Version July 2025
INTRODUCTION —
This monograph discusses the interpretation of genetic testing of CFTR, the cystic fibrosis (CF) gene.
It does not discuss the indications for testing and is not intended to replace clinical judgment in the decision to test or care of the tested individual. These subjects are discussed separately in UpToDate [1]. (See 'UpToDate topics' below.)
HOW TO READ THE REPORT
General principles — The table summarizes terminology in the report (table 1).
Before acting on results:
●Assess the report for accuracy, as outlined in the checklist (table 2).
●If testing is from direct-to-consumer testing or a research study and results would impact care, repeat testing in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (United States) or comparable laboratory in other countries.
Cystic fibrosis (CF) is a clinical and laboratory diagnosis based on clinical manifestations or physiologic corroboration of dysfunctional CF transmembrane conductance regulator (CFTR). Genetic testing supports the diagnosis, but diagnosis from genetic testing alone is not advised.
One of the main uses of genetic testing is to determine the eligibility for CFTR modulator therapies. (See "Cystic fibrosis: Treatment with CFTR modulators".)
Testing methods — Genetic testing can be done using a gene panel of known variants or gene sequencing. If there is clinical concern for CF or a related disorder and a gene panel or gene sequencing is negative, consultation with a CF and/or genetics expert is advised. (See 'Locating an expert' below.)
●Gene panel – A typical CF genotyping panel tests for 23 common CFTR pathogenic variants (PVs), typically with population frequency ≥1 percent (table 3) [2]. Some panels include additional PVs. (See "Cystic fibrosis: Carrier screening", section on 'Carrier panel selection'.)
All variants on a genotyping panel are (by definition) PVs; the report typically describes positive results as mutations or PVs. (See "Cystic fibrosis: Genetics and pathogenesis", section on 'CFTR pathogenic variants'.)
A negative panel only means the individual did not have one of the PVs on the panel. They may have other PVs in CFTR or other genes. (See 'Implications of negative testing' below.)
●Gene sequencing – The report will typically include all identified variants, with classification as pathogenic, likely pathogenic, of uncertain significance, likely benign, or benign (table 4) [3].
A negative sequencing result means that adequately sequenced regions of the CFTR gene did not contain known PVs. False-negative results are possible if there is a PV in a non-coding segment of the gene (intron, promotor region) or if sequencing reads were insufficient in certain exons. (See 'Implications of negative testing' below.)
●Reflex testing – Laboratories may perform automatic reflex testing in some cases:
•Variants I506V, I507V, and F508C may lead to false-positive reports of F508del or F507del.
•When R117H is identified, testing for 5T/7T/9T variants helps predict the likelihood of congenital bilateral absence of the vas deferens.
If two PVs are identified, laboratories will suggest testing the parents to determine if the finding is in cis (both PVs on the same allele, inherited from the same parent) or in trans (one variant on each allele, inherited from both parents). Samples from both parents are generally required for the laboratory to make this determination.
Interpretation/common variants — Over 2100 CFTR variants have been identified. Certainty regarding pathogenicity only exists for a subset.
●Pathogenicity – Pathogenicity refers to the potential to cause disease (table 1). The spectrum and severity of disease manifestations depend on penetrance and expressivity. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)
●Common pathogenic variants (PVs) – The most common PVs, F508del and W1282X, are highly penetrant; all patients with F508del or W1282X who have homozygosity for either of these variants or compound heterozygosity for either of these variants plus another PV will develop classic CF. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)
●VUS – A variant for which pathogenicity cannot be characterized is termed a variant of uncertain significance (VUS). VUSs will eventually be reclassified as data emerge. Clinicians should assess clinical manifestations in the patient, consider other possible diagnoses, and seek updated interpretation before providing counseling. Sharing information about the VUS with CF experts may help in assessing pathogenicity. (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)
●Inheritance – CF inheritance is autosomal recessive:
•Heterozygosity – Individuals who are heterozygous for a CFTR PV are generally unaffected carriers. They can transmit the variant to their offspring. (See 'Carrier screening for reproductive counseling' below.)
Exceptions may include:
-Some heterozygous individuals have CFTR-related disorder, which has a mild clinical phenotype. (See "Cystic fibrosis: Genetics and pathogenesis", section on 'CFTR-related disorder' and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'CFTR-related disorder'.)
-Some individuals with CF may appear to be heterozygous because only one of their CFTR PVs has been identified. These individuals may require consultation and more extensive genetic testing. (See 'Locating an expert' below.)
