Cystic Fibrosis - CF

Cystic fibrosis (CF) is caused by the presence of two severe pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on opposite chromosomes; over 2,000 different CFTR variants have been reported, but most are very rare and of unknown significance. CF is typically associated with recurrent pulmonary infections and exocrine pancreatic insufficiency.

  • Diagnosis
  • Algorithms
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Individuals with one or more classic symptoms of cystic fibrosis (CF)
  • Individuals with a CFTR-related disorder (CFTR-RD), such as congenital bilateral absence of the vas deferens (CBAVD), pancreatitis, or recurrent bronchiectasis
  • Children with an affected sibling
  • Infants with a positive newborn screen (NBS)
  • Carrier screening
    • Expectant couples
    • Couples planning a pregnancy
    • Individuals with positive family history of CF or CFTR-related metabolic syndrome/CF screen-positive, inconclusive diagnosis (CRMS/CFSPID)

Criteria for Diagnosis

  • Guidelines for the diagnosis of CF (Farrell, 2017)
    • CF – 2 classifications recommended to aid in diagnosis
      • Classification 1 – meeting all 4 criteria indicates positive diagnosis
        • Positive NBS AND
        • Symptoms of CF or a positive family history AND
        • Identification of 2 CF-causing variants (absence does not exclude CF) AND
        • Confirmation with sweat chloride test (value ≥60 mmol/L)
      • Classification 2 – meeting 3 criteria indicates positive diagnosis
        • Positive NBS AND
        • Variable or uncharacterized CFTR variants (2 CFTR variants) AND
        • Demonstration of CFTR dysfunction
          • Sweat chloride ≥60 mmol/L OR
          • CF-typical nasal potential difference (NPD) OR
          • CF-typical intestinal current measurement (ICM)
      • Individuals with positive NBS for CF AND
        • Sweat chloride <30 mmol/L and 2 pathogenic CFTR variants OR
        • Intermediate sweat chloride (30-5 mmol/L) and 1 or 0 CF-causing variants
    • CFTR-RD
      • Monosymptomatic clinical entity (CBAVD/pancreatitis/bronchiectasis) associated with CFTR dysfunction not meeting diagnostic criteria for CF

Laboratory Testing

  • Newborn screening for CF – all newborns in the U.S. screened

Imaging Studies/Procedures

  • Sweat chloride testing
    • Perform according to approved procedural guideline
    • Newborn window for screening
      • >36 weeks gestation
      • >2 kg body weight
      • Between 10 days and 4 weeks after birth
    • Perform bilaterally
      • Results
        • ≥60 mmol/L – diagnostic of CF
        • 30-59 mmol/L –  intermediate result
        • <30 mmol/L – normal/negative
    • Find an accredited CF care center
  • Nasal potential difference
  • Intestinal current measurement

Genetic Testing

  • Pathogenic CFTR variants
  • Extended genetic testing
  • Families with a history of CF and CRMS/CFSPID should be offered genetic testing

Differential Diagnosis

  • American College of Medical Genetics (ACMG, 2015) and American College of Obstetricians and Gynecologists' Committee on Genetics (ACOG, 2017) recommend a 23-variants panel for carrier screening; each variant occurs with >1/1,000 frequency in cystic fibrosis (CF) patients in a panethnic U.S. population
    • Offer screening to the following
      • All expectant couples or those planning a pregnancy
      • Men with congenital bilateral absence of the vas deferens (CBAVD) and their reproductive partners
      • Individuals with a positive family history of CF or CFTR-related metabolic syndrome/CF screen-positive, inconclusive diagnosis (CRMS/CFSPID)
  • CF newborn screening – supported by CDC and currently practiced in all 50 states
    • Measurement of immunoreactive trypsinogen (IRT) in blood spots
      • If newborn screen (NBS) positive – perform sweat chloride testing
      • If NBS and sweat chloride positive for infants – perform CFTR genetic testing if not done with NBS


  • Monitoring for complications of cystic fibrosis (CF) should be performed
    • Lung complications
      • Chest x-ray, spirometry can be used to monitor for infection, lung function changes
      • Infections
        • Bacterial
        • Fungal
          • Allergic bronchopulmonary aspergillosis (APBA)
            • Serum IgE
            • Aspergillus IgE
            • ABPA -009771, 200 4243
    • Bone loss
      • DXA starting at 8-10 years
    • Gastrointestinal complications
      • Pancreatitis
        • Test lipase
      • Altered nutritional status
        • Test fatty acid status
        • Other rearrangements including vitamin D
    • CF-related liver disease
      • Periodic liver function tests
    • Endocrine
      • Diabetes – annual screening when stable, more frequently in certain situations
      • Fasting/postprandial glucose
      • OGTT
    • Exocrine pancreatic insufficiency
      • Fecal pancreatic elastase -1


