1. McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China 2. Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
Primary ciliary dyskinesia (PCD) is a highly heterogeneous recessive inherited disorder. FAP54, the homolog of CFAP54 in Chlamydomonas reinhardtii, was previously demonstrated as the C1d projection of the central microtubule apparatus of flagella. A Cfap54 knockout mouse model was then reported to have PCD-relevant phenotypes. Through whole-exome sequencing, compound heterozygous variants c.2649_2657delinC (p. E883Dfs*47) and c.7312_7313insCGCAGGCTGAATTCTTGG (p. T2438delinsTQAEFLA) in a new suspected PCD-relevant gene, CFAP54, were identified in an individual with PCD. Two missense variants, c.4112A>C (p. E1371A) and c.6559C>T (p. P2187S), in CFAP54 were detected in another unrelated patient. In this study, a minigene assay was conducted on the frameshift mutation showing a reduction in mRNA expression. In addition, a CFAP54 in-frame variant knock-in mouse model was established, which recapitulated the typical symptoms of PCD, including hydrocephalus, infertility, and mucus accumulation in nasal sinuses. Correspondingly, two missense variants were deleterious, with a dramatic reduction in mRNA abundance from bronchial tissue and sperm. The identification of PCD-causing variants of CFAP54 in two unrelated patients with PCD for the first time provides strong supportive evidence that CFAP54 is a new PCD-causing gene. This study further helps expand the disease-associated gene spectrum and improve genetic testing for PCD diagnosis in the future.
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