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FOR THE TESTED INDIVIDUAL – This information is intended to assist your physician or other qualified health care professional as part of their comprehensive assessment of the best approach to managing your genetic test results. It is not specific advice for your care and it does not replace consultation with a qualified health care professional. You should not alter your medical care based on this report without speaking to, and receiving guidance from, your physician based on your specific case.
FOR THE CLINICIAN – This information was prepared on the date indicated on the file and may have been updated subsequently. Please check UpToDate (UpToDate.com) for the latest version of this and other gene test interpretation monographs. UpToDate subscribers can access these monographs by entering the gene name or the phrase "Gene test interpretation" into the UpToDate search box. Your use of this information is subject to the terms set forth at https://www.uptodate.com/legal/license and any other terms in any applicable license agreement. This information is no substitute for individual patient assessment based on the healthcare provider's evaluation of each patient that includes personal and family history, findings from the physical examination, laboratory and other testing, and other factors unique to the patient. The information should be used as a tool to help the clinician reach diagnostic and treatment decisions, bearing in mind that individual and unique circumstances may lead to decisions other than those presented. The opinions expressed are those of the monograph's authors and editors.
Supported by an unrestricted educational grant from AncestryHealth®.
- Katharine D Wenstrom, MD
- Benjamin A Raby, MD, MPH
- Section Editors:
- Louise Wilkins-Haug, MD, PhD
- George B Mallory, MD
- Deputy Editors:
- Rebecca F Connor, MD
- Alison G Hoppin, MD
- Geraldine Finlay, MD
INTRODUCTION — This monograph discusses the interpretation of genetic testing for the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene and possible actions based on results. It does not discuss the indications for testing and is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. These subjects are discussed separately in UpToDate . (See 'UpToDate topics' below.)
HOW TO READ THE REPORT
●Assess report for accuracy and interpretation (table 1).
●If the report is from direct-to-consumer testing or a research study and the results would impact clinical care, the patient should be retested using a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory with established procedures assuring proper specimen collection and labeling.
Though >2000 DNA sequence variants have been identified in the CFTR gene, certainty regarding the potential to cause disease exists for only a subset. When genetic testing consists of genotyping a specific panel of CFTR variants known to cause CF, the report typically describes positive results as either mutations or pathogenic variants (table 2). When CFTR gene sequencing is performed, the report may call all identified changes variants. The testing laboratory classifies each variant as pathogenic, likely pathogenic, benign, or likely benign based on accumulated data (table 3) . Variants that cannot be characterized this way are called variants of uncertain significance (VUS) and are likely to be reclassified as more data emerge. (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)
●Negative results – The clinical implication of a negative test depends on the method used:
•Genotyping – A negative CF genotyping panel only means that the individual does not carry any of the CFTR mutations tested. Panels test 23 to >100 of the more commonly observed pathogenic variants (table 4). Though uncommon, patients can have one or more rare variants that are not represented on such panels, and thus a negative result does not eliminate the possibility of being a CF carrier or, in the case of fetal testing, of having an affected child. The uncertainty is greatest in individuals of non-European ancestry, for whom extensive sequence data are lacking. (See 'Negative screen' below.)
•Sequencing – A negative sequencing test means that no variants were identified in the parts of the gene that were adequately sequenced or that the only identified variants are ones known to be benign (ie, ones that do not cause disease). False negative results can arise if a pathogenic variant is missed in a gene region poorly covered by the sequencing assay. If a diagnosis of CF is suspected clinically, practitioners should verify the adequacy of sequence coverage (comments are often included in the report) and consult with a specialist if suspicions remain.
Regardless of assay type, if the patient has a family history of CF or of family members who are CFTR-variant carriers, the patient should be tested explicitly for the variants known to exist in the family. If such information is not available, sequencing is recommended over genotyping.
●False positives – Additional testing may be necessary to exclude false positives. As an example, variants I506V, I507V, and F508C may lead to false positive reports of F508del or F507del. The laboratory usually performs this testing automatically (ie, reflex testing).
●5T/7T/9T testing – Additional testing, usually performed automatically (ie, reflex testing), helps predict the phenotype for certain variants. For example, when R117H is identified, testing for 5T/7T/9T variants helps predict the likelihood of congenital bilateral absence of the vas deferens.
