Topic Name

A	B	C	D	E	F	G	H	I
J	K	L	M	N	O	P	Q	R
S	T	U	V	W	X	Y	Z	#

Disease Categories > Genetic Disease

Font

Cystic Fibrosis - CF

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; over 1500 different CFTR mutations have been reported.

Epidemiology

Classic CF affects 1:3000 Caucasians and Ashkenazi Jews, 1:8000 Hispanics, 1:15,000 African Americans, 1:32,000 Asians
4% of Caucasians are carriers

Inheritance

Autosomal recessive
- 2 deleterious CFTR mutations on different chromosomes
  - Classical symptoms of cystic fibrosis – 2 severe mutations
  - Atypical symptoms – 1 severe and 1 mild mutation, 2 mild mutations, or 1 mutation and 1 5T variant
- Penetrance – high for severe mutations, variable for mild mutations

Pathophysiology

CFTR codes for a cAMP-regulated chloride channel in the apical membrane of epithelial cells
Without enough functional CFTR, 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 eventual epithelial injury
Death typically results from obstructive airway disease in the fourth decade of life

Clinical Presentation

Classic – chronic sinopulmonary disease, gastrointestinal malabsorption, pancreatic insufficiency and obstructive azoospermia
Atypical – monosymptomatic disease such as chronic pancreatitis, bilateral absence of the vas deferens, nasal polyps or bronchiectasis
Sinopulmonary disease
- Chronic lung infections – bronchiectasis, dyspnea, wheezing, chest pain, nasal polyps, clubbing
- Infectious organisms
  - Pseudomonas aeruginosa
  - Staphylococcus aureus
  - Burkholderia cepacia
Pancreas/liver/gallbladder/gastrointestinal (GI) disease
- Pancreas
  - 85% or more have pancreatic insufficiency
  - Absorption of lipids and fat soluble vitamins is reduced
Chronic or recurrent abdominal pain from pancreatitis
Steatorrhea and malnutrition result
Meconium ileus in 15% of infants
25% of adults develop diabetes
- Liver
  - Clogging of biliary ducts leads to liver and biliary cirrhosis
  - Congestion of liver secondary to hypoxia-induced cor pulmonale
- Gallbladder
  - Fecal loss of bile acids leads to reduction in bile-salt pool
  - Reduction may lead to gallstones
- GI
  - Distal intestinal obstruction (meconium ileus equivalent)
  - Constipation, intussusception, colonic strictures, hypotonic colon
Endocrine systems dysfunctions
- Male – azoospermia due to congenital bilateral absence of vas deferens (CBAVD) in >95%
- Female – modest reduction in fertility

Screening

American College of Medical Genetics (ACMG) recommends a 23 mutation panel for carrier screening; each mutation occurs with greater than 1 in 1000 frequency in panethnic US population
- Offer screening for the following indications:
  - 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

Diagnosis

Two elevated sweat chloride values (>60 mmol/L) or two known deleterious CFTR mutations on opposite chromosomes
Offer diagnostic testing for the following indications:
- Individuals with one or more typical symptoms
- Children with an affected sibling
- Infants with a positive newborn screen

Treatment

Respiratory therapy – chest physiotherapy
Antibiotic treatment of infections
Inhalant treatment – Dornase alfa
Nutritional supplementation when necessary
Lung transplantation
- Improves quality of life, but not survival

