• Diagnose cystic fibrosis (CF)

• Diagnose atypical CF in individuals with congenital bilateral
  absence of the vas deferens (CBAVD) or other conditions
  associated with the CF transmembrane conductance regulator (CFTR) gene

• Assess the risk of having a child with CF

For use when clinically indicated after 1) standard mutation panel testing has demonstrated <2 CFTR mutations; or 2) a large CFTR deletion or duplication has been detected in a family member.

CF is a common autosomal recessive disorder characterized by chronic obstructive pulmonary disease, pancreatic exocrine deficiency with malabsorption and malnutrition, and CBAVD leading to male infertility. Atypical CF often affects only 1 organ system.

CF is caused by mutations in the CFTR gene, located on the long arm of chromosome 7 (7q31.2). More than 1700 CFTR mutations have been identified to date.¹ Although most affect only 1 or a few nucleotides, more than 25 large deletions or duplications have been described. Because standard mutation panels and sequencing assays do not detect such rearrangements, their actual frequency may be grossly underestimated.

Routine carrier screening detects 23 of the most commonly identified CFTR mutations.² The sensitivity of the screening panel for identifying mutant alleles is highest for Ashkenazi Jewish Caucasians (97%) and can be much lower for other populations: 90% for non-Hispanic Caucasians, 69% for African Americans, and 57% for Hispanic Americans; the sensitivity among Asian Americans is unknown.³ Thus, further testing is sometimes needed to identify both mutations in individuals with classic or atypical CF. Family members of CF patients whose mutations are not known may also require additional testing.

Extensive sequence analysis (eg, CF Complete^® Rare Mutation Analysis) can markedly increase the sensitivity of CFTR mutation screening, but this approach will not identify large duplications or deletions. The Cystic Fibrosis CFTR Gene Deletion or Duplication assay detects deletions and duplications within the promotor region and all 27 exons of the CFTR gene. Recent studies suggest that such rearrangements may account for 16% to 24% of mutant CFTR alleles not identified after extensive sequencing.^4-7 Because of the shorter turnaround time of the CFTR deletion/duplication test, clinicians may prefer to request it first and order extensive sequencing only if the result is negative.

• Individuals with symptoms of classic or atypical CF who have <2 CFTR mutations detected with standard mutation screening

• Individuals with a family history of a large deletion or duplication in the CFTR gene

• Family members of individuals with CF whose mutations are unknown

• Semi-quantitative fluorescent polymerase chain reaction (SQF-PCR)

–   Amplification of CFTR promotor region and all exons (1-27) in a single multiplex SQF-PCR

–   Automated (capillary electrophoresis) separation of fragments and analysis of data

–   CFTR exon mutations detected as an approximate 50% signal decrease for deleted exon(s),

and a 30% to 50% signal increase for duplicated exon(s)

• Alias: CFTR deletion/duplication

Not detected

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

Diagnosis

In the presence of positive clinical findings or family history, detection of 2 known CFTR mutations—or 1 in addition to a previously identified mutation—is consistent with a diagnosis of CF. The absence of clinical correlation data for novel mutations precludes a firm interpretation of their clinical effect. However, large deletions and duplications would be expected to impair CFTR protein function and thereby lead to disease in the presence of a second mutant allele. Negative results do not rule out the presence of an undetected CFTR mutation and therefore do not exclude a diagnosis of CF. This assay will not detect translocations or mutations outside the regions tested and may not detect small mutations such as single-nucleotide substitutions. Testing with extensive CFTR sequencing may detect rare mutations not identified by this assay.

Carrier Screening

The presence of a single known CF mutation in an asymptomatic individual identifies that person as a carrier. The relevance of a single novel mutation in this setting is not known. However, as described above, large deletions or duplications would be expected to negatively affect CFTR function and lead to disease in the presence of a second mutant allele. Negative results do not eliminate the risk of being a carrier. Testing with extensive CFTR sequencing may detect rare mutations not identified by this assay.