●Compound heterozygotes – If genetic testing reveals two or more pathogenic variants at different positions within the gene, further evaluation is needed to evaluate whether the variants reside on the same chromosome (ie, they are in "cis," both inherited from one parent) or if each are on separate chromosomes (ie, in "trans," inherited from each parent separately) (figure 1). Because CF is autosomal recessive, only variants in trans cause disease.
SPECTRUM OF DISEASE — CF is a life-limiting, systemic disease with an autosomal recessive transmission pattern. Features of classic CF include bronchiectasis, sinusitis, pancreatitis, pancreatic exocrine insufficiency, malabsorption, CF-related diabetes mellitus, hepatobiliary disease with cirrhosis and/or portal hypertension, and absence of the vas deferens in males. Disease severity varies widely and is impacted by both the inherited variants and environmental factors. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)
Disease-modifying therapies have dramatically improved the prognosis for CF. Shared decision-making must acknowledge uncertainties regarding our ability to predict the future of patients born with CF today.
The most common pathogenic CFTR variants (mutations), F508del and W1282X, are highly penetrant and result in a consistent phenotype; all patients with F508del or W1282X who have another pathogenic variant will develop classic CF. In contrast, it is difficult to predict the phenotype if there is one pathogenic variant and one variant of uncertain significance (VUS). This may result in classic CF, clinical disease limited to one organ system (a CFTR-related disorder), or a carrier state. VUS may be reclassified at any time as pathogenic or benign, so clinicians must seek an updated interpretation before providing counseling.
For the purpose of prenatal screening and fetal diagnosis, predicting the potential fetal phenotype can be difficult. If the fetus shares at least one CFTR variant with an affected family member, the phenotype may be similar to that of the affected relative. However, there can be significant interindividual phenotype variation among family members with the same genotype, and the phenotype may be modified by the variant inherited from the other parent and other factors. These uncertainties must be shared with the patient. (See "Cystic fibrosis: Carrier screening", section on 'Prediction of phenotype'.)
Information on predicted phenotype is presented in separate searchable databases. (See 'Genetics resources' below.)
Carrier screening — Carrier screening is routinely offered to all women planning pregnancy or in early pregnancy. It typically examines a panel of the 23 most common mutations (pathogenic variants) in the United States (table 4). (See "Cystic fibrosis: Carrier screening".)
The clinical implication of mutations identified depends on the specific mutations and background risk (eg, family history, ethnicity). Partner testing informs the risk of having a child affected with CF with each pregnancy. Patient values and preferences will impact decisions about pregnancy. Some pregnant women will use the screening results to avoid the birth of an affected child, while others will use it to plan for the birth of an affected child. Couples at risk who are not pregnant may elect to conceive using noncarrier donor gametes or in vitro fertilization with preimplantation genetic testing and selection of unaffected embryos. (See "Preimplantation genetic testing".)
Positive screen — Individuals with a positive screening test should receive genetic counseling, and testing of the partner is indicated (algorithm 1).
If the father is unavailable for testing, the risk of an affected child is calculated based on the mother's test results and the background carrier rate for her partner's ethnicity (table 5).
If both partners carry a known mutation (pathogenic variant), there is a one in four chance that their child will be affected. Affected offspring can be identified prenatally using chorionic villus sampling or amniocentesis. Because obstetric and neonatal management is not changed by the prenatal diagnosis of CF, couples who would not terminate an affected pregnancy may elect to delay testing until after birth to avoid the small risk of miscarriage from invasive diagnostic procedures. (See 'Newborn screening' below.)
Negative screen — A negative screening test only means that the individual does not carry any of the CF mutations included in the screening panel; a negative result does not eliminate the possibility of being a CF carrier. The degree to which the risk of being a carrier is reduced after a negative test is determined by the number of mutations screened and the patient's ethnicity. There is considerable variability across ethnicity and race with regard to the most common CF-causing mutations (table 5).
If there is a family history of CF, carrier screening should include the mutations present in the affected family member in addition to those in the standard panel. If the affected family member had no or incomplete CF testing and is not available for testing, and standard screening of the member of the couple who is related is negative, CFTR sequencing should be offered.
When a CF carrier's partner has a negative screen, further testing of the screen negative partner may be indicated. A genetic counselor can help determine the next step (eg, CFTR sequencing versus expanded screening panels followed by CFTR sequencing, if negative), taking into account background risk and insurance coverage.