•Homozygosity or compound heterozygosity – To abolish CFTR function, there must be biallelic CFTR PVs. If genetic testing reveals two or more PVs at different positions within the gene, it is possible that one of the PVs is present on each CFTR allele (biallelic; PVs in trans, compound heterozygous, potentially affected) or that both PVs are on the same allele (and the same chromosome) and the other allele (and other chromosome) could be free from PVs (PVs in cis, CF carrier).
Individuals with biallelic (homozygous or compound heterozygous) PVs in CFTR are considered to have positive genetic testing for CF.
-Clinical and/or physiologic correlates are needed. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Diagnostic criteria'.)
-The possibility of trans positioning can be clarified by genotyping informative relatives (parents, siblings, children) to determine if the PVs are both on the same allele or one on each allele. (See 'Testing methods' above.)
Consultation with a CF and/or genetics expert should be sought if there is discordance between the genetic interpretation and the clinical picture.
Implications of negative testing — If no PVs were identified, the implications depend on the reason for testing and details of which variants were assessed [2]:
●Screening – A negative result from a screening panel means the individual does not carry the PVs on the panel; this may be considered sufficient for routine screening of individuals in the general population. (See 'Testing methods' above.)
However, screening panels generally focus on PVs that are common in individuals from European countries. A panel will not include all possible PVs, and a negative result on a screening panel does not eliminate the possibility of carrying a PV, especially for individuals with relatives from countries outside Europe.
●Testing for a known familial variant – When there is a known history of CF or carriers of a CFTR PV in a kindred, it is important to ensure that the familial variant(s) are tested. Individuals who test negative for a familial CFTR variant can have reasonable assurance that they do not carry the variant.
If there is a known history of CF or carriers of a CFTR PV in a kindred but the familial PV has not been identified in an affected relative, gene sequencing (rather than a gene panel) is recommended.
CONSIDERATIONS FOR SELECTED POPULATIONS
Newborn screening — CF is included in newborn screening in the United States and other countries. Newborn screening typically measures immunoreactive trypsinogen (IRT), with or without CFTR genetic testing. If IRT is abnormal, genetic testing is indicated. (See "Overview of newborn screening", section on 'Implementation of screening in the United States' and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Newborn screening'.)
Sweat chloride testing is appropriate in newborns with a pathogenic variant (PV) in the CFTR gene. This allows distinction between newborns with CF and those who are unaffected carriers. Some newborns may receive a provisional diagnosis of CFTR-related metabolic syndrome (CRMS; also called CF screen positive, inconclusive diagnosis) if the results of sweat chloride testing are inconclusive.
While newborn screening identifies most individuals with CF, some may be missed. Any person with symptoms of possible CF requires further evaluation regardless of the results of genetic testing. (See 'Symptomatic individuals' below.)
Symptomatic individuals — Universal newborn screening for CF reduces the likelihood that older children and adults will have undiagnosed CF; however, some individuals with milder symptoms may present later in life. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)
Symptoms considered suggestive of CF that may present in older children or adults include:
●Certain types of respiratory disease:
•Chronic lung infections
•Obstructive lung disease
•Chronic productive cough
●Certain types of gastrointestinal disease:
•Chronic pancreatitis
•Malabsorption
●Chronic rhinosinusitis, especially if confirmed radiologically
●Certain types of infertility such as male obstructive azoospermia
Genetic testing and counseling of such patients often benefit from CF center expertise. (See 'Locating an expert' below.)
Carrier screening for reproductive counseling — In many countries, CF carrier screening is routinely offered to all couples before pregnancy (preferable) or in early pregnancy.
●Maternal – Routine maternal screening typically uses a panel of common CFTR PVs. In 2023, the American College of Medical Genetics and Genomics (ACMG) recommended an updated list of 100 PVs for carrier screening [4]. Some laboratories continue to use a previously recommended smaller panel of 23 PVs (table 3). (See "Cystic fibrosis: Carrier screening".)
●Paternal – If the mother tests positive for a CFTR PV(s) on the screening panel, the father is tested (algorithm 1). If the father tests negative, it means they do not carry PVs included in the panel, and additional testing may be indicated such as CFTR sequencing. If the father is not available, the risk of an affected child is calculated based on the father's family history and/or background carrier rate for the father's race and ethnicity (table 5). (See "Cystic fibrosis: Carrier screening", section on 'Candidates for screening'.)
●Known PV – For kindreds with a known CFTR PV, maternal or paternal testing for the familial variant is more important than panel testing, although a panel can be used if that variant is on the panel. If the individual tests positive for the PV, the other partner is tested. (See "Cystic fibrosis: Carrier screening", section on 'Couples with a personal or family history of CF'.)