  • Incidence
    • CF
      • Ashkenazi Jews – 1/2,300
      • Caucasians – 1/2,500
      • Hispanics – 1/13,500
      • African Americans – 1/15,100
      • Asians – 1/35,100
    • CFTR-related disorders – unknown
  • Age – CF is usually diagnosed by newborn screening or in early childhood; CFTR-related disorders usually present in adulthood
  • Ethnicity – >90% are Caucasian


  • Autosomal recessive
    • CF – two severe, or one severe and one moderate, pathogenic CFTR variants on opposite chromosomes
    • CFTR-related disorders – one severe and one mild pathogenic variant on opposite chromosomes
    • Men with congenital bilateral absence of the vas deferens (CBAVD)
      • At least one pathogenic CFTR variant will be present in ~75%
      • Two pathogenic CFTR variants − ~20%
      • One pathogenic CFTR and one mild 5T variant − 25%
      • One pathogenic CFTR variant − 20%
      • One mild 5T variant − 10%
    • Individuals with idiopathic pancreatitis
      • Up to 40% are predicted to have at least one pathogenic CFTR variant
    • Purulent pansinusitis or nasal polyposis starting early in life or associated with chronic infection
      • 30% of adults have one pathogenic CFTR variant
      • 7% of adults have two pathogenic CFTR variants
  • Penetrance – high for severe pathogenic variants; variable for mild/moderate variants
  • CFTR gene
    • >2,000 variants
    • Most are very rare and not well characterized
    • Most common - F508del
  • Carrier frequency
    • Ashkenazi Jews – 1/24
    • European Caucasians – 1/25
    • Hispanic Americans – 1/58
    • African Americans – 1/61
    • Asian Americans – 1/94


  • CFTR codes for a cAMP-regulated chloride channel in the apical membrane of epithelial cells
    • Without enough functional CFTR protein, the salt concentration in sweat is elevated, and the viscosity of the mucous in the lungs and pancreas is increased, leading to obstruction
    • Obstruction sets the stage for chronic infection, inflammation, and epithelial injury
  • Death typically occurs from obstructive airway disease at an average age of 38 years

Clinical Presentation

  • CF – chronic sinopulmonary disease, exocrine pancreatic insufficiency, and obstructive azoospermia
    • Sinopulmonary disease
      • Chronic lung infections – bronchiectasis, dyspnea, wheezing, nasal polyps, clubbing of fingers
      • Infectious organisms typically involved
      • Eventual pulmonary complications may include massive hemoptysis, pneumothorax, and respiratory failure
    • Pancreas/liver/gallbladder/gastrointestinal (GI) disease
      • Pancreas
        • ≥85% have exocrine pancreatic insufficiency
        • Reduced absorption of lipids and fat-soluble vitamins
        • Steatorrhea and malabsorption result in malnutrition
        • If pancreatic sufficiency, chronic/recurrent bouts of pancreatitis
        • 25% of adults develop diabetes
      • Liver
        • Clogging of biliary ducts leads to liver and biliary cirrhosis
        • Liver congestion secondary to hypoxia-induced cor pulmonale
      • Gallbladder disease
        • Fecal loss of bile acids leads to reduction in bile-salt pool with increased incidence of gallstones
      • GI
        • Distal intestinal obstruction
        • Constipation, intussusception, colonic strictures, hypotonic colon
        • Meconium ileus in 15% of infants
    • Endocrine system dysfunction
      • Male – azoospermia due to CBAVD in >95%
      • Female – modest reduction in fertility
  • CFTR-related disorders  – monosymptomatic diseases such as idiopathic pancreatitis, CBAVD, nasal polyps, or bronchiectasis
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Cystic Fibrosis (CFTR) 165 Pathogenic Variants 2013661
Method: Polymerase Chain Reaction/Fluorescence Monitoring


Diagnostic errors can occur due to rare sequence variations

Only the 165 pathogenic CFTR variants (see Additional Technical Information) will be interrogated

Cystic Fibrosis (CFTR) 165 Pathogenic Variants with Reflex to Sequencing and Reflex to Deletion/Duplication 2013664
Method: Polymerase Chain Reaction/Fluorescence Monitoring/Sequencing/Multiplex Ligation-dependent Probe Amplification


