April 05, 2014

The Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) is comprised of 11 geographically-dispersed sites in North America and associated patient advocacy groups (PAGs). The 11 major centers include: NIAID, Principal Investigator (PI): K. Olivier, Bethesda, MD; University of Chicago, PI: P.J. McShane, Chicago, IL; University of Colorado, Denver Children's Hospital, PI: S. Sagel, Denver, CO; National Jewish Health, PI: C. Czaja, Denver, CO; Indiana University, PI: S. Davis, Indianapolis, IN; Stanford University, PI: C. Milla, Palo Alto, CA; University of Washington Children's Hospital & Regional Medical Center, PI: M. Rosenfeld, Seattle, WA; Washington University in St. Louis, PI: T. Ferkol, St. Louis, MO; The Hospital for Sick Children, PI: S. Dell, Toronto, ON; St. Michael's Hospital, PI: D. Hall, Toronto, ON; University of North Carolina at Chapel Hill, PI: M. Knowles and M. Leigh, Chapel Hill, NC. This Consortium studies a variety of rare airways diseases, including Primary Ciliary Dyskinesia (PCD), variant Cystic Fibrosis (CF), airway infection with non-tuberculous mycobacteria (NTM), rare immune disorders, and idiopathic bronchiectasis.

Over the past decade, the GDMCC has made remarkable progress that is already impacting clinical practice. For example, when the GDMCC was established, there was no fully accurate and readily available diagnostic test for PCD, a recessive genetically heterogeneous disorder. In response to that limitation, the GDMCC developed a non-invasive test for PCD (measurement of nasal nitric oxide, nNO) and recently validated that test across multiple sites in North America. The GDMCC was invited to participate in the European BESTCILIA grant proposal, which includes helping to implement nNO testing in Europe. The GDMCC has also played a key role in the discovery of mutations in 20 of the known 28 PCD-causing genes. These genetic discoveries facilitated development of a research genetic test-panel for PCD, which allows simultaneous testing for mutations in all 28 PCD-causing genes, which will identify ~70% of PCD patients. The GDMCC has established that lung disease begins early in life in children with PCD. Based on this information, it is clear that readily available genetic testing will revolutionize diagnosis and initiation of clinical care early in life. Genetic diagnoses will also allow rigorous studies of genotype and phenotype in PCD, as demonstrated by the GDMCC's recent discovery that patients with mutations in RSHP1 have milder clinical disease.

GDMCC studies also demonstrated that PCD-causing mutations are associated with situs ambiguous (heterotaxy). Additionally, these studies found that a subset of patients with heterotaxy have congenital heart disease (CHD) and worse clinical outcome because of unrecognized (and untreated) PCD lung disease. This discovery has spawned a new wave of genetic and clinical studies in patients with heterotaxy and CHD.

Additionally, the GDMCC developed a rigorous quality-of-life (QOL) instrument for pediatric and adult patients with PCD. Through the GDMCC's role in the European BESTCILIA project, this QOL instrument is now being validated in PCD patients in Europe and harmonized for use by regulatory agencies (FDA and EMA) in the U.S. and Europe. This QOL instrument will be a key outcome measure for upcoming therapeutic clinical trials in PCD that might be performed jointly in North America and Europe.

The GDMCC has now extended its concepts of the pathophysiology of Mendelian diseases of the airways to the study of patients with bronchiectasis of unknown etiology (Idiopathic Bronchiectasis), including patients with and without airway infection with NTM. The GDMCC is defining phenotypic markers of disease, including dural ectasia (dilation of the dural sac), a phenotype that overlaps with heritable connective tissue disorders (HCTD), such as Marfan syndrome. Ultimately, the GDMCC will be able to search for genetic variants in structural tissue (HTCD) genes in patients with Idiopathic Bronchiectasis.

