Value of transmission electron microscopy for primary ciliary dyskinesia diagnosis in the era of molecular medicine: Genetic defects with normal and non-diagnostic ciliary ultrastructure

References

• Boon M, Smits A, Cuppens H, et al. Primary ciliary dyskinesia: critical evaluation of clinical symptoms and diagnosis in patients with normal and abnormal ultrastructure. Orphanet J Rare Dis. 2014;9:11.
   PubMed Web of Science ®Google Scholar
• Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med. 2013;188(8):913–922.
   PubMed Web of Science ®Google Scholar
• Kouis P, Yiallouros PK, Middleton N, Evans JS, Kyriacou K, Papatheodorou SI. Prevalence of primary ciliary dyskinesia in consecutive referrals of suspect cases and the transmission electron microscopy detection rate: a systematic review and meta-analysis. Pediatr Res. 2017;81(3):398–405.
   PubMed Web of Science ®Google Scholar
• Papon JF, Coste A, Roudot-Thoraval F, et al. A 20-year experience of electron microscopy in the diagnosis of primary ciliary dyskinesia. Eur Respir J. 2010;35(5):1057–1063. doi:10.1183/09031936.00046209.
   PubMed Web of Science ®Google Scholar
• Shapiro AJ, Zariwala MA, Ferkol T, et al. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review. Pediatr Pulmonol. 2016;51(2):115–132. doi:10.1002/ppul.23304.
   PubMed Web of Science ®Google Scholar
• Bush A, Cole P, Hariri M, et al. Primary ciliary dyskinesia: diagnosis and standards of care. Eur Respir J. 1998;12(4):982–988. doi:10.1183/09031936.98.12040982.
   PubMed Web of Science ®Google Scholar
• Leigh MW, O’Callaghan C, Knowles MR. The challenges of diagnosing primary ciliary dyskinesia. Proc Am Thorac Soc. 2011;8(5):434–437.
   PubMedGoogle Scholar
• Porter ME. Axonemal dyneins: assembly, organization, and regulation. Curr Opin Cell Biol. 1996;8(1):10–17.
   PubMed Web of Science ®Google Scholar
• De Iongh RU, Rutland J. Ciliary defects in healthy subjects, bronchiectasis, and primary ciliary dyskinesia. Am J Respir Crit Care Med. 1995;151(5):1559–1567.
   PubMed Web of Science ®Google Scholar
• O’Callaghan C, Rutman A, Williams GM, Hirst RA. Inner dynein arm defects causing primary ciliary dyskinesia: repeat testing required. Eur Respir J. 2011;38(3):603–607.
   PubMed Web of Science ®Google Scholar
• Zariwala MA, Knowles MR, Leigh MW, et al. Primary ciliary dyskinesia. In: Pagon RA, Adam MP, Ardinger HH, eds. GeneReviews(R). Seattle, WA: University of Washington, Seattle University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved; 1993.
   Google Scholar
• Tanaka H, Iguchi N, Toyama Y, et al. Mice deficient in the axonemal protein Tektin-t exhibit male infertility and immotile-cilium syndrome due to impaired inner arm dynein function. Mol Cell Biol. 2004;24(18):7958–7964. doi:10.1128/MCB.24.18.7958-7964.2004.
   PubMed Web of Science ®Google Scholar
• Ben Khelifa M, Coutton C, Zouari R, et al. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2014;94(1):95–104. doi:10.1016/j.ajhg.2013.11.017.
   PubMed Web of Science ®Google Scholar
• Neesen J, Kirschner R, Ochs M, et al. Disruption of an inner arm dynein heavy chain gene results in asthenozoospermia and reduced ciliary beat frequency. Hum Mol Genet. 2001;10(11):1117–1128. doi:10.1093/hmg/10.11.1117.
   PubMed Web of Science ®Google Scholar
• Carlen B, Lindberg S, Stenram U. Absence of nexin links as a possible cause of primary ciliary dyskinesia. Ultrastruct Pathol. 2003;27(2):123–126.