Diagnostic errors can occur due to rare sequence variations

Breakpoints of large deletions/duplications and regulatory region and deep intronic variants are not detected

Variants of unknown clinical significance may be detected

Cystic Fibrosis (CFTR) Sequencing 0051110
Method: Polymerase Chain Reaction/Sequencing


Diagnostic errors can occur due to rare sequence variations

Variants of unknown clinical significance may be detected

Regulatory region variants, large deletions/duplications, and some deep intronic variants will not be detected

Cystic Fibrosis (CFTR) 165 Pathogenic Variants with Reflex to Sequencing 2013663
Method: Polymerase Chain Reaction/Fluorescence Monitoring/Sequencing


Diagnostic errors can occur due to rare sequence variations

Pathogenic (CTFR) promoter variants and large deletions/duplications will not be detected

Variants of unknown clinical significance may be identified 

Cystic Fibrosis (CFTR) Sequencing with Reflex to Deletion/Duplication 0051640
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification


Diagnostic errors can occur due to rare sequence variations

Breakpoints for large deletions/duplications will not be determined

Regulatory region and some deep intronic variants will not be detected

Cystic Fibrosis (CFTR) 165 Pathogenic Variants, Fetal 2013662
Method: Polymerase Chain Reaction/Fluorescence Monitoring


Diagnostic errors can occur due to rare sequence variations

Only the 165 pathogenic CFTR variants (see Additional Technical Information) will be interrogated


Castellani C, Cuppens H, Macek M, Cassiman JJ, Kerem E, Durie P, Tullis E, Assael BM, Bombieri C, Brown A, Casals T, Claustres M, Cutting GR, Dequeker E, Dodge J, Doull I, Farrell P, Ferec C, Girodon E, Johannesson M, Kerem B, Knowles M, Munck A, Pignatti PF, Radojkovic D, Rizzotti P, Schwarz M, Stuhrmann M, Tzetis M, Zielenski J, Elborn JS. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008; 7(3): 179-96. PubMed

Castellani C, Macek M, Cassiman J, Duff A, Massie J, Kate LP, Barton D, Cutting G, Dallapiccola B, Dequeker E, Girodon E, Grody W, Highsmith EW, Kääriäinen H, Kruip S, Morris M, Pignatti PF, Pypops U, Schwarz M, Soller M, Stuhrman M, Cuppens H. Benchmarks for cystic fibrosis carrier screening: a European consensus document. J Cyst Fibros. 2010; 9(3): 165-78. PubMed

Committee on Genetics. Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstet Gynecol. 2017; 129(3): e41-e55. PubMed

Farrell PM, White TB, Ren CL, Hempstead SE, Accurso F, Derichs N, Howenstine M, McColley SA, Rock M, Rosenfeld M, Sermet-Gaudelus I, Southern KW, Marshall BC, Sosnay PR. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017; 181S: S4-S15.e1. PubMed

Green A, Kirk J, Guidelines Development Group. Guidelines for the performance of the sweat test for the diagnosis of cystic fibrosis. Ann Clin Biochem. 2007; 44(Pt 1): 25-34. PubMed

Smyth AR, Bell SC, Bojcin S, Bryon M, Duff A, Flume P, Kashirskaya N, Munck A, Ratjen F, Schwarzenberg SJ, Sermet-Gaudelus I, Southern KW, Taccetti G, Ullrich G, Wolfe S, European Cystic Fibrosis Society. European Cystic Fibrosis Society Standards of Care: Best Practice guidelines. J Cyst Fibros. 2014; 13 Suppl 1: S23-42. PubMed

Standards and Guidelines for Clinical Genetics Laboratories . American College of Medical Genetics. [Revised: Mar 2011; Accessed: Jul 2017]

General References

Culling B, Ogle R. Genetic counselling issues in cystic fibrosis. Paediatr Respir Rev. 2010; 11(2): 75-9. PubMed

Kerem E. Atypical CF and CF related diseases. Paediatr Respir Rev. 2006; 7 Suppl 1: S144-6. PubMed

Norton ME. Genetic screening and counseling. Curr Opin Obstet Gynecol. 2008; 20(2): 157-63. PubMed

O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009; 373(9678): 1891-904. PubMed

