our findings provide critical information for the differential diagnosis of rare neurodevelopment disorders and genetic counselling.

Keywords: Genetic counselling; Neurodevelopmental disorder; Novel compound heterozygous missense variants; PCH7; TOE1; Trio-whole exome sequencing.

Publication types

  • Case Reports

MeSH terms

  • Cerebellar Diseases* / genetics
  • Child, Preschool
  • Humans
  • Mutation
  • Mutation, Missense
  • Neurodegenerative Diseases*
  • Nuclear Proteins / genetics


  • TOE1 protein, human
  • Nuclear Proteins

Supplementary concepts

  • Pontocerebellar Hypoplasia