   PubMed Web of Science ®Google Scholar
• Jorissen M, Willems T, Van Der Schueren B, Verbeken E. Secondary ciliary dyskinesia is absent after ciliogenesis in culture. Acta Otorhinolaryngol Belg. 2000;54(3):333–342.
   PubMedGoogle Scholar
• Jorissen M, Willems T. The secondary nature of ciliary (dis)orientation in secondary and primary ciliary dyskinesia. Acta Otolaryngol. 2004;124(4):527–531.
   PubMed Web of Science ®Google Scholar
• Rossman CM, Lee RM, Forrest JB, Newhouse MT. Nasal ciliary ultrastructure and function in patients with primary ciliary dyskinesia compared with that in normal subjects and in subjects with various respiratory diseases. Am Rev Respir Dis. 1984;129(1):161–167.
   PubMed Web of Science ®Google Scholar
• Knowles MR, Ostrowski LE, Loges NT, et al. Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. Am J Hum Genet. 2013;93(4):711–720. doi:10.1016/j.ajhg.2013.07.025.
   PubMed Web of Science ®Google Scholar
• Blanchon S, Legendre M, Copin B, et al. Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia. J Med Genet. 2012;49(6):410–416. doi:10.1136/jmedgenet-2012-100867.
   PubMed Web of Science ®Google Scholar
• Becker-Heck A, Zohn IE, Okabe N, et al. The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nat Genet. 2011;43(1):79–84. doi:10.1038/ng.727.
   PubMed Web of Science ®Google Scholar
• Merveille AC, Davis EE, Becker-Heck A, et al. CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet. 2011;43(1):72–78. doi:10.1038/ng.726.
   PubMed Web of Science ®Google Scholar
• Antony D, Becker-Heck A, Zariwala MA, et al. Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. Hum Mutat. 2013;34(3):462–472. doi:10.1002/humu.22261.
   PubMed Web of Science ®Google Scholar
• Schwabe GC, Hoffmann K, Loges NT, et al. Primary ciliary dyskinesia associated with normal axoneme ultrastructure is caused by DNAH11 mutations. Hum Mutat. 2008;29(2):289–298. doi:10.1002/humu.20656.
   PubMed Web of Science ®Google Scholar
• Fliegauf M, Olbrich H, Horvath J, et al. Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia. Am J Respir Crit Care Med. 2005;171(12):1343–1349. doi:10.1164/rccm.200411-1583OC.
   PubMed Web of Science ®Google Scholar
• Dougherty GW, Loges NT, Klinkenbusch JA, et al. DNAH11 Localization in the proximal region of respiratory cilia defines distinct outer dynein arm complexes. Am J Respir Cell Mol Biol. 2016;55(2):213–224. doi:10.1165/rcmb.2015-0353OC.
   PubMed Web of Science ®Google Scholar
• Knowles MR, Leigh MW, Carson JL, et al. Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. Thorax. 2012;67(5):433–441. doi:10.1136/thoraxjnl-2011-200301.
   PubMed Web of Science ®Google Scholar
• Lucas JS, Adam EC, Goggin PM, et al. Static respiratory cilia associated with mutations in Dnahc11/DNAH11: a mouse model of PCD. Hum Mutat. 2012;33(3):495–503. doi:10.1002/humu.22001.
   PubMed Web of Science ®Google Scholar
• Shapiro AJ, Davis SD, Ferkol T, et al. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy. Chest. 2014;146(5):1176–1186. doi:10.1378/chest.13-1704.
   PubMed Web of Science ®Google Scholar
• Olbrich H, Haffner K, Kispert A, et al. Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nat Genet. 2002;30(2):143–144. doi:10.1038/ng817.
   PubMed Web of Science ®Google Scholar
• Leigh MW, Hazucha MJ, Chawla KK, et al. Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia. Ann Am Thorac Soc. 2013;10(6):574–581. doi:10.1513/AnnalsATS.201305-110OC.