Taylor CJ, Hardcastle J, Southern KW. Physiological measurements confirming the diagnosis of cystic fibrosis: the sweat test and measurements of transepithelial potential difference. Paediatr Respir Rev. 2009; 10(4): 220-6. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Bennett CD, Campbell MN, Cook CJ, Eyre DJ, Nay LM, Nielsen DR, Rasmussen RP, Bernard PS. The LightTyper: high-throughput genotyping using fluorescent melting curve analysis. Biotechniques. 2003; 34(6): 1288-92, 1294-5. PubMed

Chou L, Gedge F, Lyon E. Complete gene scanning by temperature gradient capillary electrophoresis using the cystic fibrosis transmembrane conductance regulator gene as a model. J Mol Diagn. 2005; 7(1): 111-20. PubMed

Chou L, Lyon E, Wittwer CT. A comparison of high-resolution melting analysis with denaturing high-performance liquid chromatography for mutation scanning: cystic fibrosis transmembrane conductance regulator gene as a model. Am J Clin Pathol. 2005; 124(3): 330-8. PubMed

Christensen TM, Jama M, Ponek V, Lyon E, Wilson JA, Hoffmann ML, Bejjani BA. Design, development, validation, and use of synthetic nucleic acid controls for diagnostic purposes and application to cystic fibrosis testing. J Mol Diagn. 2007; 9(3): 315-9. PubMed

Heaney DL, Flume P, Hamilton L, Lyon E, Wolff DJ. Detection of an apparent homozygous 3120G>A cystic fibrosis mutation on a routine carrier screen. J Mol Diagn. 2006; 8(1): 137-40. PubMed

Lyon E, Miller C. Current challenges in cystic fibrosis screening. Arch Pathol Lab Med. 2003; 127(9): 1133-9. PubMed

Lyon E, Schrijver I, Weck KE, Ferreira-Gonzalez A, Richards S, Palomaki GE, CAP/ACMG Biochemical and Molecular Genetics Committee. Molecular genetic testing for cystic fibrosis: laboratory performance on the College of American Pathologists external proficiency surveys Genet Med. 2015; 17(3): 219-25. PubMed

Millson A, Pont-Kingdon G, Page S, Lyon E. Direct molecular haplotyping of the IVS-8 poly(TG) and polyT repeat tracts in the cystic fibrosis gene by melting curve analysis of hybridization probes. Clin Chem. 2005; 51(9): 1619-23. PubMed

Montgomery J, Wittwer CT, Kent JO, Zhou L. Scanning the cystic fibrosis transmembrane conductance regulator gene using high-resolution DNA melting analysis. Clin Chem. 2007; 53(11): 1891-8. PubMed

Pont-Kingdon G, Jama M, Miller C, Millson A, Lyon E. Long-range (17.7 kb) allele-specific polymerase chain reaction method for direct haplotyping of R117H and IVS-8 mutations of the cystic fibrosis transmembrane regulator gene. J Mol Diagn. 2004; 6(3): 264-70. PubMed

Ridge PG, Miller C, Bayrak-Toydemir P, Best H, Mao R, Swensen JJ, Lyon E, Voelkerding KV. Cystic fibrosis testing in a referral laboratory: results and lessons from a six-year period. J Clin Bioinforma. 2013; 3(1): 3. PubMed

Sebastian S, Spitzer SG, Grosso LE, Amos J, Schaefer FV, Lyon E, Wolff DJ, Hajianpour A, Taylor AK, Millson A, Stenzel TT. Multicenter characterization and validation of the intron-8 poly(T) tract (IVS8-T) status in 25 Coriell cell repository cystic fibrosis reference cell lines for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation assays. Clin Chem. 2004; 50(1): 251-4. PubMed

Siryani I, Jama M, Rumman N, Marzouqa H, Kannan M, Lyon E, Hindiyeh M. Distribution of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutations in a Cohort of Patients Residing in Palestine PLoS One. 2015; 10(7): e0133890. PubMed

Wittwer CT, Reed GH, Gundry CN, Vandersteen JG, Pryor RJ. High-resolution genotyping by amplicon melting analysis using LCGreen. Clin Chem. 2003; 49(6 Pt 1): 853-60. PubMed

Zhou L, Palais RA, Ye F, Chen J, Montgomery JL, Wittwer CT. Symmetric snapback primers for scanning and genotyping of the cystic fibrosis transmembrane conductance regulator gene. Clin Chem. 2013; 59(7): 1052-61. PubMed

Medical Reviewers

Content Reviewed: 
May 2017

Last Update: October 2017