Mutations in CCDC39 and CCDC40 are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms


  • Communicated by Ravi Savarirayan

  • Contract grant sponsors: Wellcome Trust (WT091310); National Institute of Health (5 U54 HL096458–06, 5 R01HL071798); National Center of Research Resources (ULI TR000083, 5 U54 HL096458–06, UL1 TR000154); Kindness for Kids Foundation; European Community (SYS-CILIA); Schröder-Stiftung; Action Medical Research and Newlife Foundation; The Henry Smith Charity.

Correspondence to: Hannah M. Mitchison, Molecular Genetics Unit and Birth Defects Research Centre, University College London (UCL) Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; E-mail: or Heymut Omran, Department of Pediatrics and Adolescent Medicine, University Hospital Muenster, Muenster, Germany; E-mail: or Michael R. Knowles, Department of Medicine; UNC School of Medicine, Chapel Hill, NC; E-mail.


Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed “radial spoke defect.” We sequenced CCDC39 and CCDC40 in 54 “radial spoke defect” families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice, and frameshift predicting early protein truncation, which suggests this defect is caused by “null” alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganization and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as “IDA and microtubular disorganisation defect,” rather than “radial spoke defect.”