CoChat
Sign Up
Cited by 630Cystic Fibrosis Research AdvancesGenomics and Rare DiseasesGenetic Associations and Epidemiology

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

Open access
Sosnay, Patrick R, Siklosi, Karen R, Van Goor, Fredrick, Kaniecki, Kyle, Yu, Haihui, Sharma, Neeraj, Ramalho, Anabela S, Amaral, Margarida D +13 more·2013·Nature Genetics
DOI 10.1038/ng.2745PMC PMC3874936
Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/ng.2745

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In the context of dominant disorders, the detection of a variant in trans with a pathogenic variant can be considered supporting evidence for a benign impact (BP2) or in certain well-developed disease models, may even be considered stand-alone evidence as has been validated for use in assessing CFTR variants.

    “In the context of dominant disorders, the detection of a variant in trans with a pathogenic variant can be considered supporting evidence for a benign impact (BP2) or in certain welldeveloped disease models, may even be considered stand-alone evidence as has been validated for use in assessing CFTR variants.”

    From Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (2015) · cites this paper as [3]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • The splice mutation 1717-1G->A likely does not give rise to correctable protein expression.

    “which likely does not give rise to correctable protein expression (2).”

    From Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination (2020) · cites this paper as [2]

    The Results (Functional analysis; page unavailable) say that variants affecting canonical splice-site nucleotides can lead to mRNA decay and no protein production, which supports the claim’s general rationale. Our copy does not identify 1717-1G->A specifically or assess whether protein from that variant is correctable. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 74

