TY - JOUR
T1 - Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia
AU - Knowles, Michael R.
AU - Leigh, Margaret W.
AU - Ostrowski, Lawrence E.
AU - Huang, Lu
AU - Carson, Johnny L.
AU - Hazucha, Milan J.
AU - Yin, Weining
AU - Berg, Jonathan S.
AU - Davis, Stephanie D.
AU - Dell, Sharon D.
AU - Ferkol, Thomas W.
AU - Rosenfeld, Margaret
AU - Sagel, Scott D.
AU - Milla, Carlos E.
AU - Olivier, Kenneth N.
AU - Turner, Emily H.
AU - Lewis, Alexandra P.
AU - Bamshad, Michael J.
AU - Nickerson, Deborah A.
AU - Shendure, Jay
AU - Zariwala, Maimoona A.
N1 - Funding Information:
Funding support for research was provided to M.R.K., M.W.L., J.L.C., M.J.H., S.D. Davis, S.D. Dell, T.W.F., K.N.O., S.D.S., M.R., C.E.M., and M.A.Z. by US NIH/ORDR/NHLBI grant 5U54 HL096458-06, to M.R.K., L.E.O., and M.A.Z. by NIH-NHLBI grant 5R01HL071798, to J.S. and D.A.N. by NIH-NHLBI grant 5R01HL094976, to M.J.B. by NIH-NHLBI grant RC2 HL-102923, and to J.S. by NIH/NHGRI grant 5R21HG004749 and NIH/NCATS grants UL1 TR000083, UL1 TR000154, and CFF R026-CR07. In addition, this publication was made possible by grants from the ORDR, NHLBI, NHGRI, and NCATS, components of NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.
PY - 2013/1/10
Y1 - 2013/1/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84872285578&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.11.003
DO - 10.1016/j.ajhg.2012.11.003
M3 - Article
C2 - 23261302
AN - SCOPUS:84872285578
SN - 0002-9297
VL - 92
SP - 99
EP - 106
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -