title: Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.
abstract: 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.
authors.affiliation: 1 Department of Medicine.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Ostrowski
authors.forename: Margaret W
authors.initials: MW
authors.lastname: Leigh
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Sears
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Davis
authors.forename: Whitney E
authors.initials: WE
authors.lastname: Wolf
authors.forename: Milan J
authors.initials: MJ
authors.lastname: Hazucha
authors.forename: Johnny L
authors.initials: JL
authors.lastname: Carson
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Olivier
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sagel
authors.forename: Margaret
authors.initials: M
authors.lastname: Rosenfeld
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Ferkol
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Dell
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Milla
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.forename: Weining
authors.initials: W
authors.lastname: Yin
authors.forename: Aruna
authors.initials: A
authors.lastname: Sannuti
authors.forename: Hilda M
authors.initials: HM
authors.lastname: Metjian
authors.forename: Peadar G
authors.initials: PG
authors.lastname: Noone
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Noone
authors.forename: Christina A
authors.initials: CA
authors.lastname: Olson
authors.forename: Michael V
authors.initials: MV
authors.lastname: Patrone
authors.forename: Hong
authors.initials: H
authors.lastname: Dang
authors.forename: Hye-Seung
authors.initials: HS
authors.lastname: Lee
authors.forename: Toby W
authors.initials: TW
authors.lastname: Hurd
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.forename: Martin
authors.initials: M
authors.lastname: Kircher
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Krischer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002923:Cilia / Q000502:physiology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D005820:Genetic Testing; D006720:Homozygote; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics* / Q000503:physiopathology; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009297:Nasal Mucosa / Q000502:physiology; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D005819:Genetic Markers; C484746:RSPH1 protein, human