Incidental finding — An individual may unexpectedly discover that he or she carries a pathogenic or likely pathogenic CFTR variant through testing done for research purposes, exome or genome testing performed for other clinical indications, or direct-to-consumer testing. If confirmed by repeat testing, genetic counseling is indicated (algorithm 1). Those with two copies of a pathogenic or likely pathogenic variant should be evaluated at a certified CF center.
NEWBORN SCREENING — Newborn screening typically measures blood levels of immunoreactive trypsinogen (IRT), with or without concurrent CFTR gene testing. If IRT is abnormal, genetic testing is indicated. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Diagnosis'.)
Infants with one or more pathogenic CFTR variants are referred for sweat chloride testing, which distinguishes affected children from carriers in most cases. Infants with indeterminate results may be given a provisional diagnosis of CFTR-related metabolic syndrome (CRMS), also referred to as CF screen positive, inconclusive diagnosis (CFSPID).
Some cases of CF will be missed by newborn screening. CF should be suspected in individuals with suggestive symptoms, even when results of the newborn screen are negative or equivocal. CFTR gene sequencing may identify pathogenic variants in this setting.
SYMPTOMATIC INDIVIDUALS — CFTR gene testing may be performed in individuals with a chronic condition that can be associated with CF such as pulmonary disease, recurrent pancreatitis, nasal polyps, chronic sinusitis, or male infertility due to absence of the vas deferens.
Such testing is usually conducted by a subspecialist. Genetic testing and counseling of such patients is complicated and often benefits from CF center expertise.
Since the universal adoption of newborn screening for CF in the United States, it is much less common for adults to have undiagnosed CF. However, individuals with milder CF or only a single feature of CF are more likely to present later in childhood or adulthood, and to have uncommon CFTR variants not included in the standard screening panels. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Regional variation in screening'.)
Results of CFTR gene testing helps guide treatment of CF as mutation class impacts treatment options (table 6). (See "Cystic fibrosis: Genetics and pathogenesis" and "Cystic fibrosis: Treatment with CFTR modulators".)
CONSIDERATIONS FOR THE FAMILY — CF is an autosomal recessive disorder. Relatives of individuals with pathogenic CFTR variants are at increased risk of being carriers and should be offered genetic counseling.
●Parents of patients with CF – Unaffected parents of individuals with CF are usually obligate carriers.
●Siblings of patients with CF – Each full sibling of an individual with CF has a 25 percent chance of being affected, a 50 percent chance of being an asymptomatic carrier, and a 25 percent chance of being a noncarrier. This means unaffected siblings of a child with classic CF have a two in three chance (66 percent) of being a carrier.
●Offspring of patients with CF – An affected individual will transmit one pathogenic variant to offspring; therefore, offspring will either be asymptomatic carriers or will have CF depending on the genotype of the other parent.
●Siblings of a CFTR carrier – Each full sibling of a known carrier has a 50 percent chance of being a carrier.
Resources for locating a genetic counselor or specialized CF center:
●National Society of Genetic Counselors (NSGC)
●Cystic Fibrosis Foundation (www.cff.org)
Resources for determining pathogenicity of variants:
●Clinical and functional translation of CFTR international consortium (cftr2.org)
●CF mutation database (www.genet.sickkids.on.ca/cftr/)
- Supporting references are provided in the associated UpToDate topics, with selected citation(s) below.
- Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17:405.
|Section of the report||Action(s)||Concern(s)|
||Individuals may inadvertently provide the wrong name on a test sample. Testing should be done by a laboratory that can ensure that the identification matches the tested individual.|
||All actionable medical testing (eg, positive finding or negative finding in an individual suspected of having a genetic disorder) should be conducted in a CLIA-certified laboratory that has met appropriate quality standards for performing the specific test. Some direct-to-consumer testing is not performed in CLIA-certified laboratories and may lack appropriate quality controls.|
|Date of testing||
||Germline variants do not change over time. However, as new data become available, the classification of variant pathogenicity may change, especially for variants classified as VUS. Repeat testing may be considered, as the technologies for exome sequencing may improve and may identify a variant missed on a prior test.|
||Not all genetic testing panels are comprehensive in the genes or variants in those genes they evaluate. New disease genes or clinically important variants in existing genes may be identified through further research.|
||Not all methods will identify all variants. In some cases such as HFE testing, only one or two variants are clinically relevant, and sequencing of the entire coding region of the gene is not required, whereas in other conditions, limited testing for one or two variants may miss clinically important findings. Gene panels may be especially useful when multiple genes could potentially be responsible for a clinical phenotype.|
|Classification of pathogenicity||
||Interpretation of pathogenicity takes into account many data sources including laboratory research, research databases, population studies, and pedigree analyses. In some cases, pathogenicity is well established (eg, the variant that causes sickle cell disease); in others, it is more subjective and incomplete. Variants classified as VUS, likely benign, or benign generally are not actionable and should not impact medical interventions. Consulting a publicly curated database such as ClinVar or discussing the results with an expert in the specific disease, or referral to a clinical geneticist, genetic counselor, or disease expert may be helpful.|
* Indications for testing vary according to the individual's medical history, family history, and other factors such as desire for preconception counseling. In some cases, an individual who did not have a clinical indication for testing may have an unexpected finding from genetic testing that, if accurate, would indicate the need for an intervention, and such findings may be actionable regardless of the initial reasons for testing.
