J Med Genet 50:309-323 doi:10.1136/jmedgenet-2012-101284
  • Developmental defects
  • Original article

Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement

Open Access
  1. Hannah M Mitchison1
  1. 1Molecular Medicine Unit, Birth Defects Research Centre, University College London (UCL) Institute of Child Health, London, UK
  2. 2Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
  3. 3Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands
  4. 4Institute for Genetic and Metabolic Disease, Radboud University, Nijmegen, The Netherlands
  5. 5Department of Physiology, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands
  6. 6School of Veterinary Medicine and Science, University of Nottingham, Nottingham, Leicestershire, UK
  7. 7The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
  8. 8Department of Paediatrics, Radboud University Medical Centre, Nijmegen, The Netherlands
  9. 9Department of Genetics, Environment and Evolution, UCL Genetics Institute (UGI), University College London, London, UK
  10. 10Division of Pediatric Genetics, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany
  11. 11Department of Epidemiology, Biostatistics and HTA, Radboud University Medical Centre, Nijmegen, The Netherlands
  12. 12Nijmegen Centre for Evidence Based Practice, Radboud University, Nijmegen, The Netherlands
  13. 13Department of Pediatrics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  14. 14Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
  15. 15Department of Pediatric Genetics, Marmara University Hospital, Istanbul, Turkey
  16. 16Department of Clinical Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  17. 17Institute for Medical Genetics and Human Genetics, University Hospital Charité, Berlin, Germany
  18. 18Laboratory for Genetics of Human Development, Department of Human Genetics, KU Leuven University, Leuven, Belgium
  19. 19Department of Clinical Genetics, St. Michael's Hospital, Bristol, UK
  20. 20Faculty of Medicine, University of Southampton and Essex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
  21. 21Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  22. 22Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  23. 23Istanbul Medical Faculty, Medical Genetics Department, Istanbul University, Istanbul, Turkey
  1. Correspondence to Dr Hannah M Mitchison, Molecular Medicine Unit, Birth Defects Research Centre, University College London (UCL) Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; h.mitchison{at} and Heleen H Arts, Department of Human Genetics (855), Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 10, Nijmegen 6525 GA, The Netherlands; h.arts{at}
  • Received 7 September 2012
  • Accepted 21 January 2013
  • Published Online First 1 March 2013


Background Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis.

Aims and methods To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing.

Results and conclusions We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype–phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

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