●Known CF – For kindreds with known CF, it is critical to identify the specific PVs in the affected individual(s) so they can be included in reproductive testing and counseling. Carrier screening should include the affected relative's PVs. If the affected relative had incomplete testing and is not available, CFTR sequencing should be offered to relatives who will become pregnant.
If both partners carry a PV in CFTR, there is a 25 percent chance their child will inherit both PVs and have CF, a 50 percent chance their child will inherit one or the other PV and be a carrier, and a 25 percent chance their child will inherit neither PV.
Couples may elect to use noncarrier donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing and selection of unaffected embryos. (See "Preimplantation genetic testing".)
Fetal genotype can be determined by chorionic villus sampling or amniocentesis. Prenatal diagnosis provides an opportunity to plan for the birth of an affected child or to pursue pregnancy termination. (See 'Newborn screening' above.)
Modern treatment paradigms have dramatically improved survival in individuals with CF (figure 1). However, it may not be possible to accurately predict the prognosis for a specific individual. Some individuals may reasonably omit prenatal testing if the results would not affect their decision-making regarding the pregnancy.
Testing relatives — CF inheritance is autosomal recessive. First-degree relatives of an individual with one or more CFTR PVs should be offered genetic counseling.
●For patients with CF (biallelic PVs in CFTR):
•Both parents are at least heterozygous for one of the PVs (barring nonpaternity).
•Siblings have a 25 percent chance of inheriting both variants and having CF, a 50 percent chance of inheriting one variant and being carriers, and a 25 percent chance of inheriting neither variant.
•Children have a 100 percent chance of inheriting one of the variants. They will be heterozygous carriers, or, if their other parent carries a PV, they may inherit biallelic variants and be affected with CF.
●For patients who are carriers (heterozygous for a PV in CFTR):
•At least one parent is at least heterozygous for the PV.
•Siblings have a 50 percent chance of being heterozygous for the PV; siblings' risk for CF depends on the status of the other parent.
•Children have a 50 percent chance of inheriting that variant; children's risk for CF depends on the status of the other parent. (See 'Carrier screening for reproductive counseling' above.)
Incidental finding — Unexpected finding of a CFTR PV may occur during research testing, exome or genome sequencing, or direct-to-consumer testing. If the finding is confirmed, genetic counseling is indicated (algorithm 2). Those with biallelic PVs should be evaluated at a certified CF center. (See 'Resources' below.)
Established diagnosis of CF — CF is a life-limiting systemic disease.
●Classic CF – Features of classic CF are outlined above and described in detail separately. (See 'Symptomatic individuals' above and "Cystic fibrosis: Clinical manifestations and diagnosis".)
●CFTR-related disorder – A CFTR-related disorder refers to clinical disease limited to one organ system with CFTR dysfunction that does not meet full criteria for diagnosis of CF. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'CFTR-related disorder'.)
In individuals with CF, determining the specific CFTR mutation class is essential for determining eligibility for treatment (table 6). (See "Cystic fibrosis: Genetics and pathogenesis" and "Cystic fibrosis: Treatment with CFTR modulators".)
Up to 90 percent of individuals with CF have CFTR genotypes that are responsive to therapy. In these individuals, modifier medications can dramatically improve lung function and improve quality of life [5,6].
RESOURCES
UpToDate topics
●Genetics – (See "Cystic fibrosis: Genetics and pathogenesis".)
●Carrier screening – (See "Cystic fibrosis: Carrier screening".)
●Diagnosis – (See "Cystic fibrosis: Clinical manifestations and diagnosis".)
●Pulmonary disease – (See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)
●Gastrointestinal disease – (See "Cystic fibrosis: Overview of gastrointestinal disease".)
●Diabetes – (See "Cystic fibrosis-related diabetes mellitus".)
●Nutrition – (See "Cystic fibrosis: Nutritional issues".)
●Treatment – (See "Cystic fibrosis: Treatment with CFTR modulators" and "Cystic fibrosis: Overview of the treatment of lung disease".)
Locating an expert
●National Society of Genetic Counselors (NSGC)
●American College of Medical Genetics and Genomics (ACMG)
●Cystic Fibrosis Foundation (CFF.org)
Websites for variant interpretation — Information on predicted phenotype is presented in searchable databases.
●Clinical and Functional Translation of CFTR International Consortium (cftr2.org)
●Cystic Fibrosis Mutation Database (www.genet.sickkids.on.ca/cftr/)
●CFTR-France (https://cftr.chu-montpellier.fr/)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Benjamin A Raby, MD, MPH, George B Mallory, MD, and Katharine D Wenstrom, MD, who contributed to earlier versions of this topic review.
