• Detect cystic fibrosis (CF) carriers

• Determine a couple’s risk of having a child with CF

• Identify familial mutations in affected individuals

• Diagnose CF (pre- and postnatally)

CF is a common autosomal recessive disease affecting Caucasians, with an incidence of approximately 1 in 3,000 births and a carrier rate of 1 in 25 in this population.^1,2 CF also occurs in other ethnic groups with less frequency. The disorder may be characterized by chronic obstructive pulmonary disease, pancreatic exocrine deficiency with malabsorption and malnutrition, liver disease, and congenital bilateral absence of the vas deferens (CBAVD) leading to male infertility.^3,4 Clinical onset of mild disease typically occurs in adulthood. Diagnosis of severe disease, however, usually occurs within the first years of life and is based on chronic obstructive lung disease, persistent pulmonary infection (primarily Pseudomonas and Staphylococcus), meconium ileus, and pancreatic insufficiency with failure to thrive.^3,4 Diagnosis is confirmed by a positive sweat chloride test and/or detection of a CF-associated mutation on both chromosomes.¹ Treatment is focused on improved airway clearance, antibiotic therapy for lung infections, medications to increase lung function, pancreatic enzyme replacement, proper nutrition, and psychosocial support.^3,5 Median predicted survival for CF is approximately 37 years,⁶ with the majority of deaths occurring because of lung disease.⁵

CF has been attributed to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on the long arm of chromosome 7 (7q31.2).⁴ Over 1,700 mutations have been identified⁷; however, the ΔF508 mutation accounts for about 70% of all CFTR mutations in many, but not all, ethnic groups.⁸ Mutations result in a defective CFTR protein that, in turn, results in defective cellular chloride transport.

• Individuals with a family history of CF or CFTR mutations

• Symptomatic children and adults

• Males with CBAVD

• Patients with chronic or idiopathic pancreatitis

• Reproductively active individuals or couples

• Amplification of selected regions of the CFTR gene, followed by detection of wild-type and mutant sequences

• Includes the 23 most common CF mutations as recommended by ACMG and ACOG; also includes 9 other mutations that occur at low frequency

• Report form specifies mutations screened, mutations identified, and interpretive information

• Synonyms: Cystic fibrosis transmembrane conductance regulator or CFTR, CF carrier screening

The following information will help with interpretation of test results. Additional assistance is available from our Genetic Counselors by calling 1-866-GENE-INFO (1-866-436-3463).

Diagnosis

Detection of 2 mutant alleles in conjunction with positive clinical findings or family history is consistent with CF. Failure to detect 1 or more mutant alleles in a symptomatic patient, however, does not exclude a diagnosis of CF. Approximately 18% of affected Caucasian individuals have only 1 detectable mutation, and 1% have no detectable mutations when using this screen.⁹ Sweat chloride testing should be performed in all suspected CF cases.

Carrier Detection

The presence of a single CF mutation in an asymptomatic individual identifies that person as a carrier. As shown in the Table below, absence of a CF mutation significantly reduces, but does not eliminate, the risk of being a carrier. The residual risk of being a carrier (ie, of having a CF mutation not screened for in this assay) is influenced by the individual’s clinical and family history and ethnicity. If clinically indicated, additional testing is available.

IVS8 5T/7T/9T Polymorphism  

• A single 5T variant with an R117H mutation on the same chromosome (in cis) acts as a classic CF mutation. Thus, an individual with this genotype is a CF carrier.^1,2 A 5T variant occurring in trans (on different chromosomes) with an R117H mutation may result in CBAVD.¹

• A 7T or 9T variant in cis with an R117H mutation acts as a mild CF mutation.^1,2 Thus, an individual with this genotype is a CF carrier. When coupled with a classic CF mutation, male patients may have CBAVD.

In summary, identification of an R117H mutation is followed by reflex testing for the 5T/7T/9T polymorphism in intron 8. If a 5T variant is identified, testing of family members is required to determine if the variant is in cis or trans.¹ Genetic counseling is recommended.

I506V and I507V Variants

• I506V and I507V are not associated with CF or CBAVD.

• Individuals heterozygous for a ΔF507 or ΔF508 mutation who have an I506V or I507V variant on the other chromosome appear to be homozygotes on many CF detection assays (ie, carriers may be misclassified as CF-affected individuals). Thus, when results indicate a ΔF507 or ΔF508 homozygote, reflex testing for I506V and I507V is performed to rule out a false-positive CF test.¹

Risk Calculation for a CF-affected Fetus 

A couple’s risk of having a CF-affected fetus = [(mother’s carrier risk) (father’s carrier risk)] ÷ 4.³ This risk is the same for each pregnancy, regardless of the outcomes of prior pregnancies.