RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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: Nada Hornef; Heike Olbrich; Judit Horvath; Maimoona A Zariwala; Manfred Fliegauf; Niki Tomas Loges; Johannes Wildhaber; Peadar G Noone; Marcus Kennedy; Stylianos E Antonarakis; Jean-Louis Blouin; Lucia Bartoloni; Thomas Nüsslein; Peter Ahrens; Matthias Griese; Heiner Kuhl; Ralf Sudbrak; Michael R Knowles; Richard Reinhardt; Heymut Omran Journal: Am J Respir Crit Care Med Date: 2006-04-20 Impact factor: 21.405
Authors: Rim Hjeij; Anna Lindstrand; Richard Francis; Maimoona A Zariwala; Xiaoqin Liu; You Li; Rama Damerla; Gerard W Dougherty; Marouan Abouhamed; Heike Olbrich; Niki T Loges; Petra Pennekamp; Erica E Davis; Claudia M B Carvalho; Davut Pehlivan; Claudius Werner; Johanna Raidt; Gabriele Köhler; Karsten Häffner; Miguel Reyes-Mugica; James R Lupski; Margaret W Leigh; Margaret Rosenfeld; Lucy C Morgan; Michael R Knowles; Cecilia W Lo; Nicholas Katsanis; Heymut Omran Journal: Am J Hum Genet Date: 2013-07-11 Impact factor: 11.025
Authors: Anne-Christine Merveille; Erica E Davis; Anita Becker-Heck; Marie Legendre; Israel Amirav; Géraldine Bataille; John Belmont; Nicole Beydon; Frédéric Billen; Annick Clément; Cécile Clercx; André Coste; Rachelle Crosbie; Jacques de Blic; Stephane Deleuze; Philippe Duquesnoy; Denise Escalier; Estelle Escudier; Manfred Fliegauf; Judith Horvath; Kent Hill; Mark Jorissen; Jocelyne Just; Andreas Kispert; Mark Lathrop; Niki Tomas Loges; June K Marthin; Yukihide Momozawa; Guy Montantin; Kim G Nielsen; Heike Olbrich; Jean-François Papon; Isabelle Rayet; Gilles Roger; Miriam Schmidts; Henrique Tenreiro; Jeffrey A Towbin; Diana Zelenika; Hanswalter Zentgraf; Michel Georges; Anne-Sophie Lequarré; Nicholas Katsanis; Heymut Omran; Serge Amselem Journal: Nat Genet Date: 2010-12-05 Impact factor: 38.330
Authors: Christina Austin-Tse; Jan Halbritter; Maimoona A Zariwala; Renée M Gilberti; Heon Yung Gee; Nathan Hellman; Narendra Pathak; Yan Liu; Jennifer R Panizzi; Ramila S Patel-King; Douglas Tritschler; Raqual Bower; Eileen O'Toole; Jonathan D Porath; Toby W Hurd; Moumita Chaki; Katrina A Diaz; Stefan Kohl; Svjetlana Lovric; Daw-Yang Hwang; Daniela A Braun; Markus Schueler; Rannar Airik; Edgar A Otto; Margaret W Leigh; Peadar G Noone; Johnny L Carson; Stephanie D Davis; Jessica E Pittman; Thomas W Ferkol; Jeffry J Atkinson; Kenneth N Olivier; Scott D Sagel; Sharon D Dell; Margaret Rosenfeld; Carlos E Milla; Niki T Loges; Heymut Omran; Mary E Porter; Stephen M King; Michael R Knowles; Iain A Drummond; Friedhelm Hildebrandt Journal: Am J Hum Genet Date: 2013-10-03 Impact factor: 11.025
Authors: Philippe Duquesnoy; Estelle Escudier; Laetitia Vincensini; Judy Freshour; Anne-Marie Bridoux; André Coste; Antoine Deschildre; Jacques de Blic; Marie Legendre; Guy Montantin; Henrique Tenreiro; Anne-Marie Vojtek; Céline Loussert; Annick Clément; Denise Escalier; Philippe Bastin; David R Mitchell; Serge Amselem Journal: Am J Hum Genet Date: 2009-12 Impact factor: 11.025
Authors: Jagathpala Shetty; Kenneth L Klotz; Michael J Wolkowicz; Charles J Flickinger; John C Herr Journal: Gene Date: 2007-03-23 Impact factor: 3.688
Authors: Daniel J Moore; Alexandros Onoufriadis; Amelia Shoemark; Michael A Simpson; Petra I zur Lage; Sandra C de Castro; Lucia Bartoloni; Giuseppe Gallone; Stavroula Petridi; Wesley J Woollard; Dinu Antony; Miriam Schmidts; Teresa Didonna; Periklis Makrythanasis; Jeremy Bevillard; Nigel P Mongan; Jana Djakow; Gerard Pals; Jane S Lucas; June K Marthin; Kim G Nielsen; Federico Santoni; Michel Guipponi; Claire Hogg; Stylianos E Antonarakis; Richard D Emes; Eddie M K Chung; Nicholas D E Greene; Jean-Louis Blouin; Andrew P Jarman; Hannah M Mitchison Journal: Am J Hum Genet Date: 2013-07-25 Impact factor: 11.025
