Article Text

Original article
Intragenic CAMTA1 rearrangements cause non-progressive congenital ataxia with or without intellectual disability
  1. Julien Thevenon1,2,
  2. Estelle Lopez2,
  3. Boris Keren3,4,
  4. Delphine Heron5,
  5. Cyril Mignot5,
  6. Cecilia Altuzarra6,
  7. Mylène Béri-Dexheimer7,
  8. Céline Bonnet7,
  9. Eloi Magnin8,
  10. Lydie Burglen9,
  11. Delphine Minot1,
  12. Jacqueline Vigneron10,
  13. Sophie Morle6,
  14. Mathieu Anheim5,
  15. Perrine Charles5,
  16. Alexis Brice3,4,
  17. Louise Gallagher11,
  18. Jeanne Amiel12,
  19. Emmanuel Haffen8,
  20. Corinne Mach3,
  21. Christel Depienne3,4,
  22. Diane Doummar13,
  23. Marlène Bonnet14,
  24. Laurence Duplomb2,
  25. Virginie Carmignac2,
  26. Patrick Callier2,15,
  27. Nathalie Marle15,
  28. Anne-Laure Mosca-Boidron15,
  29. Virginie Roze16,
  30. Bernard Aral17,
  31. Ferechte Razavi18,
  32. Philippe Jonveaux8,
  33. Laurence Faivre1,2,
  34. Christel Thauvin-Robinet1,2
  1. 1Centre de Génétique et Centre de Référence «Anomalies du Développement et Syndromes Malformatifs», Hôpital d'Enfants, CHU Dijon, Dijon, France
  2. 2Equipe Génétique et Anomalies du Développement, Université de Bourgogne, Faculté de Médecine, Dijon, France
  3. 3INSERM, U975 and CNRS 7225, CRICM, Hôpital Pitié-Salpêtrière, Paris, France
  4. 4AP-HP, Département de Génétique et de Cytogénétique, Centre de Génétique Moléculaire et Chromosomique, Hôpital Pitié-Salpêtrière, Paris, France
  5. 5Département de Génétique et Centre de Référence "Déficiences intellectuelles de causes rares", Groupe Hospitalier Pitié-Salpêtrière et CRICM, INSERM UMRS975, La Pitié Salpêtrière, Paris, France
  6. 6Service de Neuropédiatrie, CHU de Besançon, Besançon, France
  7. 7Laboratoire de Génétique et EA 4368, CHU de Nancy, Nancy, France
  8. 8Neurologie, CHU de Besançon, Besançon, France
  9. 9Centre de référence des malformations et maladies congénitales du cervelet et Service de Génétique Médicale, APHP, Hôpital Trousseau, et INSERM U676, Hôpital Robert Debré, Paris, France
  10. 10U.F. de Génétique Clinique, Maternité Régionale, Nancy, France
  11. 11Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
  12. 12Département de Génétique, Hôpital Necker Enfant Malade, AP-HP et Université René Descartes, Paris, France
  13. 13Département de Neuropédiatrie, Hôpital A.Trousseau, AP-HP, Paris, France
  14. 14Centre de Référence des Troubles du Langage et des apprentissages, Pédiatrie, CHU Dijon, Dijon, France
  15. 15Laboratoire de Cytogénétique, Plateau Technique de Biologie, CHU de Dijon, Dijon, France
  16. 16Laboratoire de Cytogénétique, CHU de Besançon, Besançon, France
  17. 17Laboratoire de Génétique Moléculaire, Plateau Technique de Biologie, CHU de Dijon, Dijon, France
  18. 18Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, Paris, France
  1. Correspondence to Dr Christel Thauvin-Robinet, Hôpital d'Enfants, Centre de Génétique, 10 Bd Maréchal de Lattre de Tassigny, Dijon 21079, France; christel.thauvin{at}


Background Non-progressive congenital ataxias (NPCA) with or without intellectual disability (ID) are clinically and genetically heterogeneous conditions. As a consequence, the identification of the genes responsible for these phenotypes remained limited.

Objective Identification of a new gene responsible for NPCA and ID.

Methods Following the discovery of three familial or sporadic cases with an intragenic calmodulin-binding transcription activator 1 (CAMTA1) rearrangement identified by an array-CGH and recruited from a national collaboration, the authors defined the clinical and molecular characteristics of such rearrangements, and searched for patients with point mutations by direct sequencing.

Results Intragenic copy number variations of CAMTA1 were all located in the CG-1 domain of the gene. It segregated with autosomal dominant ID with non-progressive congenital cerebellar ataxia (NPCA) in two unrelated families, and was de novo deletion located in the same domain in a child presenting with NPCA. In the patients with ID, the deletion led to a frameshift, producing a truncated protein, while this was not the case for the patient with isolated childhood ataxia. Brain MRI of the patients revealed a pattern of progressive atrophy of cerebellum medium lobes and superior vermis, parietal lobes and hippocampi. DNA sequencing of the CG-1 domain in 197 patients with sporadic or familial non-syndromic intellectual deficiency, extended to full DNA sequencing in 50 patients with ID and 47 additional patients with childhood ataxia, identified no pathogenic mutation.

Conclusion The authors have evidence that loss-of-function of CAMTA1, a brain-specific calcium responsive transcription factor, is responsible for NPCA with or without ID.

Accession numbers CAMTA1 reference sequence used was ENST00000303635. Protein sequence was ENSP00000306522.

  • 1p36.31 micro deletion
  • intragenic rearrangement
  • CAMTA1 gene
  • autosomal dominant intellectual disability
  • non-progressive congenital ataxia
  • genetics
  • molecular genetics
  • cytogenetics
  • neurology
  • memory disorders
  • clinical genetics
  • epilepsy and seizures
  • multiple sclerosis
  • neurosciences
  • genetic screening/counselling
  • psychiatry
  • mood disorders (including depression)
  • developmental

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  • Funding Funding provided by the Regional Council of Burgundy.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the local ethics committee.

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

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