J Med Genet 49:410-416 doi:10.1136/jmedgenet-2012-100867
  • Genotype-phenotype correlations
  • Original article

Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia

  1. Serge Amselem1
  1. 1Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S933, Université Pierre et Marie Curie (UPMC) - Paris 6; and Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Armand-Trousseau, Service de génétique et d'embryologie médicales, Paris, France
  2. 2AP-HP, Hôpital Armand-Trousseau, Unité de pneumologie pédiatrique, Centre National de Référence des Maladies Respiratoires Rares, Paris, France
  3. 3AP-HP, Hôpital Saint-Antoine, Unité de Recherche Clinique; and UPMC-Paris 6, Unité fonctionnelle de pharmacologie, Paris, France
  4. 4AP-HP, Hôpital inter communal et Groupe Hospitalier Henri Mondor-Albert Chenevier, Service d'ORL et de chirurgie cervico-faciale, Créteil, France
  5. 5AP-HP, Hôpital Armand-Trousseau, Service de physiologie-explorations fonctionnelles respiratoires, Paris, France
  6. 6Hôpital Universitaire de Caen, Département de pédiatrie, Caen, France
  7. 7AP-HP, Hôpital Bichat, Service de Pneumologie A, Paris, France
  8. 8Centre Hospitalier Régional Universitaire, clinique de pédiatrie Jeanne de Flandre; and Université Nord de France, Lille, France
  9. 9Université Libre de Bruxelles, Hôpital Erasme, Département de génétique médicale, Bruxelles, Belgique
  10. 10Centre Hospitalier Régional Universitaire, Service de génétique médicale, Strasbourg, France
  11. 11Centre Hospitalo-universitaire, Service de médecine infantile 3 et génétique clinique; and Université de Lorraine, Nancy, France
  12. 12Hôpital intercommunal, Service d'anatomo-pathologie, Créteil, France
  13. 13AP-HP, Groupe Hospitalier Necker-Enfants Malades, Service de pneumologie et allergologie pédiatriques, Paris, France
  1. Correspondence to Serge Amselem, Service de génétique et d'embryologie médicales, Hôpital Armand-Trousseau, 26 avenue du Dr Arnorld Netter, 75012 Paris, France; serge.amselem{at}
  1. Contributors Involvement in the conception, hypotheses delineation, and design of the study: SB, ML, ACo, JdB, ACl, EE, SA. Acquisition of the data or the analysis and interpretation of such information: SB, ML, BC, PD, GM, EK, FD, LJ, MC, AR, JFP, NB, JB, BC, AD, JD, HD, BL, AT, CT, AMV, DE, ACo, JdB, ACl, EE, SA. Writing the article or substantial involvement in its revision before to submission: SB, ML, AR, DE, EE, SA.

  • Received 5 March 2012
  • Revised 16 April 2012
  • Accepted 18 April 2012


Background CCDC39 and CCDC40 genes have recently been implicated in primary ciliary dyskinesia (PCD) with inner dynein arm (IDA) defects and axonemal disorganisation; their contribution to the disease is, however, unknown. Aiming to delineate the CCDC39/CCDC40 mutation spectrum and associated phenotypes, this study screened a large cohort of patients with IDA defects, in whom clinical and ciliary phenotypes were accurately described.

Methods All CCDC39 and CCDC40 exons and intronic boundaries were sequenced in 43 patients from 40 unrelated families. The study recorded and compared clinical features (sex, origin, consanguinity, laterality defects, ages at first symptoms and at phenotype evaluation, neonatal respiratory distress, airway infections, nasal polyposis, otitis media, bronchiectasis, infertility), ciliary beat frequency, and quantitative ultrastructural analyses of cilia and sperm flagella.

Results Biallelic CCDC39 or CCDC40 mutations were identified in 30/34 (88.2%) unrelated families with IDA defects associated with axonemal disorganisation (22 and eight families, respectively). Fourteen of the 28 identified mutations are novel. No mutation was found in the six families with isolated IDA defects. Patients with identified mutations shared a similar phenotype, in terms of both clinical features and ciliary structure and function. The sperm flagellar ultrastructure, analysed in 4/7 infertile males, showed evidence of abnormalities similar to the ciliary ones.

Conclusions CCDC39 and CCDC40 mutations represent the major cause of PCD with IDA defects and axonemal disorganisation. Patients carrying CCDC39 or CCDC40 mutations are phenotypically indistinguishable. CCDC39 and CCDC40 analyses in selected patients ensure mutations are found with high probability, even if clinical or ciliary phenotypes cannot prioritise one analysis over the other.


  • SB and ML contributed equally to this work.

  • Competing interests None.

  • Ethics approval The ethical review board of the French National Center for Rare Respiratory Diseases (CCTIRS, n°08.015bis).

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