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Mutations in EXOSC2 are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt
  1. Nataliya Di Donato1,2,
  2. Teresa Neuhann3,
  3. Anne-Karin Kahlert1,4,
  4. Barbara Klink1,
  5. Karl Hackmann1,
  6. Irmingard Neuhann5,
  7. Barbora Novotna6,
  8. Jens Schallner6,
  9. Claudia Krause1,
  10. Ian A Glass2,7,8,
  11. Shawn E Parnell9,
  12. Anna Benet-Pages3,
  13. Anke M Nissen3,
  14. Wolfgang Berger10,
  15. Janine Altmüller11,
  16. Holger Thiele11,
  17. Bernhard H F Weber12,
  18. Evelin Schrock1,
  19. William B Dobyns2,7,13,
  20. Andrea Bier14,
  21. Andreas Rump1
  1. 1Carl Gustav Carus Faculty of Medicine, Institute for Clinical Genetics, TU Dresden, Dresden, Germany
  2. 2Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA
  3. 3Medical Genetics Center, Munich, Germany
  4. 4Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany
  5. 5MVZ Prof. Neuhann, Munich, Germany
  6. 6Department of Sozialpaediatrisches Zentrum, Klinik fuer Kinder und Jugendmedizin, Universitaetsklinikum Dresden, Dresden, Germany
  7. 7Division of Genetic Medicine, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
  8. 8Division of Genetic Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA
  9. 9Department of Radiology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
  10. 10Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland
  11. 11Cologne Center for Genomics, Cologne, Germany
  12. 12Institute of Human Genetics, University of Regensburg, Regensburg, Germany
  13. 13Departments of Pediatrics and Neurology, University of Washington, Seattle, Washington, USA
  14. 14Gemeinschaftspraxis für Humangenetik, Dresden, Germany
  1. Correspondence to Dr Nataliya Di Donato, Institute for Clinical Genetics, TU Dresden, Fetscherstrasse 74, Dresden 01307, Germany; Nataliya.didonato{at}


Background Retinitis pigmentosa in combination with hearing loss can be a feature of different Mendelian disorders. We describe a novel syndrome caused by biallelic mutations in the ‘exosome component 2’ (EXOSC2) gene.

Methods Clinical ascertainment of three similar affected patients followed by whole exome sequencing.

Results Three individuals from two unrelated German families presented with a novel Mendelian disorder encompassing childhood myopia, early onset retinitis pigmentosa, progressive sensorineural hearing loss, hypothyroidism, short stature, brachydactyly, recognisable facial gestalt, premature ageing and mild intellectual disability. Whole exome sequencing revealed homozygous or compound heterozygous missense variants in the EXOSC2 gene in all three patients. EXOSC2 encodes the ‘ribosomal RNA-processing protein 4’ (RRP4)—one of the core components of the RNA exosome. The RNA exosome is a multiprotein complex that plays key roles in RNA processing and degradation. Intriguingly, the EXOSC2-associated phenotype shows only minimal overlap with the previously reported diseases associated with mutations in the RNA exosome core component genes EXOSC3 and EXOSC8.

Conclusion We report a novel condition that is probably caused by altered RNA exosome function and expands the spectrum of clinical consequences of impaired RNA metabolism.

  • Clinical genetics
  • EXOSC2
  • RNA processing
  • exosome component 2 protein
  • novel Mendelian disease

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