The 11 high-quality GDMCC sites consider training new investigators a priority. These sites have either CTSA awards or are leading research institutions in Canada. Over the past decade, the GDMCC has trained 34 individuals with a focus on physician-scientists entering academic careers, particularly for rare disorders. New investigators are trained via participation in Consortium studies, in conjunction with institutional resources, such as CTSA awards. Trainees have been lead or contributing authors for 23 peer-reviewed publications, two book chapters, and 40 abstracts at national conferences. Of the 16 trainees who have completed post-graduate and fellowship training, 13 have academic positions. Fifteen trainees are currently in medical school, residency, or fellowship training programs.

None of this progress would have been possible without the visionary and effective leadership of Steve Groft, Pharm. D., who recently retired as the Director of the Office of Rare Diseases Research (ORDR). Dr. Groft listened to the rare diseases community and initiated the Rare Diseases Clinical Research Network (RDCRN). The RDCRN was first recommended in 2001 in the Report on Steps to Coordinate Rare Diseases Research Programs by a Special Emphasis Panel of the NIH on the Coordination of Rare Diseases Research. This network was subsequently written into law in the Rare Diseases Act of 2002 (PL 1070280). Dr. Groft led and expanded the very successful RDCRN with great enthusiasm and effective administrative leadership. Thank you, Dr. Steve Groft!

The Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) (9U54HL096458-06) is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), and the National Heart Lung and Blood Institute (NHLBI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Michael Knowles

Michael Knowles, MD

PI, Genetic Disorders of Mucociliary Clearance Consortium,
Professor of Medicine
Codirector, Cystic Fibrosis Clinical Center

