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Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene

Nature Genetics volume 45, pages 1160–1167 (2013)Cite this article

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Abstract

Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of ł0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.

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Figure 1: Data collected for the CFTR2 project.
Figure 2: The process used to define CFTR variants as cystic fibrosis causing on the basis of a biochemical measure.
Figure 3: The process used to define CFTR variants as cystic fibrosis causing on the basis of functional analysis.
Figure 4: Assignment of disease liability to the 159 most frequent CFTR variants using three criteria.

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Acknowledgements

The authors would like to thank the subjects who participated in their national/clinic registries. The authors thank D. Gruenert (University of California, San Francisco) for CFBE 41o- cells and M. Welsh (University of Iowa) for FRT cells. This work was supported by grants from the NIDDK (5R37DK044003 to G.R.C.) and the US NIH (DK49835 to P.J.T.) and by funding from Cystic Fibrosis Foundation Therapeutics, Inc. (to P.J.T.), the US Cystic Fibrosis Foundation (CUTTING08A, CUTTING09A and CUTTING10A to G.R.C. and SOSNAY10Q to P.R.S.) and FCTPortugal (PIC/IC/83103/2007 and PEstOE/BIA/UI4046/2011 to M.D.A. and BioFIG). Assistance with statistical analysis was provided by E. Johnson, M.B. Drummond, D. Cutler and D. Arking. The authors received considerable guidance from the CFTR2 clinical expert panel: C. De Boeck, P. Durie, S. Elborn, P. Farrell, M. Knowles and I. Sermet; from the CFTR2 functional studies expert panel: R. Bridges, G. Lukacs and D. Sheppard; and from M. Sheridan who provided critical review.

DNA samples from fathers of individuals with cystic fibrosis were contributed by T. Casals (Bellvitge Biomedical Research Institute, Spain), G. Cutting (Johns Hopkins University, USA), C. Dechecchi (University Hospital of Verona, Italy), R. Dorfman (The Hospital for Sick Children, Canada), C. Ferec (Centre Hospitalier Universitaire, France), E. Girodon (GH Henri Mondor, France), M. Macek Jr. (Charles University, Czech Republic), D. Radojkovic (Institute of Molecular Genetics and Genetic Engineering, Serbia), M. Schwarz (St. Mary's Hospital, UK), M. Seia (Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Italy), M. Stuhrmann (Medical School Hannover, Germany), M. Tzetis (National Kapodistrian University of Athens, Greece) and J. Zielenski (The Hospital for Sick Children, Canada, with partial support from Genome Canada, through the Ontario Genomics Institute per research agreement 2004-OGI-3-05).

CFTR2 data were contributed by C. Barreto (Hospital Santa Maria, Portugal), D. Bilton (Royal Brompton and Harefield Hospital, UK), J. Borg (University of Malta, Malta), C. Colombo (University of Milan, Italy), S. Doudounakis (Aghia Sophia Children's Hospital, Greece), H. Ellemunter (Innsbruck Medical University, Austria), G. Fletcher (Cystic Fibrosis Registry of Ireland, Ireland), I. Galeva (University Hospital Aleksandrovska, Bulgaria), S. Gartner (Hospital Vall de Hebron Unidad de Fibrosis Quistica, Spain), V.A.M. Gulmans (Dutch Cystic Fibrosis Foundation, The Netherlands), E. Hatziagorou (Aristotle University, Greece), L. Hjelte (Karolinska Institutet, Sweden), T. Kahre (University of Tartu, Estonia), N. Kashirskaya (Russian Academy of Medical Sciences, Russia), A. Katelari (Aghia Sophia Children's Hospital, Greece), P. Laissue (Universidad del Rosario, Colombia), L. Lemonnier (Association Vaincre La Mucoviscidose, France), A. Lindblad (Sahlgrenska University Hospital, Sweden), V. Lucidi (Ospedale Bambino Gesù, Italy), M. Macek Jr. (Charles University, Czech Republic), H. Makukh (Ukrainian Academy of Medical Sciences, Ukraine), B. Marshall (US Cystic Fibrosis Foundation, USA), I. McIntosh (Cystic Fibrosis Canada, Canada), M. Mei-Zahav (Tel Aviv University, Israel), P. Minic (Mother and Child Health Institute of Serbia, Serbia), H. Vebert Olesen (Aarhus University Hospital, Denmark), N. Petrova (Russian Academy of Medical Sciences, Russia), T. Pressler (University of Copenhagen, Denmark), D. Radivojevic (Mother and Child Health Institute of Serbia, Serbia), S. Ravilly (Association Vaincre La Mucoviscidose, France), N. Regamey (University Hospital Bern, Switzerland), G. Repetto (Universidad del Desarrollo, Chile), M.T. Sanseverino (Hospital de Clinicas de Porto Alegre, Brazil), C. Scerri (University of Malta, Malta), A. Stephenson (Cystic Fibrosis Canada, Canada), M. Stern (University of Tübingen, Germany), V. Svabe (Riga Stradins University, Latvia), M. Thomas (Belgian Cystic Fibrosis Registry, Belgium), J. Tsanakas (Aristotle University, Greece), V. Vavrova (Charles University and University Hospital Motol, Czech Republic) and P. Wenzlaff (Centre for Quality and Management in Health Care, Germany).

