Genotype-phenotype correlations in patients with primary ciliary dyskinesia with central complex defects related to RSPH1, RSPH4A or RSPH9 mutations

Background The RSPH1 , RSPH4A and RSPH9 genes have been implicated in primary ciliary dyskinesia (PCD) with ultrastructural abnormalities of the central complex (CC). We studied phenotypic features of patients with RSPH1 , RSPH4A or RSPH9 mutations to guide the strategy for molecular analyses in patients with CC defects. Methods RSPH1 , RSPH4A and RSPH9 coding exons and their flanking intronic sequences were sequenced in 65 unrelated families (84 patients). We compared the following parameters: sex, origin, consanguinity, laterality defects, neonatal respiratory distress, airway infections, bronchiectasis, nasal polyposis, otitis media, hearing loss, infertility, nasal nitric oxide (NO), ciliary beat frequency and quantitative ultrastructural analyses of cilia. Results Biallelic RSPH1 , RSPH4A or RSPH9 mutations were identified in 21 (32%) unrelated families (30 patients): 10 (15%) with RSPH1 mutations, 7 (11%) with RSPH4A mutations and 4 (6%) with RSPH9 mutations. Patients with identified mutations shared a similar phenotype in terms of clinical features (sinopulmonary syndrome with no situs inversus), decreased nasal NO in most patients, presence of beating cilia normal frequency together with slow beating and immotile cilia, and CC defects in a minority of cilia. Conclusion Patients with RSPH1 , RSPH4A or RSPH9 mutations are phenotypically indistinguishable. Given the contribution of the 3 genes in this phenotype, the 1st one to be tested is RSPH1 , then RSPH4A before RSPH9 . The molecular analyses are decisive specialy when the diagnosis of PCD is difficult to establish. The molecular basis of PCD remains to be identified in 44 (68%) families.