Genetic Disorders of Mucociliary Clearance Publications

Journal Articles

  1. Fliegauf M, Olbrich H, Horvath J, Wildhaber JH, Zariwala MA, Kennedy M, Knowles MR, Omran H. Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia. Am. J. Respir. Crit. Care Med. Jun 15 2005;171(12):1343-1349. PMID: 15750039, PMCID: PMC2718478
  2. Kennedy MP, Omran H, Leigh MW, Dell S, Morgan L, Molina PL, Robinson BV, Minnix SL, Olbrich H, Severin T, Ahrens P, Lange L, Morillas HN, Noone PG, Zariwala MA, Knowles MR. Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation. Jun 5 2007;115(22):2814-2821. PMID: 17515466
  3. Brown DE, Pittman JE, Leigh MW, Fordham L, Davis SD. Early lung disease in young children with primary ciliary dyskinesia. Pediatr. Pulmonol. May 2008;43(5):514-516. PMID: 18383332
  4. Leigh MW, Zariwala MA, Knowles MR. Primary ciliary dyskinesia: improving the diagnostic approach. Curr. Opin. Pediatr. Jun 2009;21(3):320-325. PMID: 19300264, PMCID: PMC3665363
  5. Leigh MW, Pittman JE, Carson JL, Ferkol TW, Dell SD, Davis SD, Knowles MR, Zariwala MA. Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet. Med. Jul 2009;11(7):473-487. PMID: 19606528, PMCID: PMC3739704
  6. Loges NT, Olbrich H, Becker-Heck A, Haffner K, Heer A, Reinhard C, Schmidts M, Kispert A, Zariwala MA, Leigh MW, Knowles MR, Zentgraf H, Seithe H, Nurnberg G, Nurnberg P, Reinhardt R, Omran H. Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects. Am. J. Hum. Genet. Dec 2009;85(6):883-889. PMID: 19944400, PMCID: PMC2795801
  7. Lie H, Zariwala MA, Helms C, Bowcock AM, Carson JL, Brown DE, 3rd, Hazucha MJ, Forsen J, Molter D, Knowles MR, Leigh MW, Ferkol TW. Primary ciliary dyskinesia in Amish communities. J. Pediatr. Jun 2010;156(6):1023-1025. PMID: 20350728, PMCID: PMC2875274
  8. Czaja C, Stewart D, Levin A, Aksamit T, LaVange L, O'Donnell A, Knowles M, Thomashow B, Daley C. Prevalence and clinical significance of mucoid pseudomonas aeruginosa infection in adults with non-cystic fibrosis bronchiectasis – results from the Bronchiectasis Research Registry. Am. J. Respir. Crit. Care Med. 2011;183.
  9. Berg JS, Evans JP, Leigh MW, Omran H, Bizon C, Mane K, Knowles MR, Weck KE, Zariwala MA. Next generation massively parallel sequencing of targeted exomes to identify genetic mutations in primary ciliary dyskinesia: implications for application to clinical testing. Genet. Med. Mar 2011;13(3):218-229. PMID: 21270641, PMCID: PMC3755008
  10. Leigh MW, O'Callaghan C, Knowles MR. The challenges of diagnosing primary ciliary dyskinesia. Proc. Am. Thorac. Soc. Sep 2011;8(5):434-437. PMID: 21926395, PMCID: PMC3209576
  11. Zariwala MA, Omran H, Ferkol TW. The emerging genetics of primary ciliary dyskinesia. Proc. Am. Thorac. Soc. Sep 2011;8(5):430-433. PMID: 21926394, PMCID: PMC3209577
  12. Sagel SD, Davis SD, Campisi P, Dell SD. Update of respiratory tract disease in children with primary ciliary dyskinesia. Proc. Am. Thorac. Soc. Sep 2011;8(5):438-443. PMID: 21926396, PMCID: PMC3209579
  13. Davis SD, Knowles M, Leigh M. Introduction: primary ciliary dyskinesia and overlapping syndromes. Proc. Am. Thorac. Soc. Sep 2011;8(5):421-422. PMID: 21926392 
  14. Mateos-Corral D, Coombs R, Grasemann H, Ratjen F, Dell SD. Diagnostic value of nasal nitric oxide measured with non-velum closure techniques for children with primary ciliary dyskinesia. J. Pediatr. Sep 2011;159(3):420-424. PMID: 21514598
  15. Ostrowski LE, Dutcher SK, Lo CW. Cilia and models for studying structure and function. Proc. Am. Thorac. Soc. Sep 2011;8(5):423-429. PMID: 21926393, PMCID: PMC3209580
  16. Stillwell PC, Wartchow EP, Sagel SD. Primary Ciliary Dyskinesia in Children: A Review for Pediatricians, Allergists, and Pediatric Pulmonologists. Pediatric allergy, immunology, and pulmonology. Dec 2011;24(4):191-196. PMID: 22276227, PMCID: PMC3255511
  17. Noone PJ, Olson CA, Zariwala MA, Baker BR, Burns KA, Omran H, Leigh M, Knowles M. Characterization of ciliary axonemal defects in PCD patients with biallelic mutations in 5 PCD-causing genes. Am. J. Respir. Crit. Care Med. 2012;185.
