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Cystic fibrosis: Carrier screening

Cystic fibrosis: Carrier screening
Literature review current through: Jan 2024.
This topic last updated: Apr 27, 2022.

INTRODUCTION — Cystic fibrosis (CF) is a life-limiting autosomal recessive disease affecting the airways, pancreas, liver, intestines, sweat glands, and, in males, the vas deferens. It is the most common monogenic disorder in non-Hispanic White people of Northern European descent, with a carrier frequency of 1in 24 to 1 in 25 and birth prevalence of 1 in 2500. Carrier screening is offered to people planning pregnancy or in early pregnancy to identify couples at risk of conceiving a child with classic CF.

This topic will review CF carrier screening and reproductive options for carrier couples, including prenatal diagnosis. Other issues related to CF are discussed separately, including:

(See "Cystic fibrosis: Clinical manifestations and diagnosis".)

(See "Cystic fibrosis: Genetics and pathogenesis".)

CF MUTATIONS — CF is caused by mutations (also called pathogenic variants) in a single large gene on chromosome 7. This gene encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which regulates chloride channel function of epithelial cells of the sweat gland, airway, pancreas, and intestine.

Clinical disease occurs when disease-causing pathogenic variants are present in both copies of the CFTR gene. The two inherited pathogenic variants may be the same (homozygote) or different (compound heterozygote). Over 2100 different mutations in the CFTR gene have been identified [1], although the vast majority of CFTR pathogenic variants occur at frequencies less than 1 in 1000 (<0.1 percent) [2].

The specific pathogenic variants that an individual carries are a major determinant of clinical severity. The range of clinical expression likely reflects the degree to which protein function is changed by the mutation, modulation of the phenotype by other genes, and variation in susceptibility to environmental factors. (See "Cystic fibrosis: Genetics and pathogenesis".)

CFTR mutation prevalence — Mutation types and carrier frequencies vary among populations, as shown in the table (table 1). The highest carrier frequency is observed in non-Hispanic White individuals and individuals of Ashkenazi Jewish descent, of whom 1 in 29 carries a CFTR pathogenic variant. The delta F508 deletion-CFTR accounts for a large proportion of disease-causing alleles in White (70 percent), Hispanic (46 percent), African American (48 percent), Ashkenazi Jewish (30 percent) and Asian (30 percent) populations. Some Native American populations, specifically Pueblo and Zuni people, have CFTR mutation carrier rates (1 in 3970 and 1 in 1580, respectively); however, their pathogenic variants do not involve delta F508.

Among individuals of Ashkenazi Jewish descent, the most common mutation is W1282X (accounting for 46 percent of all CF cases); other common mutations are F508del-CFTR, G542X, 3849+10kb C>T, and N1303K, which together with W1282X account for 94 to 97 percent of CF cases [3,4].

Among individuals with ethnic origins in Greece, Bulgaria, Georgia, or Libya, CFTR mutation carrier rates range from 1 in 24 to 1 in 29; for those with ethnic origins in Iran or Iraq, the carrier rate is 1 in 90.

BENEFITS AND LIMITATIONS OF SCREENING

Benefits — Preconception or prenatal carrier screening and prenatal diagnosis of CF have several potential benefits:

Couples at increased risk of having a child with CF can be identified so that they can make an informed decision about their reproductive options. (See 'Reproductive options for carrier couples' below.)

Couples can be educated about CF before the birth of an affected child, and they can better prepare for the birth. Such preparation is largely psychological, since the management of prenatal care, labor, and delivery is not changed by the prenatal diagnosis.

Prenatal diagnosis of CF allows the pediatricians caring for the neonate to perform additional tests that might recognize a CF-related problem earlier. For example, prenatal diagnosis of CF in fetuses with echogenic bowel can facilitate diagnosis and treatment of neonatal meconium ileus, which is the earliest clinical manifestation of CF, occurring in 10 to 20 percent of fetuses with the disorder.

