• Michael R Knowles, Lawrence E Ostrowski, Margaret W Leigh, Patrick R Sears, Stephanie D Davis, Whitney E Wolf, Milan J Hazucha, Johnny L Carson, Kenneth N Olivier, Scott D Sagel, Margaret Rosenfeld, Thomas W Ferkol, Sharon D Dell, Carlos E Milla, Scott H Randell, Weining Yin, Aruna Sannuti, Hilda M Metjian, Peadar G Noone, Peter J Noone, Christina A Olson, Michael V Patrone, Hong Dang, Hye-Seung Lee, Toby W Hurd, Heon Yung Gee, Edgar A Otto, Jan Halbritter, Stefan Kohl, Martin Kircher, Jeffrey Krischer, Michael J Bamshad, Deborah A Nickerson, Friedhelm Hildebrandt, Jay Shendure, and Maimoona A Zariwala.
• 1 Department of Medicine.
• Am. J. Respir. Crit. Care Med. 2014 Mar 15; 189 (6): 707-17.

RationalePrimary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD.ObjectivesTo identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD.MethodsWhole-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 ResultsWe 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 (6.1 ± Hz at 25°C), but an abnormal, circular beat pattern.ConclusionsThe 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.

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