Authors: Michael R Knowles; Lawrence E Ostrowski; Niki T Loges; Toby Hurd; Margaret W Leigh; Lu Huang; Whitney E Wolf; Johnny L Carson; Milan J Hazucha; Weining Yin; Stephanie D Davis; Sharon D Dell; Thomas W Ferkol; Scott D Sagel; Kenneth N Olivier; Charlotte Jahnke; Heike Olbrich; Claudius Werner; Johanna Raidt; Julia Wallmeier; Petra Pennekamp; Gerard W Dougherty; Rim Hjeij; Heon Yung Gee; Edgar A Otto; Jan Halbritter; Moumita Chaki; Katrina A Diaz; Daniela A Braun; Jonathan D Porath; Markus Schueler; György Baktai; Matthias Griese; Emily H Turner; Alexandra P Lewis; Michael J Bamshad; Deborah A Nickerson; Friedhelm Hildebrandt; Jay Shendure; Heymut Omran; Maimoona A Zariwala Journal: Am J Hum Genet Date: 2013-09-19 Impact factor: 11.025
Authors: Stephanie D Davis; Thomas W Ferkol; Margaret Rosenfeld; Hye-Seung Lee; Sharon D Dell; Scott D Sagel; Carlos Milla; Maimoona A Zariwala; Jessica E Pittman; Adam J Shapiro; Johnny L Carson; Jeffrey P Krischer; Milan J Hazucha; Matthew L Cooper; Michael R Knowles; Margaret W Leigh Journal: Am J Respir Crit Care Med Date: 2015-02-01 Impact factor: 21.405
Authors: Louis J Vuga; Neil R Aggarwal; Lora A Reineck; Roya Kalantari; Koyeli Banerjee; James Kiley Journal: Chest Date: 2019-05-20 Impact factor: 9.410
Authors: Eva P Szymanski; Janice M Leung; Cedar J Fowler; Carissa Haney; Amy P Hsu; Fei Chen; Priya Duggal; Andrew J Oler; Ryan McCormack; Eckhard Podack; Rebecca A Drummond; Michail S Lionakis; Sarah K Browne; D Rebecca Prevots; Michael Knowles; Gary Cutting; Xinyue Liu; Scott E Devine; Claire M Fraser; Hervé Tettelin; Kenneth N Olivier; Steven M Holland Journal: Am J Respir Crit Care Med Date: 2015-09-01 Impact factor: 21.405
Authors: Weining Yin; Alessandra Livraghi-Butrico; Patrick R Sears; Troy D Rogers; Kimberlie A Burns; Barbara R Grubb; Lawrence E Ostrowski Journal: Am J Respir Cell Mol Biol Date: 2019-09 Impact factor: 6.914
Authors: Adam J Shapiro; Sharon D Dell; Benjamin Gaston; Michael O'Connor; Nadzeya Marozkina; Michele Manion; Milan J Hazucha; Margaret W Leigh Journal: Ann Am Thorac Soc Date: 2020-02
Authors: Adrien Frommer; Rim Hjeij; Niki T Loges; Christine Edelbusch; Charlotte Jahnke; Johanna Raidt; Claudius Werner; Julia Wallmeier; Jörg Große-Onnebrink; Heike Olbrich; Sandra Cindrić; Martine Jaspers; Mieke Boon; Yasin Memari; Richard Durbin; Anja Kolb-Kokocinski; Sascha Sauer; June K Marthin; Kim G Nielsen; Israel Amirav; Nael Elias; Eitan Kerem; David Shoseyov; Karsten Haeffner; Heymut Omran Journal: Am J Respir Cell Mol Biol Date: 2015-10 Impact factor: 6.914
Authors: Elma El Khouri; Lucie Thomas; Ludovic Jeanson; Emilie Bequignon; Benoit Vallette; Philippe Duquesnoy; Guy Montantin; Bruno Copin; Florence Dastot-Le Moal; Sylvain Blanchon; Jean François Papon; Patrick Lorès; Li Yuan; Nathalie Collot; Sylvie Tissier; Catherine Faucon; Gérard Gacon; Catherine Patrat; Jean Philippe Wolf; Emmanuel Dulioust; Bruno Crestani; Estelle Escudier; André Coste; Marie Legendre; Aminata Touré; Serge Amselem Journal: Am J Hum Genet Date: 2016-08-04 Impact factor: 11.025
Authors: Adam J Shapiro; Stephanie D Davis; Deepika Polineni; Michele Manion; Margaret Rosenfeld; Sharon D Dell; Mark A Chilvers; Thomas W Ferkol; Maimoona A Zariwala; Scott D Sagel; Maureen Josephson; Lucy Morgan; Ozge Yilmaz; Kenneth N Olivier; Carlos Milla; Jessica E Pittman; M Leigh Anne Daniels; Marcus Herbert Jones; Ibrahim A Janahi; Stephanie M Ware; Sam J Daniel; Matthew L Cooper; Lawrence M Nogee; Billy Anton; Tori Eastvold; Lynn Ehrne; Elena Guadagno; Michael R Knowles; Margaret W Leigh; Valery Lavergne Journal: Am J Respir Crit Care Med Date: 2018-06-15 Impact factor: 21.405