  1. [1]Chenevix-Trench G Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance Cancer Res 2006 66 2019 2027 16489001
  2. [2]Easton DF A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes Am J Hum. Genet 2007 81 873 883 17924331 PMC2265654
  3. [3]Plon SE Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results Hum. Mutat 2008 29 1282 1291 18951446 PMC3075918
  4. [4]Richards CS ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007 Genet. Med 2008 10 294 300 18414213
  5. [5]Bamshad MJ Exome sequencing as a tool for Mendelian disease gene discovery Nat. Rev. Genet 2011 12 745 755 21946919
  6. [6]Kricka LJ Di RC Translating genes into health Nat. Genet 2013 45 4 5 23268128
  7. [7]Samuels ME Rouleau GA The case for locus-specific databases Nat. Rev. Genet 2011 12 378 379 21540879
  8. [8]Celli J Dalgleish R Vihinen M Taschner PE den Dunnen JT Curating gene variant databases (LSDBs): toward a universal standard Hum. Mutat 2012 33 291 297 21990126
  9. [9]Vihinen M den Dunnen JT Dalgleish R Cotton RG Guidelines for establishing locus specific databases Hum. Mutat 2012 33 298 305 22052659
  10. [10]Xue Y Deleterious- and Disease-Allele Prevalence in Healthy Individuals: Insights from Current Predictions, Mutation Databases, and Population-Scale Resequencing Am. J. Hum. Genet 2012 91 1022 1032 23217326 PMC3516590
  11. [11]Watson MS Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel Genet. Med 2004 6 387 391 15371902 PMC3110945
  12. [12]Southern KW A survey of newborn screening for cystic fibrosis in Europe J Cyst. Fibros 2007 6 57 65 16870510
  13. [13]Krulisova V Prospective and parallel assessments of cystic fibrosis newborn screening protocols in the Czech Republic: IRT/DNA/IRT versus IRT/PAP and IRT/PAP/DNA Eur. J. Pediatr 2012 171 1223 1229 22581207
  14. [14]Vernooij-van Langen AM Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study Thorax 2012 67 289 295 22271776
  15. [15]Massie RJ Curnow L Glazner J Armstrong DS Francis I Lessons learned from 20 years of newborn screening for cystic fibrosis Med. J. Aust 2012 196 67 70 22256939
  16. [16]Amos JA Bridge-Cook P Ponek V Jarvis MR A universal array-based multiplexed test for cystic fibrosis carrier screening Expert. Rev. Mol. Diagn 2006 6 15 22 16359263
  17. [17]Strom CM Cystic fibrosis testing 8 years on: lessons learned from carrier screening and sequencing analysis Genet. Med 2011 13 166 172 21068670
  18. [18]Grody WW Cutting GR Watson MS The Cystic Fibrosis mutation “arms race”: when less is more Genet Med 2007 9 739 744 18007142
  19. [19]Dorfman R Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? Clin Genet 2010 77 464 473 20059485
  20. [20]Rishishwar L Relating the disease mutation spectrum to the evolution of the cystic fibrosis transmembrane conductance regulator (CFTR) PLoS One 2012 7 e42336 22879944 PMC3413703
  21. [21]Masica DL Sosnay PR Cutting GR Karchin R Phenotype-optimized sequence ensembles substantially improve prediction of disease-causing mutation in cystic fibrosis Hum. Mutat 2012 33 1267 1274 22573477 PMC4364283
  22. [22]Giardine B Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach Nat. Genet 2011 43 295 301 21423179 PMC3878152
  23. [23]Patrinos GP Microattribution and nanopublication as means to incentivize the placement of human genome variation data into the public domain Hum. Mutat 2012 33 1503 1512 22736453
  24. [25]Welsh MJ Ramsey BW Accurso FJ Cutting GR Scriver CR Beaudet AL Valle D Sly WS Cystic Fibrosis in The Metabolic and Molecular Bases of Inherited Disease 2001 5121 5188 McGraw-Hill, Inc. New York
  25. [26]DI SANT’AGNESE PA Darling RC Perera GA Shea E Sweat electrolyte disturbances associated with childhood pancreatic disease Am. J. Med 1953 15 777 784 13104449
  26. [28]LeGrys VA Yankaskas JR Quittell LM Marshall BC Mogayzel PJ Jr Diagnostic sweat testing: the Cystic Fibrosis Foundation guidelines J. Pediatr 2007 151 85 89 17586196
  27. [29]Farrell PM Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report J Pediatr 2008 153 S4 S14 18639722 PMC2810958
  28. [30]Wilschanski M Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials Am J Respir. Crit Care Med 2006 174 787 794 16840743 PMC2648063
  29. [31]Frischmeyer PA Dietz HC Nonsense-mediated mRNA decay in health and disease Hum. Mol. Genet 1999 8 1893 1900 10469842
  30. [32]Bhuvanagiri M Schlitter AM Hentze MW Kulozik AE NMD: RNA biology meets human genetic medicine Biochem. J 2010 430 365 377 20795950
  31. [33]Ramalho AS Transcript analysis of the cystic fibrosis splicing mutation 1525-1G>A shows use of multiple alternative splicing sites and suggests a putative role of exonic splicing enhancers J Med. Genet 2003 40 e88 12843337 PMC1735516
  32. [34]Highsmith WE Jr A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations N. Engl. J. Med 1994 331 974 980 7521937
  33. [35]Chillon M A novel donor splice site in intron 11 of the CFTR gene, created by mutation 1811+1.6kbA-->G, produces a new exon: high frequency in Spanish cystic fibrosis chromosomes and association with severe phenotype Am J Hum. Genet 1995 56 623 629 7534040 PMC1801150
  34. [36]Highsmith WE Jr Identification of a splice site mutation (2789+5G>A) associated with small amounts of normal CFTR mRNA and mild cystic fibrosis Hum. Mutat 1997 9 332 338 9101293
  35. [37]Beck S Cystic fibrosis patients with the 3272-26A-->G mutation have mild disease, leaky alternative mRNA splicing, and CFTR protein at the cell membrane Hum. Mutat 1999 14 133 144 10425036
  36. [38]Ramalho AS Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis Am. J. Respir. Cell Mol. Biol 2002 27 619 627 12397022
  37. [39]Dujardin G Commandeur D Le Jossic-Corcos C Ferec C Corcos L Splicing defects in the CFTR gene: minigene analysis of two mutations, 1811+1G>C and 1898+3A>G J. Cyst. Fibros 2011 10 212 216 21317048
