CFAP74-mutations as cause of Primary Ciliary Dyskinesia (PCD): Clinical presentation and diagnostic challenges

Abstract

Challenges in diagnosing PCD include the underrecognition of the disease, the broad spectrum of clinical airway disease and the still ongoing identification of disease causing genes. CFAP74 encodes for a central pair associated protein. CFAP74 mutations were recently published as the cause of multiple morphological abnormalities of sperm flagella (MMAF), but respiratory cilia were not investigated.

The aim of our study was to establish whether CFAP74 mutations cause PCD.

PCD-candidate patients were screened for CFAP74-mutations. Additionally to diagnostic workup including clinical characterization, nasal NO measurement, high-speed video microscopy analysis (HSVMA), high-resolution immunofluorescence (IF) microscopy and transmission electron microscopy (TEM), we cultured respiratory cells, performed Western Blot analyses and particle tracking analyses in affected CFAP74 individuals.

In our PCD-cohort we identified three individuals from two families with compound heterozygous loss-of-function mutations in CFAP74. Western blot analyses proved the missing expression of CFAP74. All patients presented with a respiratory phenotype of varying degree. Interestingly, nasal NO production rates and TEM analyses showed normal results. HSVMA identified subtle ciliary beat abnormalities. The mucociliary clearance capacity, characterized by a fluid flow over the epithelial surface under air-liquid interface condition, was impaired.

Mutations in CFAP74 can cause PCD with subtle ciliary beating defects and impaired mucociliary clearance. As the affected present normal nasal NO levels and ciliary ultrastructure, genetic testing including CFAP74 is essential in the diagnostic workup for PCD.