Indications for Ordering

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

Test Name and Number	Recommended Use	Limitations
Cystic Fibrosis (CFTR) 32 Mutations 0056040 Method: Polymerase Chain Reaction/Oligonucleotide Ligation	Tests for 32 of the most common CF gene mutations Order for any of the following indications: Carrier testing in an expectant couple or those planning a pregnancy Patient with symptoms of CF Patient with family history of CF	Mutations other than the 32 tested will not be detected Primer site mutations may affect this assay
Cystic Fibrosis (CFTR) 32 Mutations with Reflex to Sequencing 0051150 Method: Polymerase Chain Reaction/Oligonucleotide Ligation/Scanning/Sequencing	Tests for 32 of the most common CF gene mutations; full gene sequencing is performed if two CF mutations are not identified on the panel Order for patients with either of the following indications who have not been previously tested: Patients with symptoms of classic CF Patients with a positive sweat chloride Clinical sensitivity: 97%	CFTR promoter mutations and larger gene deletions/duplications will not be detected
Cystic Fibrosis (CFTR) 32 Mutations with Reflex to Sequencing and Reflex to Deletion/Duplication 0051732 Method:	Tests for 32 of the most common CF gene mutations; full gene sequencing is performed if two CF panel mutations are not identified; deletion/duplication testing is performed if two mutations have not be identified by sequencing Order for patients with either of the following indications who have not been previously tested: Patients with symptoms of classic CF Patients with a positive sweat chloride Clinical sensitivity: 99%
Cystic Fibrosis, Mutation Panel, Fetal 0050393 Method: Polymerase Chain Reaction/Oligonucleotide Ligation	Test amniocytes for 32 of the most common CF gene mutations Order in fetal samples for the following indications: Both parents have known CF panel mutations One parent has a known CF panel mutation and the other parent is unavailable Echogenic or cystic dilatation of the fetal bowel on ultrasound	Only the 32 mutations tested will be detected; further mutations within the primer/probe regions could affect this assay
Cystic Fibrosis (CFTR) Deletion/Duplication 0051642 Method: Multiplex Ligation Probe Amplification	Detects large CFTR duplications and deletions within the exons and intron/exon borders Order for patients who have a positive sweat chloride or atypical CF but only one or no detectable mutations upon CFTR sequencing Approximately 1-2% of CFTR mutations are large deletions or duplications	Deletion/duplication breakpoints will not be determined. CFTR single-base pair substitutions, small deletions/duplications, and deep intronic and promoter mutations will not be detected. Mutations within the primer/probe regions could affect this assay
Cystic Fibrosis (CFTR) Sequencing 0051110 Method:	Detects point mutations and small insertions/deletions within the coding region intron/exon boundaries Order for patients with positive sweat chloride or CF symptoms without two detectable mutations on the CF mutation panel Clinical sensitivity: 97%	CFTR promoter mutations, rare intronic mutations and large gene deletions/duplications will not be detected
Cystic Fibrosis (CFTR) Sequencing with Reflex to Deletion/Duplication0051640 Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation Probe Amplification	Detects mutations in CFTR exons and intron/exon borders Order for patients with positive sweat chloride or CF symptoms without two detectable mutations on the CF mutation panel Clinical sensitivity: 99%	CFTR promoter mutations and rare intronic mutations will not be detected
Cystic Fibrosis Cis-Trans 0056006 Method: Polymerase Chain Reaction/Oligonucleotide Ligation	Tests whether the R117H mutation and 5T variant are on the same chromosome Order only for patients who have a previously identified R117H mutation and 5T variant
Cystic Fibrosis Mutation Panel, Atypical 0050756 Method: Polymerase Chain Reaction/Oligonucleotide Ligation	Tests for 32 of the most common CF gene mutations and the 5T variant Order in patients with one or more of the following symptoms: Recurrent pancreatitis Bilateral absence of the vas deferens Nasal polyps Bronchiectasis	Mutations other than the 32 CFTR panel mutations and the 5T variant will not be detected Primer site mutations may affect the analytic sensitivity of this assay
Cystic Fibrosis 3199del6 Only (ARUP Medical Director or Genetic Counselor approval required prior to testing) 0050098 Method: Polymerase Chain Reaction/Fluorescence Monitoring	Tests for 3199del6 mutation only Order only for patients who have a previously identified I148T mutation
Trypsin, Fecal 0020383 Method: Film Digestion	Screen for pancreatic insufficiency caused by cystic fibrosis
Pancreatic Elastase, Fecal 0080526 Method: Enzyme-Linked Immunosorbent Assay	Screen for pancreatic insufficiency caused by cystic fibrosis	Watery stool samples may produce falsely decreased results due to a dilution effect

Additional Tests Available

Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Comments
Cystic Fibrosis (CFTR) 5T Mutation 0056003 Method: Polymerase Chain Reaction/Fragment Analysis	Do not order without ARUP's genetic counselor approval

Guidelines

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

Watson MS, Cutting GR, Desnick RJ, Driscoll DA, Klinger K, Mennuti M, Palomaki GE, Popovich BW, Pratt VM, Rohlfs EM, Strom CM, Richards CS, Witt DR, Grody WW. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med. 2004;6(5):387-391. (Link to PubMed)

General References

Accurso FJ. Update in cystic fibrosis 2005. Am J Respir Crit Care Med. 2006;173(9):944-947. (Link to PubMed)

Biagioli FE, DeVoe JE, Hamilton A, WinklerPrins V. Clinical inquiries. What are appropriate screening tests for infants and children?. J Fam Pract. 2006;55(9):803-808. (Link to PubMed)

Davies JC. New tests for cystic fibrosis. Paediatr Respir Rev. 2006;7 Suppl 1:S141-S143. (Link to PubMed)

Kerem E. Atypical CF and CF related diseases. Paediatr Respir Rev. 2006;7 Suppl 1:S144-S146. (Link to PubMed)

Lyon E, Miller C. Current challenges in cystic fibrosis screening. Arch Pathol Lab Med. 2003;127(9):1133-1139. (Link to PubMed)

Quinton HB, O'Connor GT. Current issues in quality improvement in cystic fibrosis. Clin Chest Med. 2007;28(2):459-472. (Link to PubMed)

Rowe SM, Clancy JP. Advances in cystic fibrosis therapies. Curr Opin Pediatr. 2006;18(6):604-613. (Link to PubMed)

Smyth R, Jahnke N. Cochrane systematic reviews in cystic fibrosis. J R Soc Med. 2006;99 Suppl 46:6-12. (Link to PubMed)

Southern KW, Peckham D. Establishing a diagnosis of cystic fibrosis. Chron Respir Dis. 2004;1(4):205-210. (Link to PubMed)

Strausbaugh SD, Davis PB. Cystic fibrosis: a review of epidemiology and pathobiology. Clin Chest Med. 2007;28(2):279-288. (Link to 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):1288-5. (Link to PubMed)

Chou LS, 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):111-120. (Link to PubMed)

Chou LS, 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):330-338. (Link to 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):315-319. (Link to 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):137-140. (Link to 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):1619-1623. (Link to 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):1891-1898. (Link to 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):264-270. (Link to 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):251-254. (Link to 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):853-860. (Link to PubMed)

Reviewed by

Grenache, David G., Ph.D. Medical Director, Special Chemistry at ARUP Laboratories; Assistant Professor, Clinical Pathology, University of Utah

Lyon, Elaine, Ph.D. Medical Director, Molecular Genetics at ARUP Laboratories; Associate Professor, Pathology, University of Utah

Mao, Rong , M.D. Co-Medical Director, Molecular Genetics at ARUP Laboratories; Assistant Professor, Pathology, University of Utah

Roberts, William L. , M.D., Ph.D. Medical Director, Automated Core Laboratory at ARUP Laboratories; Professor, Pathology, University of Utah

Comprehensive Review: May 2008
Last Update: July 2008