EXOSC3 mutations in pontocerebellar hypoplasia type 1: Novel mutations and genotype-phenotype correlations

Veerle R.C. Eggens, Peter G. Barth, Jikke Mien F. Niermeijer, Jonathan N. Berg, Niklas Darin, Abhijit Dixit, Joel Fluss, Nicola Foulds, Darren Fowler, Tibor Hortobágyi, Thomas Jacques, Mary D. King, Periklis Makrythanasis, Adrienn Máté, James A.R. Nicoll, Declan O'Rourke, Sue Price, Andrew N. Williams, Louise Wilson, Mohnish SuriLaszlo Sztriha, Marit B. Dijns-De Wissel, Mia T. Van Meegen, Fred Van Ruissen, Eleonora Aronica, Dirk Troost, Charles B.L.M. Majoie, Henk A. Marquering, Bwee Tien Poll-Thé, Frank Baas

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Background: Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1. Methods. We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed. Results: EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele. Conclusions: EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.

Original languageEnglish
Article number23
JournalOrphanet journal of rare diseases
Issue number1
Publication statusPublished - Feb 13 2014


  • EXOSC3 gene
  • Genotype-phenotype correlations
  • Neurodegeneration
  • Pontocerebellar hypoplasia

ASJC Scopus subject areas

  • Genetics(clinical)
  • Pharmacology (medical)

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    Eggens, V. R. C., Barth, P. G., Niermeijer, J. M. F., Berg, J. N., Darin, N., Dixit, A., Fluss, J., Foulds, N., Fowler, D., Hortobágyi, T., Jacques, T., King, M. D., Makrythanasis, P., Máté, A., Nicoll, J. A. R., O'Rourke, D., Price, S., Williams, A. N., Wilson, L., ... Baas, F. (2014). EXOSC3 mutations in pontocerebellar hypoplasia type 1: Novel mutations and genotype-phenotype correlations. Orphanet journal of rare diseases, 9(1), [23]. https://doi.org/10.1186/1750-1172-9-23