  38. [40]Chu C-S Trapnell BC Curristin SM Cutting GR Crystal RG Extensive post-translational deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis J. Clin. Invest 1992 90 785 790 1381723 PMC329931
  39. [41]Johnson LG Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis Nature Genet 1993 2 21 25 1284642
  40. [42]Cheng SH Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis Cell 1990 63 827 834 1699669
  41. [43]Mendoza JL Requirements for efficient correction of DeltaF508 CFTR revealed by analyses of evolved sequences Cell 2012 148 164 174 22265409 PMC3266553
  42. [44]Bombieri C Recommendations for the classification of diseases as CFTR-related disorders J Cyst. Fibros 2011 10 Suppl 2 S86 102 21658649
  43. [45]Taussig LM Lobeck C di Sant ’Agnese PA Ackerman D Kattwinkel J Fertility in males with cystic fibrosis N. Engl. J. Med 1972 287 586 589 5055208
  44. [46]Anguiano A Congenital bilateral absence of the vas deferens - a primarily genital form of cystic fibrosis JAMA 1992 267 1794 1797 1545465
  45. [48]Chu C-S Trapnell BC Curristin S Cutting GR Crystal RG Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA Nature Genet 1993 3 151 156 7684646
  46. [49]Estivill X Complexity in a monogenic disease Nature Genet 1996 12 348 350 8630481
  47. [50]Castellani C European best practice guidelines for cystic fibrosis neonatal screening J Cyst. Fibros 2009 8 153 173 19246252
  48. [51]Wagener JS Zemanick ET Sontag MK Newborn screening for cystic fibrosis Curr. Opin. Pediatr 2012 24 329 335 22491493
  49. [52]Ramsey BW A CFTR potentiator in patients with cystic fibrosis and the G551D mutation N. Engl. J. Med 2011 365 1663 1672 22047557 PMC3230303
  50. [53]Mitchell AA Chakravarti A Cutler DJ On the probability that a novel variant is a disease-causing mutation Genome Res 2005 15 960 966 15965029 PMC1172040
  51. [54]Clarke GM Basic statistical analysis in genetic case-control studies Nat. Protoc 2011 6 121 133 21293453 PMC3154648
  52. [55]Cuppens H Marynen P De BC Cassiman JJ Detection of 98.5% of the mutations in 200 Belgian cystic fibrosis alleles by reverse dot-blot and sequencing of the complete coding region and exon/intron junctions of the CFTR gene Genomics 1993 18 693 697 7508414
  53. [56]Bombieri C A new approach for identifying non-pathogenic mutations An analysis of the cystic fibrosis transmembrane regulator gene in normal individuals. Hum. Genet 2000 106 172 178 10746558
  54. [57]Kearney HM Thorland EC Brown KK Quintero-Rivera F South ST American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants Genet. Med 2011 13 680 685 21681106
  55. [58]Pagani F New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12 Hum. Mol. Genet 2003 12 1111 1120 12719375
  56. [59]Raynal C A Classification Model Relative to Splicing for Variants of Unknown Clinical Significance: Application to the CFTR Gene Hum. Mutat 2013 23381846
  57. [60]Scott A Petrykowska HM Hefferon T Gotea V Elnitski L Functional analysis of synonymous substitutions predicted to affect splicing of the CFTR gene J. Cyst. Fibros 2012 11 511 517 22591852 PMC3440543
  58. [61]Mailman MD The NCBI dbGaP database of genotypes and phenotypes Nat. Genet 2007 39 1181 1186 17898773 PMC2031016
  59. [62]Newcomb PA Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer Cancer Epidemiol. Biomarkers Prev 2007 16 2331 2343 17982118
  60. [63]Tuffery-Giraud S Genotype-phenotype analysis in 2, 405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase Hum. Mutat 2009 30 934 945 19367636
  61. [64]Mons B The value of data Nat. Genet 2011 43 281 283 21445068
  62. [65]Castellani C Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice J Cyst. Fibros 2008 7 179 196 18456578 PMC2810954
  63. [66]Rohlfs EM The I148T CFTR allele occurs on multiple haplotypes: A complex allele is associated with cystic fibrosis Genetics in Medicine 2002 4 319 323 12394343
  64. [67]Wang X Dockery DW Wypij D Fay ME Ferris BG Jr Pulmonary function between 6 and 18 years of age Pediatr. Pulmonol 1993 15 75 88 8474788
  65. [68]Hankinson JL Odencrantz JR Fedan KB Spirometric reference values from a sample of the general U.S. population Am J Respir. Crit Care Med 1999 159 179 187 9872837
  66. [69]Cooper TA Use of minigene systems to dissect alternative splicing elements Methods 2005 37 331 340 16314262
  67. [70]Clackson T Winter G ‘Sticky feet’-directed mutagenesis and its application to swapping antibody domains Nucleic Acids Res 1989 17 10163 10170 2690014 PMC335290
  68. [71]Ramalho AS Clarke LA Amaral MD Quantification of CFTR transcripts Methods Mol. Biol 2011 741 115 135 21594782
  69. [72]Sheridan MB CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR J. Med. Genet 2011 48 235 241 21097845 PMC3065505
  70. [73]Yu H Ivacaftor potentiation of multiple CFTR channels with gating mutations J. Cyst. Fibros 2012 11 237 245 22293084
  71. [74]Krasnov KV Tzetis M Cheng J Guggino WB Cutting GR Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships Hum. Mutat 2008 29 1364 1372 18951463 PMC2785447
  72. [75]Van Goor F Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770 Proc. Natl. Acad. Sci. U. S. A 2009 106 18825 18830 19846789 PMC2773991
  73. [76]Neuberger T Burton B Clark H Van Goor F Use of primary cultures of human bronchial epithelial cells isolated from cystic fibrosis patients for the pre-clinical testing of CFTR modulators Methods Mol. Biol 2011 741 39 54 21594777
  74. [77]Thongnoppakhun W Simple, efficient, and cost-effective multiplex genotyping with matrix assisted laser desorption/ionization time-of-flight mass spectrometry of hemoglobin beta gene mutations J. Mol. Diagn 2009 11 334 346 19460936 PMC2710711

