{"doi":"10.17615/tghp-rn94","title":"Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype","abstract":"Rationale: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD. Objectives: To identify disease-causingmutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD. Methods: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis. Measurements and Main Results: We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P , 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 % predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.16Hz at 258C), but an abnormal, circular beat pattern. Conclusions: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.","journal":"UNC Libraries","year":2020,"id":68855,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9077,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":365671,"name":"M.A. Zariwala","orcid":null,"position":1,"is_corresponding":false},{"id":365672,"name":"C.A. Olson","orcid":null,"position":2,"is_corresponding":false},{"id":365673,"name":"W. Yin","orcid":null,"position":3,"is_corresponding":false},{"id":365674,"name":"L.E. Ostrowski","orcid":null,"position":4,"is_corresponding":false},{"id":365675,"name":"Sylvia Kohl","orcid":null,"position":5,"is_corresponding":false},{"id":365676,"name":"H.Y. Gee","orcid":null,"position":6,"is_corresponding":false},{"id":365677,"name":"S.D. Sagel","orcid":null,"position":7,"is_corresponding":false},{"id":365678,"name":"K.N. Olivier","orcid":null,"position":8,"is_corresponding":false},{"id":365679,"name":"J.L. Carson","orcid":null,"position":9,"is_corresponding":false},{"id":365680,"name":"C.E. Milla","orcid":null,"position":10,"is_corresponding":false},{"id":365681,"name":"M.J. Hazucha","orcid":null,"position":11,"is_corresponding":false},{"id":364654,"name":"Hansen Dang","orcid":"0000-0002-3947-0099","position":12,"is_corresponding":false},{"id":255141,"name":"Edgar A. Otto","orcid":"0000-0002-2387-9973","position":13,"is_corresponding":false},{"id":365682,"name":"A. Sannuti","orcid":null,"position":14,"is_corresponding":false},{"id":365683,"name":"M.J. Bamshad","orcid":null,"position":15,"is_corresponding":false},{"id":365684,"name":"W.E. Wolf","orcid":null,"position":16,"is_corresponding":false},{"id":365685,"name":"P.G. Noone","orcid":null,"position":17,"is_corresponding":false},{"id":365686,"name":"J. Krischer","orcid":null,"position":18,"is_corresponding":false},{"id":365687,"name":"H.M. Metjian","orcid":null,"position":19,"is_corresponding":false},{"id":365688,"name":"M.V. Patrone","orcid":null,"position":20,"is_corresponding":false},{"id":365689,"name":"M.W. Leigh","orcid":null,"position":21,"is_corresponding":false},{"id":365690,"name":"Patrick R Sears","orcid":null,"position":22,"is_corresponding":false},{"id":36510,"name":"Jay Shendure","orcid":"0000-0002-1516-1865","position":23,"is_corresponding":false},{"id":365691,"name":"S.D. Dell","orcid":null,"position":24,"is_corresponding":false},{"id":365692,"name":"S.H. Randell","orcid":null,"position":25,"is_corresponding":false},{"id":365693,"name":"T.W. Hurd","orcid":null,"position":26,"is_corresponding":false},{"id":365694,"name":"H.-S. Lee","orcid":null,"position":27,"is_corresponding":false},{"id":365695,"name":"M. Rosenfeld","orcid":null,"position":28,"is_corresponding":false},{"id":365696,"name":"S.D. Davis","orcid":null,"position":29,"is_corresponding":false},{"id":365697,"name":"F. Hildebrandt","orcid":null,"position":30,"is_corresponding":false},{"id":7654,"name":"Martin Kircher","orcid":"0000-0001-9278-5471","position":31,"is_corresponding":false},{"id":365698,"name":"T.W. Ferkol","orcid":null,"position":32,"is_corresponding":false},{"id":365699,"name":"P.J. Noone","orcid":null,"position":33,"is_corresponding":false},{"id":365700,"name":"M.R. Knowles","orcid":null,"position":34,"is_corresponding":false},{"id":365701,"name":"J. Halbritter","orcid":null,"position":35,"is_corresponding":false},{"id":365670,"name":"D.A. Nickerson","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T21:41:52.279368Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}