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.