Author information

Authors and Affiliations

  1. Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA

    Patrick R Sosnay

  2. Perdana University Graduate School of Medicine, Serdang, Malaysia

    Patrick R Sosnay

  3. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA

    Patrick R Sosnay, Karen R Siklosi, Kyle Kaniecki, Neeraj Sharma & Garry R Cutting

  4. Vertex Pharmaceuticals, Inc., San Diego, California, USA

    Fredrick Van Goor & Haihui Yu

  5. Department of Genetics and Development, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Kyle Kaniecki

  6. Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), Faculty of Sciences, University of Lisboa, Lisbon, Portugal

    Anabela S Ramalho & Margarida D Amaral

  7. Department of Genetics, National Institute of Health, Lisbon, Portugal

    Anabela S Ramalho & Margarida D Amaral

  8. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada

    Ruslan Dorfman, Julian Zielenski & Johanna M Rommens

  9. Geneyouin, Inc., Maple, Ontario, Canada

    Ruslan Dorfman

  10. Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA

    David L Masica & Rachel Karchin

  11. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Linda Millen & Philip J Thomas

  12. Department of Pharmacy, School of Health Sciences, University of Patras, University Campus, Patras, Greece

    George P Patrinos

  13. Program in Child Evaluative Health Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada

    Mary Corey

  14. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    Mary Corey

  15. Genetics and Public Policy Center, Berman Institute for Bioethics, Johns Hopkins University, Baltimore, Maryland, USA

    Michelle H Lewis

  16. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    Johanna M Rommens

  17. Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy

    Carlo Castellani

  18. Cystic Fibrosis Foundation, Bethesda, Maryland, USA

    Christopher M Penland

  19. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Garry R Cutting

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  1. Patrick R Sosnay
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Contributions

P.R.S. jointly supervised research, collected and curated clinical data, performed statistical analysis, analyzed the data and wrote the manuscript. K.R.S. curated clinical data, analyzed the data and wrote the manuscript. F.V.G. and H.Y. conceived, designed and performed chloride conduction experiments and analyzed the data. K.K. conceived, designed and performed the penetrance analysis and analyzed the data. N.S., A.S.R. and M.D.A. conceived, designed and performed splicing analysis and analyzed the data. R.D. and J.Z. curated variant data for CFMD. D.L.M. and R.K. performed algorithm analysis. L.M. and P.J.T. conceived, designed and performed the CFTR processing experiments and analyzed the data. G.P.P. advised and aided in the design and implementation of the microattribution process. M.C. jointly supervised research and analyzed the data. M.H.L. jointly supervised research and analyzed the data. J.M.R. curated data for CFMD, jointly supervised research and analyzed the data. C.C. coordinated the collection of clinical data, jointly supervised research and analyzed the data. C.M.P. jointly supervised research and analyzed the data. G.R.C. supervised research, conceived and designed experiments, analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Garry R Cutting.

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Competing interests

F.VG. is employed by Vertex Pharmaceuticals. H.Y. is employed by Vertex Pharmaceuticals and owns stock in the company. P.J.T. has financial interest in and sponsored research from Reata Pharmaceuticals. G.R.C. is a consultant for the Cystic Fibrosis Foundation, Vertex Pharmaceuticals, Illumina, aTyr Pharma and Canon Biosciences.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–7 and Supplementary Tables 1, 3 and 4 (PDF 515 kb)

Supplementary Table 2

Phenotype summary and curated disease liability of 159 CFTR mutations (XLSX 197 kb)

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Sosnay, P., Siklosi, K., Van Goor, F. et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet 45, 1160–1167 (2013). https://doi.org/10.1038/ng.2745

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