title: Applying Cystic Fibrosis Transmembrane Conductance Regulator Genetics and CFTR2 Data to Facilitate Diagnoses.
abstract: As a Mendelian disease, genetics plays an integral role in the diagnosis of cystic fibrosis (CF). The identification of 2 disease-causing mutations in the CF transmembrane conductance regulator (CFTR) in an individual with a phenotype provides evidence that the disease is CF. However, not all variations in CFTR always result in CF. Therefore, for CFTR genotype to provide the same level of evidence of CFTR dysfunction as shown by direct tests such as sweat chloride or nasal potential difference, the mutations identified must be known to always result in CF. The use of CFTR genetics in CF diagnosis, therefore, relies heavily on mutation interpretation.
  
  
  
  Progress that has been made on mutation interpretation and annotation was reviewed at the recent CF Foundation Diagnosis Consensus Conference. A modified Delphi method was used to identify consensus statements on the use of genetic analysis in CF diagnosis.
  
  
  
  The largest recent advance in CF genetics has come through the Clinical and Functional Translation of CFTR (CFTR2) project. This undertaking seeks to characterize CFTR mutations from patients with CF around the world. The project also established guidelines for the clinical, functional, and population/penetrance criteria that can be used to interpret mutations not yet included in CFTR2's review.
  
  
  
  The use of CFTR genetics to aid in diagnosis of CF requires that the mutations identified have a known disease liability. The demonstration of 2 in trans mutations known to always result in CF is satisfactory evidence of CFTR dysfunction. However, if the identified mutations are known to be associated with variable outcomes, or have unknown consequence, that genotype may not result in a CF phenotype. In these cases, other tests of CFTR function may help.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Sosnay
authors.affiliation: Department of Pediatrics, Division of Pediatric Pulmonology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Danieli B
authors.initials: DB
authors.lastname: Salinas
authors.affiliation: Cystic Fibrosis Foundation, Bethesda, MD.
authors.forename: Terry B
authors.initials: TB
authors.lastname: White
authors.affiliation: Section of Pediatric Pulmonology, Allergy, and Sleep Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Clement L
authors.initials: CL
authors.lastname: Ren
authors.affiliation: Departments of Pediatrics and Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Farrell
authors.affiliation: McKusick-Nathans Institute of Medical Genetics, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Raraigh
authors.affiliation: Service de Génétique et Biologie Moléculaires, Groupe Hospitalier Cochin - Broca - Hôtel Dieu, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Girodon
authors.affiliation: Cystic Fibrosis Center, Ospedale Civile Maggiore, Verona, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Castellani
mesh_terms: D003550:Cystic Fibrosis / Q000175:diagnosis* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation; D015997:Neonatal Screening
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR genetic testing; CFTR mutations; CFTR-related disorder; MVCC; cystic fibrosis; genotype; genotype-phenotype correlation mutation; penetrance; variant