College of American Pathologists



Diagnostics in Cystic Fibrosis

Posted July 2, 2013

Caroline Raasch Alquist, MD, PhD

Cystic fibrosis (CF) affects roughly one in every 2,800 United States newborns each year, making it the most common life-threatening autosomal recessive disease in America.1,2 Characterized by abnormal chloride, sodium, and/or bicarbonate transport across epithelium, resultant viscous secretions lead to chronic sinopulmonary infections, gastrointestinal and nutritional abnormalities, and sterility. Prenatal testing and newborn screening, coupled with CF transmembrane conductance regulator (CFTR) gene analysis, have improved outcomes via rapid and accurate identification of children and adolescents with CF. These testing modalities in the newborn are even more crucial in the absence of a positive family history or the telltale, albeit not CF-specific, sign of meconium ileus.

Parental prenatal screening is useful in identifying the 4% of the population that may carry a single copy of the CF allele.3 Such carrier screening of the 23 recommended mutations may either be done by two-step or couples models.3,4 In the two-step model, considered a more economical approach in populations with low carrier frequencies, a man is only tested following a positive female screen. Physicians may prefer simultaneous couples testing in Caucasian couples of Ashkenazi Jewish and Northern European descent, particularly when screening for additional genetic disorders.3

All states now utilize some form of newborn screening for CF. If blood levels of immunoreactive trypsinogen (IRT), an enzyme elevated in most pancreatic sufficient and pancreatic insufficient CF-affected newborns, are elevated (>60–80 ng/mL), a second test is performed.5,6 Some states reevaluate IRT blood levels at two weeks, while others will immediately perform DNA analysis for one or more CFTR gene mutations. Cut-off values for elevated IRT and diagnostic algorithms remain areas of debate to best balance sensitivity and specificity in CF detection.5,6 A confirmatory sweat chloride test may also be ordered, as high levels of chloride (above 60mmol/L) are indicative of CF, while levels between 30–59 mmol/L (ages six months or less) and 40–59 mmol/L (for those over the age of six months) require further diagnostic evaluation.2,6

The varied presentations of cystic fibrosis, including those that may occur later in life, require laboratories to utilize step-wise genetic testing strategies to examine the more than 1,900 known CFTR gene sequence changes.2,7 While commercially available mutation screening panels identify many known mutations, the tests may miss novel sequence changes and only provide information regarding the genotype. CFTR gene mutation consequences can range from infertility, chronic sinusitis, hepatobiliary dysfunction, and pancreatic and lung disease, to other less well-defined pathologic correlates. Some genotypes have been correlated with pancreatic function and sweat chloride abnormalities, but an explanation for phenotypic heterogeneity of CF lung disease, even with identical CFTR genotypes, remains elusive.6 Several genetic loci and environmental factors that modify the severity of CF-related lung disease have also been identified, which may help to explain phenotypic variability in the future.

While large areas for improvement remain in the field of genotype-phenotype correlation, the diagnosis of cystic fibrosis, once fully reliant on the clinicians’ identification of classic signs and symptoms, now benefits from the significant advancement of carrier screening, newborn screening, and CFTR genotype analysis.


  1. Bobadilla JL, Macek M, Fine JP, Farrell PM. Cystic fibrosis: A worldwide analysis of CFTR mutations—correlation with incidence data and application to screening. Hum Mutat. 2002;19(6): 575–606.
  2. Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation Consensus report. J Pediatr. 2008;153(2):S4–S14. doi: 10.1016/j.jpeds.2008.05.005.
  3. Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, and Desnick RJ; Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetic Services Committee, ACMG; American College of Medical Genetics. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med. 2001; 3(2):149–154.
  4. American College of Medical Genetics. Technical Standards and Guidelines for CFTR Mutation Testing. 2008 ed. Standards and Guidelines for Clinical Genetics Laboratories. Updated March 2011. Accessed January 11, 2013.
  5. Sontag MK, Wright D, Beebe J, Accurso FJ, and Sagal SD. A new cystic fibrosis newborn screening algorithm: IRT/IRT1upward arrow/DNA. J Pediatr. 2009;155(5):618–622. doi: 10.1016/j.jpeds.2009.03.057.
  6. Deucher A and Schrijver I Newborn screening for cystic fibrosis. In PN Leatte. Cystic Fibrosis: Etiology, Diagnosis and Treatments. Hauppauge, New York: Nova Science Publishers Inc., 2009; 1–29.
  7. Cystic Fibrosis Genetic Analysis Consortium. Cystic Fibrosis Mutation Database. Toronto, ON, Canada: Cystic Fibrosis Centre, Hospital for Sick Children. Updated April 25, 2011. Accessed January 11, 2013.

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NewsPath® Editor: Kyle L. Eskue, MD, FCAP
This newsletter is produced in cooperation with the College of American Pathologists Member and Public Communications Committee and the NewsPath Editorial Board and may be reproduced in whole or in part as a service to the medical community. Copyright © 2013 by the College of American Pathologists.
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