   PubMedGoogle Scholar
• Dawe HR, Shaw MK, Farr H, Gull K. The hydrocephalus inducing gene product, Hydin, positions axonemal central pair microtubules. BMC Biol. 2007;5:33.
   PubMed Web of Science ®Google Scholar
• Olbrich H, Schmidts M, Werner C, et al. Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry. Am J Hum Genet. 2012;91(4):672–684. doi:10.1016/j.ajhg.2012.08.016.
   PubMed Web of Science ®Google Scholar
• Raidt J, Wallmeier J, Hjeij R, et al. Ciliary beat pattern and frequency in genetic variants of primary ciliary dyskinesia. Eur Respir J. 2014;44(6):1579–1588. doi:10.1183/09031936.00052014.
   PubMed Web of Science ®Google Scholar
• Wallmeier J, Al-Mutairi DA, Chen CT, et al. Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Genet. 2014;46(6):646–651. doi:10.1038/ng.2961.
   PubMed Web of Science ®Google Scholar
• Boon M, Wallmeier J, Ma L, et al. MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Commun. 2014;5:4418.
   PubMed Web of Science ®Google Scholar
• Amirav I, Wallmeier J, Loges NT, et al. Systematic analysis of CCNO variants in a defined population: implications for clinical phenotype and differential diagnosis. Hum Mutat. 2016;37(4):396–405. doi:10.1002/humu.22957.
   PubMed Web of Science ®Google Scholar
• Casey JP, McGettigan PA, Healy F, et al. Unexpected genetic heterogeneity for primary ciliary dyskinesia in the Irish Traveller population. Eur J Hum Genet. 2015;23(2):210–217. doi:10.1038/ejhg.2014.79.
   PubMed Web of Science ®Google Scholar
• Bower R, Tritschler D, Vanderwaal K, et al. The N-DRC forms a conserved biochemical complex that maintains outer doublet alignment and limits microtubule sliding in motile axonemes. Mol Biol Cell. 2013;24(8):1134–1152. doi:10.1091/mbc.E12-11-0801.
   PubMed Web of Science ®Google Scholar
• Wirschell M, Olbrich H, Werner C, et al. The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans. Nat Genet. 2013;45(3):262–268. doi:10.1038/ng.2533.
   PubMed Web of Science ®Google Scholar
• Olbrich H, Cremers C, Loges NT, et al. Loss-of-function GAS8 mutations cause primary ciliary dyskinesia and disrupt the nexin–dynein regulatory complex. Am J Hum Genet. 2015;97(4):546–554. doi:10.1016/j.ajhg.2015.08.012.
   PubMed Web of Science ®Google Scholar
• Horani A, Brody SL, Ferkol TW, et al. CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia. PLoS ONE. 2013;8(8):e72299. doi:10.1371/journal.pone.0072299.
   PubMed Web of Science ®Google Scholar
• Austin-Tse C, Halbritter J, Zariwala MA, et al. Zebrafish ciliopathy screen plus human mutational analysis identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia. Am J Hum Genet. 2013;93(4):672–686. doi:10.1016/j.ajhg.2013.08.015.
   PubMed Web of Science ®Google Scholar
• Davis SD, Ferkol TW, Rosenfeld M, et al. Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med. 2015;191(3):316–324. doi:10.1164/rccm.201409-1672OC.
   PubMed Web of Science ®Google Scholar
• Castleman VH, Romio L, Chodhari R, et al. Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. Am J Hum Genet. 2009;84(2):197–209. doi:10.1016/j.ajhg.2009.01.011.
   PubMed Web of Science ®Google Scholar
• Alsaadi MM, Gaunt TR, Boustred CR, et al. From a single whole exome read to notions of clinical screening: primary ciliary dyskinesia and RSPH9 p.Lys268del in the Arabian Peninsula. Ann Hum Genet. 2012;76(3):211–220. doi:10.1111/j.1469-1809.2012.00704.x.
