Cystic Fibrosis (CFTR) Expanded Variant Panel

Cystic fibrosis (CF) is an autosomal recessive disorder caused by variants in the CFTR gene. Age of onset, manifestations, and symptom severity vary greatly. Symptoms of classic CF include chronic sinopulmonary disease, pancreatic insufficiency, hepatic disease, prolapsed rectum, meconium ileus, obstructive azoospermia, and salt loss syndromes. Life expectancy is reduced. CFTR-related disorders are less severe and may be characterized by idiopathic pancreatitis, bilateral absence of the vas deferens, bronchiectasis, and/or nasal polyposis. These disorders typically present in adulthood and may not decrease life expectancy. Molecular testing may be used for carrier screening and diagnostic testing.

The American College of Medical Genetics (ACMG) and the American College of Obstetricians and Gynecologists (ACOG) recommend CTFR carrier screening for all couples planning a pregnancy or currently expecting. ^, 

ACMG now recommends carrier screening for 100 specific, pathogenic CFTR variants, an increase from the previously recommended 23 variants (known as "ACMG-23").  The Cystic Fibrosis (CFTR) Expanded Variant Panel detects 165 variants, which include the previously established 23 pathogenic CFTR variants and 69 of the 100 ACMG-recommended variants. Refer to the Variants Tested section for a complete list.

Disease Overview

Genetics

Gene

CFTR

Variants

There are more than 2,000 identified variants in the CFTR gene, although most are very rare and not well characterized. CFTR is the only gene known to be causative for CF. Classic CF is caused by two severe pathogenic CFTR variants on opposite chromosomes. CFTR-related disorders are generally caused by one severe and one mild CFTR variant on opposite chromosomes.

For a full list of variants tested, see the Variants Tested table.

Inheritance

Autosomal recessive

Penetrance

• Complete for two severe variants on opposite chromosomes
• Incomplete when there are two pathogenic variants on opposite chromosomes and at least one is mild or a variant of varying clinical consequence (i.e., one severe and one mild variant). Such combinations may or may not cause symptoms of a CFTR-related disorder.

Test Description

All variants in the Variants Tested table are assessed.

If one copy of the R117H variant is detected, then testing for the mild 5T variant is performed. If the 5T variant is also detected, cis/trans testing is performed to determine whether the variants are on the same chromosome. The mild 5T variant, c.1210−12[5], will only be reported if either the R117H variant is detected or the individual is reported to be symptomatic.

Test Interpretation

Sensitivity/Specificity

Clinical Sensitivity

Clinical sensitivity varies depending on ethnicity.

Analytic Sensitivity/Specificity

99%

Limitations

• Diagnostic errors can occur due to rare sequence variations.
• Only CFTR variants listed in the Variants Tested table will be interrogated.

Variants Tested