Most newborns with CF are asymptomatic; without neonatal screening for CF, the average age at diagnosis is 2.9 years. All 50 states in the United States include CF in their newborn screening panel; therefore, waiting for results from neonatal screening is another reasonable option for carriers who definitely would not terminate an affected pregnancy [5]. Newborn screening is less costly than prenatal diagnosis and avoids the small risk of pregnancy loss associated with invasive procedures for definitive fetal diagnosis. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Meconium ileus and distal ileal obstruction' and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Newborn screening'.)

It is possible that, in the future, early detection of the CF variant may provide an opportunity for in utero gene therapy.

Limitations — Limitations and challenges of carrier screening for CF include:

Prenatal risk assessment is limited in some ethnic groups because the specific mutations responsible for CF in these groups are incompletely understood or unknown [6]. In addition, many people are of mixed ancestry, making selection of an appropriate panel of mutations for screening difficult.

Although CF screening provides an opportunity to obtain important information about a current or future pregnancy, the information can also provoke significant and prolonged anxiety because of the inability to reliably predict phenotype after a positive screen, the inability of a negative screen to reliably exclude clinical disease in all cases, and the improving prognosis for individuals with CF (median survival >50 years for individuals born after 2000 [7]).

Once an individual is identified as carrying a CF mutation, family members may learn that they are at increased risk of being a carrier even though they might not have wanted this information.

CANDIDATES FOR SCREENING — We offer CF screening to all couples actively planning pregnancy and all pregnant people regardless of personal or family history or ethnicity, in accordance with guidelines from several professional organizations [6,8,9]. Counseling and screening are ideally performed before conception but can be done in the first or early second trimester.

Risk factors for carrying the CF mutation:

Positive personal or family history of CF – Couples in whom one or both partners have a personal or family history of CF (first-degree relative [son, daughter, sibling, mother, father] or second-degree relative [aunt, uncle, nephew, niece, grandparent]) are at high risk of carrying a CF mutation. A modified screening strategy may be appropriate for these couples. (See 'Couples with a personal or family history of CF' below.)

Race and ethnicity – Non-Hispanic White individuals and individuals of Ashkenazi Jewish descent have higher carrier rates (1 in 29) (table 1), whereas African American, Hispanic, and Asian individuals have lower carrier rates (1 in 60 to 1 in 65, 1 in 46, and 1 in 90, respectively), and they may have different CFTR mutations than the most common mutations included in the standard panel.

Because mixed ethnicity is common, it is important that all couples understand that CF screening is most accurate for non-Hispanic White people of Northern European descent and those of Ashkenazi Jewish descent since a high proportion of disease in these groups is attributable to common identifiable mutations (table 2). Individuals of other ethnic backgrounds may not have as great a benefit from current standard CF screening tests if their carrier rate is low or if common CF-causing mutations have not been identified in their ethnic group and therefore are not included in the screening panel. Although couples of ethnicities with low carrier rates may decide to forego testing for this reason, this information and the option for testing should be presented to these patients. (See 'Negative screen' below.)

Findings on ultrasound examination – In couples who decline preconception or early pregnancy carrier screening, visualization of echogenic bowel in the second trimester, particularly with dilated bowel and a nonvisualized gallbladder [10], is another indication for offering carrier screening or, for carrier couples, fetal diagnostic testing. Sonographic evidence of echogenic fetal bowel in the second trimester has been associated with CF (risk of approximately 1 percent), as well as other fetal disorders. This subject is discussed in detail separately. (See "Fetal echogenic bowel".)

CARRIER TEST SELECTION — Because over 2100 different mutations in the CF gene have been identified, it is not possible to screen for all known mutations. The key to effective CF screening is determining which mutations should be included in the screening panel. This requires knowledge of the most common CFTR mutations in the general population and in individuals of specific ethnic groups. For couples with an affected family member, it requires knowledge of the specific mutations identified in that relative.

