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Cystic Fibrosis and CF-Related Disorders NGS Panel


Syndrome Information

Clinical Description

Classic Cystic Fibrosis (CF) consists of progressive lung disease, exocrine pancreatic insufficiency, and male infertility.  Patients have elevated sweat chloride concentrations.  Patients sometimes termed 'non-classic' still meet diagnostic criteria for CF, but may have lower sweat chloride levels or may be pancreatic sufficient. 

Mild presentations of recessive pseudohypoaldosteronism (PHA) Type 1 caused by mutations in the epithelial sodium channel genes (SCNN1ASCNN1BSCNN1G) can present with elevated sweat chloride concentration, chronic cough, and frequent lower respiratory infections. These patients do not have the more severe symptoms of either CF (severe lung disease, pancreatic insufficiency, infertility) or PHA1 (salt-wasting, volume depletion).

Patients with carbonic anhydrase XII deficiency caused by muations in CA12 have elevated sweat chloride concentrations. The most common presentation is severe infantile hyponatremic dehydration with hyperkalemia and failure to thrive.  Clinically asymptomatic adults have been described, and sweat chloride concentrations can be, but are not always, elevated in this subgroup of patients.

Inheritance Pattern

Autosomal Recessive

Genotype-Phenotype Correlation

There is a correlation between pancreatic status and CFTR mutation; however, lung disease seems to be more highly influenced by environmental factors or other modifier genes.

Mutations in SCNN1ASCNN1B, and SCNN1G associated with residual function lead to a phenotype that has some overlap with cystic fibrosis, whereas mutations that cause complete loss of function are associated with classic presentations of severe, salt-wasting pseudohypoaldosteronism type 1 (PHA1).

No genotype-phenotype correlation is known for Carbonic anhydrase XII deficiency.

Test Information

Test Method

Next Generation Sequencing (NGS) of the coding regions and intron-exon boundaries of the listed genes;Deletion/Duplication:  Dosage analysis by normalization of NGS read depth for the listed genes; Sanger sequencing for potential fill in / confirmation 

This test is also available as part of one or more NGS panels for cystic fibrosis and related disorders.

Clinical Utility

Identification of causative mutations in known or suspected cases of cystic fibrosis; targeted carrier testing of relatives ofproband; predictive prenatal testing when familial mutations are known.   

This panel is especially useful in patients who do not have a classic presentation of cystic fibrosis and who have not had previous CFTR sequencing.

Clinical Sensitivity

Approximately 98% of classic cystic fibrosis is caused by point mutations in the CFTR gene. This sequence analysis will detect >99% of those point mutations. This analysis will not detect other types of mutations in the CFTR gene.  It is estimated that about 2% of CFTR mutations are large rearrangements, including deletions and duplications.  This test will detect full gene deletions and most previously reported multi- and single exon deletions and duplications, but not translocations or rearrangements limited to an intron.

Recessive pseudohypoaldosteronism Type 1 and carbonic anhydrase XII deficiency are rare disorders and series of patients have not been described.  It is not known what percentage of patients with a clinical diagnosis of cystic fibrosis actually have these disorders.   

Analytic Sensitivity

> 99% for inherited single nucleotide and small insertion/deletion variants for the nucleotides evaluated; >99% for multi-exon deletions and >98% for single exon deletions; >90% for multi-exon duplications and >75% for single exon duplications. Sequencing of CFTR and the other genes included in this panel is not recommended in the carrier screening setting.

Sample Requirements

3-6ml whole blood in EDTA (purple topped) tubes. (see Pediatric or Adult blood sample algorithms for additional information)

We prefer whole blood for all tests.

Turn Around Time

Approximately 4 weeks

Fee and CPT Codes

$2750 for routine testing on a blood sample
CPT Code: 81223; 81222, 81406 x 3; 81479

Direct analysis of the CFTR intron 8 for T and TG tract length
CPT Code: 81223; 81222

Special Considerations

Sequencing of CFTR and the other genes included in this panel is not recommended in the carrier screening setting.

This test is also available as part of one or more NGS panels for cystic fibrosis and related disorders.

INFORMED CONSENT from the patient is required prior to ordering a genetic test. The DNA Diagnostic Lab's consent is located on the second page of the requisition form. There is also a patient brochure, "Things Every Patient Should Know Before Consenting to a Genetic Test", available for download.