   PubMed Web of Science ®Google Scholar
• Jeanson L, Copin B, Papon JF, et al. RSPH3 Mutations cause primary ciliary dyskinesia with central-complex defects and a near absence of radial spokes. Am J Hum Genet. 2015;97(1):153–162. doi:10.1016/j.ajhg.2015.05.004.
   PubMed Web of Science ®Google Scholar
• Daniels ML, Leigh MW, Davis SD, et al. Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia. Hum Mutat. 2013;34(10):1352–1356. doi:10.1002/humu.22371.
   PubMed Web of Science ®Google Scholar
• Burgoyne T, Lewis A, Dewar A, et al. Characterizing the ultrastructure of primary ciliary dyskinesia transposition defect using electron tomography. Cytoskeleton. 2014;71(5):294–301. doi:10.1002/cm.21171.
   PubMed Web of Science ®Google Scholar
• Knowles MR, Ostrowski LE, Leigh MW, et al. Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. Am J Respir Crit Care Med. 2014;189(6):707–717. doi:10.1164/rccm.201311-2047OC.
   PubMed Web of Science ®Google Scholar
• Frommer A, Hjeij R, Loges NT, et al. Immunofluorescence analysis and diagnosis of primary ciliary dyskinesia with radial spoke defects. Am J Respir Cell Mol Biol. 2015;53(4):563–573. doi:10.1165/rcmb.2014-0483OC.
   PubMed Web of Science ®Google Scholar
• Onoufriadis A, Shoemark A, Schmidts M, et al. Targeted NGS gene panel identifies mutations in RSPH1 causing primary ciliary dyskinesia and a common mechanism for ciliary central pair agenesis due to radial spoke defects. Hum Mol Genet. 2014;23(13):3362–3374. doi:10.1093/hmg/ddu046.
   PubMed Web of Science ®Google Scholar
• Kott E, Legendre M, Copin B, et al. Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. Am J Hum Genet. 2013;93(3):561–570. doi:10.1016/j.ajhg.2013.07.013.
   PubMed Web of Science ®Google Scholar
• Bukowy-Bieryllo Z, Zietkiewicz E, Loges NT, et al. RPGR mutations might cause reduced orientation of respiratory cilia. Pediatr Pulmonol. 2013;48(4):352–363. doi:10.1002/ppul.22632.
   PubMed Web of Science ®Google Scholar
• Moore A, Escudier E, Roger G, et al. RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa. J Med Genet. 2006;43(4):326–333. doi:10.1136/jmg.2005.034868.
   PubMed Web of Science ®Google Scholar
• Zito I, Downes SM, Patel RJ, et al. RPGR mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infections. J Med Genet. 2003;40(8):609–615. doi:10.1136/jmg.40.8.609.
   PubMed Web of Science ®Google Scholar
• Ohga H, Suzuki T, Fujiwara H, Furutani A, Koga H. [A case of immotile cilia syndrome accompanied by retinitis pigmentosa]. Nippon Ganka Gakkai Zasshi. 1991;95(8):795–801.
   PubMedGoogle Scholar
• Van Dorp DB, Wright AF, Carothers AD, Bleeker-Wagemakers EM. A family with RP3 type of X-linked retinitis pigmentosa: an association with ciliary abnormalities. Hum Genet. 1992;88(3):331–334.
   PubMed Web of Science ®Google Scholar
• Tee JJ, Smith AJ, Hardcastle AJ, Michaelides M. RPGR-associated retinopathy: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol. 2016;100(8):1022–1027.
   PubMed Web of Science ®Google Scholar
• Budny B, Chen W, Omran H, et al. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet. 2006;120(2):171–178. doi:10.1007/s00439-006-0210-5.
   PubMed Web of Science ®Google Scholar
• Horani A, Brody SL, Ferkol TW. Picking up speed: advances in the genetics of primary ciliary dyskinesia. Pediatr Res. 2014;75(1–2):158–164.
   PubMed Web of Science ®Google Scholar