Article Text

Download PDFPDF
Original research
New insights into CC2D2A-related Joubert syndrome
  1. Madeleine Harion1,2,3,
  2. Leila Qebibo4,5,
  3. Audrey Riquet4,6,
  4. Christelle Rougeot4,7,
  5. Alexandra Afenjar4,8,
  6. Catherine Garel1,4,9,
  7. Malek Louha4,5,
  8. Emmanuelle Lacaze3,4,
  9. Frédérique Audic-Gérard10,
  10. Magali Barth11,
  11. Patrick Berquin12,
  12. Dominique Bonneau11,13,14,
  13. Frédéric Bourdain15,
  14. Tiffany Busa10,
  15. Estelle Colin11,
  16. Jean-Marie Cuisset6,
  17. Vincent Des Portes16,
  18. Nathalie Dorison17,
  19. Christine Francannet18,19,
  20. Bénédicte Héron3,
  21. Cécile Laroche20,
  22. Marine Lebrun21,
  23. Julia Métreau22,
  24. Sylvie Odent23,24,
  25. Laurent Pasquier23,
  26. Yaumara Perdomo Trujillo25,
  27. Laurine Perrin26,
  28. Lucile Pinson27,
  29. François Rivier28,29,
  30. Sabine Sigaudy10,
  31. Christel Thauvin-Robinet30,31,
  32. Ulrike Walther Louvier32,
  33. Olivier Labayle33,
  34. Diana Rodriguez3,4,34,
  35. Stéphanie Valence3,4,35,
  36. Lydie Burglen4,5,36
  1. 1 Université de Médecine, Sorbonne Université, Paris, France
  2. 2 INSERM UMR 1163, Paris, France
  3. 3 Service de neuropédiatrie, APHP, Hôpital Trousseau, Paris, France
  4. 4 Centre de Référence Maladies Rares "Malformations et Maladies Congénitales du Cervelet", Paris, Lyon, Lille, France
  5. 5 Département de Génétique, Hôpital Trousseau, Paris, France
  6. 6 Département de Neurologie Pédiatrique, Hôpital Roger Salengro, Lille, France
  7. 7 Département de Neurologie Pédiatrique et Centre de Référence Déficiences Intellectuelles, Centre Hospitalier Universitaire de Lyon, Lyon, France
  8. 8 Service de Génétique Clinique, Hôpital Trousseau, Paris, France
  9. 9 Service de Radiologie Pédiatrique, Hôpital Trousseau, Paris, France
  10. 10 Département de Génétique, Hôpital de la Timone, Marseille, France
  11. 11 Department of Biochemistry and Genetics, Angers University Hospital, Angers, France
  12. 12 Service de Neurologie Pédiatrique, Hôpital Nord, Amiens, France
  13. 13 U771-CNRS6214, UMR INSERM, Angers, France
  14. 14 School of Medicine, University of Angers, Angers, France
  15. 15 Centre Hospitalier de la Côte Basque, Bayonne, France
  16. 16 Service de Neuropédiatrie, CHU de Lyon, Lyon, France
  17. 17 Service de Neurochirurgie Pédiatrique, Paris, France
  18. 18 Service de génétique clinique, Hopital Hotel Dieu, Clermont-Ferrand, France
  19. 19 Centre de Référence Maladies Rares "Anomalies du Développement et syndromes malformatifs du Sud-Est", Clermont Ferrand, France
  20. 20 Pediatrics—CHREC, Limoges University Hospital, Limoges, France
  21. 21 Service de Génétique Clinique, Chromosomique et Moléculaire, CHU Hôpital Nord, Saint-Etienne, France
  22. 22 APHP, Service de neurologie pédiatrique, Hôpital Universitaire Bicêtre, Le Kremlin-Bicêtre, Paris, Île-de-France, France
  23. 23 Service de Génétique Clinique, CLAD Ouest, CHU Rennes, Rennes, France
  24. 24 Equipe Genetique Humaine, UMR 6061 CNRS, Université de Rennes1, Rennes, France
  25. 25 Service de Génétique Médicale, Centre des Affections Rares en Génétique Ophtalmologique - CARGO, Hôpital Civil, Strasbourg, France
  26. 26 Service de Médecine Physique et de Réadaptation Pédiatrique, Hôpital Bellevue, CHU, Saint-Etienne, France
  27. 27 Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, CHU Montpellier, Montpellier, France
  28. 28 Neuropédiatrie, CR Maladies Neuromusculaires, CHRU Montpellier, Montpellier, France
  29. 29 U1046, INSERM, Université Montpellier, Montpellier, France
  30. 30 Centre de Génétique, Hôpital d'Enfants CHU Dijon, Dijon, France
  31. 31 Centre de Référence Maladies Rares Déficiences Intellectuelles de causes rare, FHU TRANSLAD, Dijon, France
  32. 32 Service de Neurologie Pédiatrique, Montpellier, France
  33. 33 University of Edinburgh, Edinburgh, UK
  34. 34 Universite Paris Diderot, Paris, Île-de-France, France
  35. 35 Centre de Référence Maladies Rares "Déficience intellectuelle de cause rare et polyhandicap", Paris, France
  36. 36 Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris, France
  1. Correspondence to Dr Madeleine Harion, Sorbonne Université, Paris 75012, France; madeleine.harion{at}


Purpose In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A.

Methods We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature.

Results Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype–phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.

Conclusion This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

  • phenotype
  • genotype
  • cerebellar diseases
  • genetic testing
  • nervous system malformations

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

View Full Text


  • SV and LB contributed equally.

  • Contributors The corresponding author MH contributed to the planning, reporting, conception, data acquisition, organising, and interpretation; statistical analysis; graphic figures designing; drafting and correcting of this original research. LQ contributed in data acquisition and interpretation as well as the revising of the work. LB and SV contributed equally to the conducting, planning, conception and interpretation of data as well as the revising of this article. LB is guarantor of this work. DR contributed in the planning, conducting, data acquisition and revising of this work. CG participated in the analysis of data; in particular she interpreted the brain MRIs. She also participated in revising the work. AR, CR and AA helped in data acquisition, conceptualisation of the work, interpretation of data and revising of the document. ML helped in data acquisition and interpretation as well as the revising of the work. EL contributed to the acquisition and interpretation of the neuropsychological tests of patients as well as the revising of the work. OL contributed to the statistical analysis using Julia software and revising of the document. The rest of the authors contributed to data acquisitions as well as revising of the final work.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.