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Original article
Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity
  1. R Bachmann-Gagescu1,
  2. J C Dempsey2,
  3. I G Phelps2,
  4. B J O'Roak3,
  5. D M Knutzen4,
  6. T C Rue5,
  7. G E Ishak6,
  8. C R Isabella2,
  9. N Gorden7,
  10. J Adkins8,
  11. E A Boyle9,
  12. N de Lacy10,
  13. D O'Day2,
  14. A Alswaid11,
  15. Radha Ramadevi A12,
  16. L Lingappa13,
  17. C Lourenço14,
  18. L Martorell15,
  19. À Garcia-Cazorla16,
  20. H Ozyürek17,
  21. G Haliloğlu18,
  22. B Tuysuz19,
  23. M Topçu18,
  24. University of Washington Center for Mendelian Genomics,
  25. P Chance2,
  26. M A Parisi20,
  27. I A Glass2,21,
  28. J Shendure9,
  29. D Doherty2,21
  1. 1Institute for Molecular Life Sciences and Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
  2. 2Department of Pediatrics, University of Washington, Seattle, Washington, USA
  3. 3Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA
  4. 4Department of Oncology, Franciscan Health System, Tacoma, Washington, USA
  5. 5Department of Biostatistics, University of Washington, Seattle, Washington, USA
  6. 6Department of Radiology, University of Washington, Seattle Children's Hospital, Seattle, Washington, USA
  7. 7Department of Internal Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
  8. 8Division of Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, Arizona, USA
  9. 9Department of Genome Sciences, University of Washington, Seattle, Washington, USA
  10. 10Department of Psychiatry, University of Washington, Seattle, Washington, USA
  11. 11Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia
  12. 12Rainbow Children's Hospital, Hyderabad, India
  13. 13Department of Child Neurology, Rainbow Children Hospital, Hyderabad, India
  14. 14Department of Neurosciences and Behavior Neurosciences, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
  15. 15Department of Genetica Molecular, Hospital Sant Joan de Deu, Barcelona, Spain
  16. 16Department of Neurology, Neurometabolic Unit, Hospital Sant Joan de Déu and CIBERER, ISCIII, Barcelona, Spain
  17. 17Department of Pediatric Neurology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
  18. 18Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey
  19. 19Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
  20. 20National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA
  21. 21Seattle Children's Research Institute, Seattle, Washington, USA
  1. Correspondence to Dr Dan Doherty, University of Washington, 1959 NE Pacific St, Room RR247, Box 356320, Seattle, WA 98195-6320, USA; ddoher{at}


Background Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene–phenotype associations in JS.

Methods We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off.

Results We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a ‘pure JS’ phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes.

Conclusions This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.

  • Joubert syndrome
  • ciliopathy
  • genotype-phenotype
  • next generation sequencing
  • genetic heterogeneity

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