2. Academic Validation
  3. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia

Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia

  • Am J Hum Genet. 2013 Jan 10;92(1):99-106. doi: 10.1016/j.ajhg.2012.11.003.
Michael R Knowles 1,  Margaret W Leigh,  Lawrence E Ostrowski,  Lu Huang,  Johnny L Carson,  Milan J Hazucha,  Weining Yin,  Jonathan S Berg,  Stephanie D Davis,  Sharon D Dell,  Thomas W Ferkol,  Margaret Rosenfeld,  Scott D Sagel,  Carlos E Milla,  Kenneth N Olivier,  Emily H Turner,  Alexandra P Lewis,  Michael J Bamshad,  Deborah A Nickerson,  Jay Shendure,  Maimoona A Zariwala,  Genetic Disorders of Mucociliary Clearance Consortium
Affiliations

Affiliation

  • 1 Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA. knowles@med.unc.edu
PMID: 23261302 DOI: 10.1016/j.ajhg.2012.11.003
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.

Figures