|Autosomal dominant||Pattern of inheritance that requires only one affected variant allele (a variant inherited from one parent or that arises de novo) to transmit the trait or risk of disease. Not sex-linked. First-degree relatives (siblings, children) have a 50% chance of sharing (or inheriting) the variant allele.|
|Autosomal recessive||Pattern of inheritance that generally requires both variants on both alleles (one from each parent) in order to transmit the trait or risk of disease. Not sex-linked. Individuals with one variant are sometimes called carriers.|
|Carrier||Individual who has a specific variant in one allele of the gene in their germline DNA (inherited from one parent or arising de novo). For recessive disorders, refers to a heterozygote who is generally (or mostly) unaffected. For dominant disorders, carriers are generally considered at risk for the disorder.|
|Expressivity||Differences in the severity of disease manifestations in individuals who share the same genotype (eg, cystic fibrosis is said to have variable expressivity because two individuals with the same genotype may have differences in the degree of pancreatic or lung dysfunction).|
|Genotyping||Determining the DNA sequence of a particular gene or portion of a gene in an individual. Can be done on DNA from sources such as nucleated epithelial cells from saliva, tumor cells from a biopsy, or WBCs from peripheral blood. Can be used to determine germline or somatic sequence, depending on the source of the cells.|
|Germline||Derived from the gametes (sperm or egg cells) and present in the early embryo; germline variants are typically present in all body cells and do not change. Germline variants can be passed down to subsequent generations.|
|Mutation||Term that may be used to describe changes in DNA or protein sequence compared with a reference sequence. The American College of Genetics and Genomics (ACMG) has expressed concern that this term can cause confusion or incorrect assumptions regarding pathogenicity, and the ACMG recommends that findings from genetic testing be described using the term "variant" with a qualifier regarding pathogenicity (or lack thereof).|
|Pathogenicity||Likelihood that a specific variant is capable of causing disease or conferring disease risk. Does not determine the likelihood that disease will occur (which depends on other factors such as disease penetrance). Refer to separate table in UpToDate for the categories.|
|Pedigree||Diagram of a family showing relationships among family members, sex of each family member, presence or absence of one or more genetic disorders, and often the age at which they manifested. Used in genetic counseling to identify possible inherited causes of disease and their inheritance patterns.|
|Penetrance||Likelihood that a person with a disease-associated variant will manifest one or more features of the disease. Many disease variants have incomplete or variable penetrance, meaning that not all individuals with the variant will manifest the associated disorder.|
|Somatic||Referring to tissues that are not within the germline. Variation that arises in somatic tissues is not passed from parent to offspring. Somatic mutations are common in cancer.|
|Variant||Change in the sequence of DNA compared with a reference sequence. Variants can be benign (associated with normal gene function), pathogenic (associated with altered gene function and/or clinical disease, also called mutations), or somewhere in between. The term polymorphism is often (but not exclusively) used for benign variants. Refer to a separate table in UpToDate that defines the categories.|
|VUS||Variant of uncertain significance (or unknown significance). Refers to a variant for which insufficient information is available to classify as benign or pathogenic.|
|Pathogenic||Associated with disease risk|
|Likely pathogenic||>90% likelihood of disease risk association|
|Variant of uncertain significance (VUS)||Available data do not allow classification into one of the other categories|
|Likely benign||>90% likelihood that variant is not associated with disease risk|
|Benign||Not associated with disease risk|
- Population data (allele frequency; prevalence of variant in affected individuals versus controls)
- Computational data (predicted effect on protein sequence or function)
- Functional data (functional studies show or do not show deleterious effect)
- Segregation data (variant segregates with disorder in families)
Supported by an unrestricted educational grant from AncestryHealth®.