  18. Leigh M, Chawla KK, Baker BR, Hazucha MJ, Brown DE, LaVange L, Horton BJ, Qaqish BF, Carson JL, Davis SD, Dell SD, Ferkol TW, Atkinson JJ, Olivier KN, Sagel SD, Rosenfeld C, Milla C, Zariwala MA, Knowles M. For the Genetic Diseases of Mucociliary Clearance Consortium. Standardization of nasal nitric oxide as screening test for primary ciliary dyskinesia. Am. J. Respir. Crit. Care Med. 2012;185. PMID: 21926395, PMCID: PMC3209576
  19. Ferkol TW, Druley T, Horani M, Zariwala MA, Leigh M, Knowles M, Brody SL, Dutcher S. Whole-exome sequencing identifies a recessive HEATR2 mutation in Amish PCD patients. Am. J. Respir. Crit. Care Med. 2012;185.
  20. Ferkol TW, Leigh MW. Ciliopathies: the central role of cilia in a spectrum of pediatric disorders. J. Pediatr. Mar 2012;160(3):366-371. PMID: 22177992, PMCID: PMC3282141
  21. Knowles MR, Leigh MW, Zariwala MA. Cutting edge genetic studies in primary ciliary dyskinesia. Thorax. May 2012;67(5):464; author reply 464. PMID: 22328589
  22. Knowles MR, Leigh MW, Carson JL, Davis SD, Dell SD, Ferkol TW, Olivier KN, Sagel SD, Rosenfeld M, Burns KA, Minnix SL, Armstrong MC, Lori A, Hazucha MJ, Loges NT, Olbrich H, Becker-Heck A, Schmidts M, Werner C, Omran H, Zariwala MA. Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. Thorax. May 2012;67(5):433-441. PMID: 22184204, PMCID: PMC3739700
  23. Horani A, Druley TE, Zariwala MA, Patel AC, Levinson BT, Van Arendonk LG, Thornton KC, Giacalone JC, Albee AJ, Wilson KS, Turner EH, Nickerson DA, Shendure J, Bayly PV, Leigh MW, Knowles MR, Brody SL, Dutcher SK, Ferkol TW. Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia. Am. J. Hum. Genet. Oct 5 2012;91(4):685-693. PMID: 23040496, PMCID: PMC3484505
  24. Knowles MR, Leigh MW, Ostrowski LE, Huang L, Carson JL, Hazucha MJ, Yin W, Berg JS, Davis SD, Dell SD, Ferkol TW, Rosenfeld M, Sagel SD, Milla CE, Olivier KN, Turner EH, Lewis AP, Bamshad MJ, Nickerson DA, Shendure J, Zariwala MA. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am. J. Hum. Genet. Jan 10 2013;92(1):99-106. PMID: 23261302, PMCID: PMC3542458
  25. Sears PR, Thompson K, Knowles MR, Davis CW. Human airway ciliary dynamics. Am. J. Physiol. Lung Cell. Mol. Physiol. Feb 1 2013;304(3):L170-183. PMID: 23144323, PMCID: PMC3567369
  26. Antony D, Becker-Heck A, Zariwala MA, Schmidts M, Onoufriadis A, Forouhan M, Wilson R, Taylor-Cox T, Dewar A, Jackson C, Goggin P, Loges NT, Olbrich H, Jaspers M, Jorissen M, Leigh MW, Wolf WE, Daniels ML, Noone PG, Ferkol TW, Sagel SD, Rosenfeld M, Rutman A, Dixit A, O'Callaghan C, Lucas JS, Hogg C, Scambler PJ, Emes RD, Uk10k, Chung EM, Shoemark A, Knowles MR, Omran H, Mitchison HM. Mutations in CCDC39 and CCDC40 are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms. Hum. Mutat. Mar 2013;34(3):462-472. PMID: 23255504, PMCID: PMC3630464 
  27. Fowler CJ, Olivier KN, Leung JM, et al. Abnormal nasal nitric oxide production, ciliary beat frequency, and Toll-like receptor response in pulmonary nontuberculous mycobacterial disease epithelium. Am. J. Respir. Crit. Care Med. Jun 15 2013;187(12):1374-1381. PMID: 23593951, PMCID: PMC3734613
  28. Ferkol TW, Puffenberger EG, Lie H, et al. Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities. J. Pediatr. Aug 2013;163(2):383-387. PMID: 23477994, PMCID: PMC3725203
  29. Hjeij R, Lindstrand A, Francis R, et al. ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry. Am. J. Hum. Genet. Aug 8 2013;93(2):357-367. PMID: 23849778, PMCID: PMC3738828 
  30. Zariwala MA, Gee HY, Kurkowiak M, et al. ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. Am. J. Hum. Genet. Aug 8 2013;93(2):336-345. PMID: 23891469, PMCID: PMC3738827 
  31. Tarkar A, Loges NT, Slagle CE, et al. DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nat. Genet. Sep 2013;45(9):995-1003. PMID: 23872636 
  32. 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. Oct 3 2013;93(4):711-720. PMID: 24055112, PMCID: PMC3791252 
  33. 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. Oct 15 2013;188(8):913-922. PMID: 23796196, PMCID: PMC3826280 
  34. 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. Feb 25 2014. PMID: 24568568 
  35. 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. Feb 27 2014. PMID: 24577564

By Michael Knowles, MD
May 2014