title: Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia.
abstract: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 14 genes, but they collectively account for only ~60% of all PCD. To identify mutations that cause PCD, we performed exome sequencing on six unrelated probands with ciliary outer dynein arm (ODA) defects. Mutations in CCDC114, an ortholog of the Chlamydomonas reinhardtii motility gene DCC2, were identified in a family with two affected siblings. Sanger sequencing of 67 additional individuals with PCD with ODA defects from 58 families revealed CCDC114 mutations in 4 individuals in 3 families. All 6 individuals with CCDC114 mutations had characteristic oto-sino-pulmonary disease, but none had situs abnormalities. In the remaining 5 individuals with PCD who underwent exome sequencing, we identified mutations in two genes (DNAI2, DNAH5) known to cause PCD, including an Ashkenazi Jewish founder mutation in DNAI2. These results revealed that mutations in CCDC114 are a cause of ciliary dysmotility and PCD and further demonstrate the utility of exome sequencing to identify genetic causes in heterogeneous recessive disorders.
authors.affiliation: Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA. knowles@med.unc.edu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Margaret W
authors.initials: MW
authors.lastname: Leigh
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Ostrowski
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.forename: Johnny L
authors.initials: JL
authors.lastname: Carson
authors.forename: Milan J
authors.initials: MJ
authors.lastname: Hazucha
authors.forename: Weining
authors.initials: W
authors.lastname: Yin
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Berg
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Davis
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Dell
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Ferkol
authors.forename: Margaret
authors.initials: M
authors.lastname: Rosenfeld
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sagel
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Milla
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Olivier
authors.forename: Emily H
authors.initials: EH
authors.lastname: Turner
authors.forename: Alexandra P
authors.initials: AP
authors.lastname: Lewis
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
mesh_terms: D000328:Adult; D002675:Child, Preschool; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020033:Protein Isoforms; D017422:Sequence Analysis, DNA
chemical_list: D008869:Microtubule-Associated Proteins; C578794:ODAD1 protein, human; D020033:Protein Isoforms