Standard panel — Most CF testing laboratories screen for a specific panel of mutations with a frequency of at least 0.1 percent in the North American population [6]; the current standard CF targeted screening panel includes, at a minimum, 23 of the more common mutations in this group (table 3) [2]. Although the standard panel performs well [11], sensitivity varies in different populations. The following carrier detection rates by racial/ethnic group have been reported for this panel in the United States: people of Ashkenazi Jewish descent (94 percent), non-Hispanic White people (88 percent), Hispanic White people (72 percent), African American people (64 percent), Asian American people (49 percent) [9]. Among these groups, Asian American people have the lowest proportion of detectable mutations and the lowest birth prevalence of CF, which makes them least likely to benefit from prenatal carrier testing.

Reflex testing — In two situations, additional "reflex" testing will also be done.

If the test identifies F508del-CFTR or F507del, the result could be a false positive due to variant codons at positions 506, 507, or 508. Accordingly, when F508del-CFTR or F507del are identified, the sample is specifically tested for the variant codons I506V, I507V, and F508C to clarify the risk of having an actual (pathogenic) CF mutation and thus the full CF phenotype. Identification of a variant suggests a false positive.

If the test identifies the R117H mutation, this mutation can cause classic CF if it is on the same chromosome as a mutation consisting of an intronic poly-T tract, called the 5T variant, located in a noncoding region of the CF gene, and there is a CF mutation on the other chromosome. The outcome of the R117H with other poly-T sizes (7T, 9T) and a second disease-causing CFTR mutation can be quite variable, ranging from no symptoms to mild lung disease. However, if an R117H mutation is on one chromosome and the 5T variant is on the other chromosome, or any of several other arrangements, and the fetus is male, the likelihood of having congenital bilateral absence of the vas deferens (CBAVD) is significantly increased (table 4). To resolve these possibilities, when R117H is identified, additional testing for the 5T/7T/9T variants is performed and, if possible, the cis/trans location of the alleles is determined.

Additional information on genetic testing for carriers can be obtained from the Cystic Fibrosis Foundation.

Expanded panel — For individuals of non-White, non-Ashkenazi Jewish ethnicities, an expanded screening panel could theoretically provide a higher carrier detection rate than the standard panel [12]. However, determining which CF mutations to add to the standard panel can be difficult since, in these populations, CF mutation types and frequencies and their clinical significance are not well understood. For this reason, commercially available panethnic expanded panels may not have higher sensitivity than the standard panel, and may include mutations of unclear clinical significance, which make prediction of the phenotype of offspring problematic. (See 'Prediction of phenotype' below.)

In cases in which the standard screening panel has identified a CF mutation in one partner, some clinicians offer the expanded panel to the other partner to improve identification of couples at risk of having an affected child.

CFTR sequencing — CFTR sequencing is not appropriate for routine carrier screening. It is generally performed in patients with a family history of CF but whose family test results are not available and either ethnicity is other than non-Hispanic White person of North European ancestry or standard carrier screening test results are negative. CFTR sequencing may also be considered for prenatal screening when one partner is known to be a CF carrier and the other partner is unavailable for screening, testing the other partner would be too expensive, the partner's results would not be available in time to assist decision making, or the pregnant person is undergoing amniocentesis or chorionic villus sampling for some other reason [2].

Full genomic sequencing is the most thorough method for identifying CF mutations; however, even genomic sequencing cannot identify all CF mutations, and all mutations in the CFTR gene do not result in classic CF. One study of individuals with CF reported that, in approximately 10 percent of cases, the responsible CF mutations could not be identified after comprehensive CFTR analysis that included deletion/duplication analysis and extensive sequencing [11]. (See 'Prediction of phenotype' below.)

In the past, the main drawback to CFTR sequencing was the cost, so it was used primarily for cases in which an individual met clinical criteria for CF but standard screening did not identify CF mutations. Many genetic testing companies in the United States now offer CFTR sequencing at a price comparable to or lower than the cost of the standard or expanded screening panel, although the cost of the test may not be covered by all insurance carriers.