|Standard or basic mutation panel|
|F508del-CFTR, I507del, G542X, G551D, W1282X, N1303K, R553X, 621+1G>T, R117H, 1717-1G>A, A455E, R560T, R1162X, G85E, R334W, R347P, 711+1G>T, 1898+1G>A, 2184delA, 3849+10kbC>T, 2789+5G>A, 3659delC, 3120+1G>A|
|I506V*, I507V*, F508C*, 5T/7T/9T¶|
* Benign variants. This test distinguishes between the F508del-CFTR mutation and these benign variants. I506V, I507V, and F508C testing is performed only as reflex tests for unexpected homozygosity for F508del-CFTR and/or I507del.
¶ 5T/7T/9T analysis is performed only when R117H is detected for the following reasons: The R117H mutation can result in classic CF only if there is a 5T variant on the same chromosome and another CF mutation on the opposite chromosome. R117H on one chromosome and 5T or 7T on the opposite chromosome or homozygosity for 5T (5T on each chromosome) can result in congenital bilateral absence of the vas deferens (CBAVD).
- American College of Medical Genetics. Technical standards and guidelines for CFTR mutation testing. 2006.
- Committee on Genetics, American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Number 325, December 2005. Update on carrier screening for cystic fibrosis. Obstet Gynecol 2005; 106;1465.
- Castellani C, Cuppens H, Macek M Jr, et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros 2008; 7:179.
* Ensure that the genetic testing is performed properly, the patient identification is correct, and the interpretation of pathogenicity is accurate based on the most recent data analysis.
¶ VUS lacks sufficient information from clinical and bench research to be classified as pathogenic or benign. Patients with a VUS should seek updated interpretation to inform future pregnancies.
Δ Asymptomatic patients with two copies of a pathogenic or likely pathogenic variant should be evaluated at a certified CF center. Occasionally, individuals with one or two variants are thought to be asymptomatic because they do not have classic CF symptoms. However, on further review, they have a single feature associated with CF (eg, male infertility, absence of the vas deferens, nasal polyps, recurrent pancreatitis). Such patients should be referred to the appropriate medical subspecialist at a CF center for evaluation.
◊ Since CF is an autosomal recessive disorder, CF in any individual related by blood is considered a positive family history.
§ Genetic counseling can be offered to all individuals with a family history of CF contemplating pregnancy.
|Group||Incidence of cystic fibrosis||Carrier frequency of a CFTR gene mutation||F508del-CFTR, percent|
|Hispanics||1/8000 to 9000||1/58||46|
|Native Americans||1/3970 Pueblo||1/31 Pueblo||0|
|1/1500 Zuni||1/20 Zuni|
- National Institutes of Health. Genetic testing for cystic fibrosis. NIH Consensus Statement 1997; 15:1.
- American College of Obstetricians and Gynecologists. Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Committee on Genetics. Obstet Gynecol 2017;129:e41-e55.
|I||Defective protein production results in complete absence of functional CFTR protein.||G542X, W1282X, R553X|
|II||Defective protein processing. Misfolded CFTR protein is unable to reach the cell surface.||F508del, N1303K|
|III||Defective regulation. CFTR chloride channel gate does not open properly.||G551D|
|IV||Defective conductance of CFTR chloride channel.||R117H|
|V||Normal protein is created, but in insufficient quantities.||A455E|
Contributor DisclosuresKatharine D Wenstrom, MDNothing to discloseBenjamin A Raby, MD, MPHConsultant/Advisory Boards: Sanofi; Genzyme; Regeneron; Teva [Asthma]. Employment (spouse): Parexel [Hematology (CRO)].Louise Wilkins-Haug, MD, PhDNothing to discloseGeorge B Mallory, MDGrant/Research/Clinical Trial Support: TOPP-2 [Pulmonary hypertension].Rebecca F Connor, MDNothing to discloseAlison G Hoppin, MDNothing to discloseGeraldine Finlay, MDConsultant/Advisory Boards: LAM Board of directors, LAM scientific grant review committee for The LAM Foundation.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.