Cited by

Sorted by citations

Authors
Sosnay, P. R., Siklosi, K. R., Van Goor, F., Kaniecki, K., Yu, H., Sharma, N., Ramalho, A. S., Amaral, M. D., Dorfman, R., Zielenski, J., Masica, D. L., Karchin, R., Millen, L., Thomas, P. J., Patrinos, G. P., Corey, M., Lewis, M. H., Rommens, J. M., Castellani, C., Penland, C. M., & Cutting, G. R.
Affiliations
  • Johns Hopkins University (US)
  • Vertex Pharmaceuticals (United States) (US)
  • University of Lisbon (PT)
  • Hospital for Sick Children (CA)
  • The University of Texas Southwestern Medical Center (US)
  • University of Patras (GR)
  • University of Toronto (CA)
  • Azienda Ospedaliera Universitaria Integrata Verona (IT)
  • Cystic Fibrosis Foundation (US)
Corresponding author
Cutting, Garry R
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2013-08-25
Volume
45
Issue
10
Pages
1160-1167
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.2745
PMC
PMC3874936
OpenAlex
W1990725675
Cited by
630
References
3
Citations by year
2026: 24 · 2025: 36 · 2024: 37 · 2023: 30 · 2022: 36 · 2021: 45 · 2020: 57 · 2019: 66 · 2018: 61 · 2017: 56 · 2016: 70 · 2015: 67 · 2014: 38 · 2013: 4 · 2012: 1
FWCI
48.88
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
Funders
  • Cystic Fibrosis Foundation
  • Cystic Fibrosis Foundation Therapeutics
  • Science and Engineering Research Board
  • National Heart, Lung, and Blood Institute (T32HL072748)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R37DK049835, DK49835, R01DK049835, R37DK044003, R01DK044003)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
cystic fibrosis, CFTR, CFTR mutations, causal variants, allele frequency, clinical severity, functional characterization, disease penetrance, allelic heterogeneity, variant interpretation, genotype-phenotype correlation
MeSH terms
Cystic Fibrosis, Female, Gene Frequency, Genotype, Humans, Male, Phenotype, Cystic Fibrosis Transmembrane Conductance Regulator

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review