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Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. 2014
Michael R Knowles, and
Lawrence E Ostrowski, and
Margaret W Leigh, and
Patrick R Sears, and
Stephanie D Davis, and
Whitney E Wolf, and
Milan J Hazucha, and
Johnny L Carson, and
Kenneth N Olivier, and
Scott D Sagel, and
Margaret Rosenfeld, and
Thomas W Ferkol, and
Sharon D Dell, and
Carlos E Milla, and
Scott H Randell, and
Weining Yin, and
Aruna Sannuti, and
Hilda M Metjian, and
Peadar G Noone, and
Peter J Noone, and
Christina A Olson, and
Michael V Patrone, and
Hong Dang, and
Hye-Seung Lee, and
Toby W Hurd, and
Heon Yung Gee, and
Edgar A Otto, and
Jan Halbritter, and
Stefan Kohl, and
Martin Kircher, and
Jeffrey Krischer, and
Michael J Bamshad, and
Deborah A Nickerson, and
Friedhelm Hildebrandt, and
Jay Shendure, and
Maimoona A Zariwala
1 Department of Medicine.
BACKGROUND 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. OBJECTIVE To identify disease-causing mutations 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. 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 (6.1 ± Hz at 25°C), 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.
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