SCREENING STRATEGIES

Couples with no personal or family history of CF

Single partner screening – The least expensive and probably most widely used screening strategy is to offer the 23 mutation targeted testing panel to the person who will be or is pregnant [2]. The risk of an affected child is calculated based on this person's positive or negative test result (table 5) and the background carrier rate for their partner's ethnicity. Some couples will be reassured by this estimate and will not request screening of the other partner, especially if the only goal of screening is to determine if the child is at high risk of being affected. This approach is also appropriate when the biologic father is unavailable for testing or is unknown. (See 'Father unavailable' below.)

Couples who conceive using donor gametes can be reassured that donors identified through the health care system usually undergo genetic screening and are screen negative, thus testing of the "partner" has already been done; however, this should be confirmed.

Serial screening – The next least expensive screening strategy (called serial screening) is to screen the person who will be or is pregnant first. If this person is screen negative, the child is assumed to be at low risk, and the partner is not offered screening. If this person is screen positive, the partner is screened using the standard panel, and the risk of an affected child is then calculated. For partners whose ethnicity requires testing for less common mutations, or for the reasons stated above, an expanded panel or CFTR sequencing may improve sensitivity.

Couple screening – The most expensive, accurate, and efficient approach is to screen both members of the couple at the same time (called couple screening) [2]. This method is most appropriate for couples who need to know their risk of having an affected child rapidly and cannot wait for results from serial screening, for couples who want the most accurate risk assessment of having an affected child, and for couples who want to use their results to inform their siblings about their potential CF carrier status.

Couples with a personal or family history of CF — Ideally, when a family member has confirmed CF, other family members should be screened by the same laboratory that tested the affected relative [2]. The screening panel should include familial mutations previously identified as well as the mutations in the standard panel.

If a specific gene mutation has not yet been identified in the affected family member and CFTR sequencing has not been done, CFTR sequencing should be arranged for that individual. If the affected family member had no or incomplete prior CF testing and is not available for testing, CFTR sequencing should be offered to the member of the couple who is related.

If results from any of these testing methods show that one partner is a CF carrier, the other partner should be tested by the standard panel of the most common CF mutations in their ethnic group or, if appropriate, by an expanded mutation panel or CFTR sequencing [2].

Father unavailable — If the father is unavailable for testing or is unknown, only the person who will be or is pregnant is screened. The risk of an affected child is calculated based on this person's positive or negative targeted screening test result (table 5) or CFTR sequencing and the background carrier rate for the partner's ethnicity (eg, 1 in 25 for Northern European people or people of Ashkenazi Jewish descent), if known.

TEST REQUISITION — The laboratory requisition should include information about the indication for the test, the racial/ethnic background of the individual being screened, and pertinent family history [2]. If a family member has CF, the requisition should include the affected family member's name and birth date and the familial mutation(s), if known.

TEST PERFORMANCE — The following table (table 6) shows the proportion of high-risk couples (couples in whom each member carries a CFTR mutation) correctly identified according to the percentage of CF cases accounted for by the mutations in the targeted screening panel [13]. When 100 non-Hispanic White couples of Northern European ancestry who are true carriers are tested for CFTR mutations that account for 90 percent of all CF cases (the standard screening panel): In 81 couples both partners will be correctly identified as carriers, in 18 couples only one partner will be correctly identified as a carrier, and in one couple neither partner will be correctly identified as a carrier.

INTERPRETATION OF SCREENING RESULTS — The screening test report should list the mutations in the screening panel and provide a posttest interpretation of the individual's residual carrier frequency based on ethnicity. The residual carrier frequency indicates the fetal risk based on the screening test results, the incidence of CF in the patient’s ethnic group, and consideration that the panel does not include all CF mutations. The possibility of de novo fetal CFTR mutations is not considered because they have never been reported.

The following discussion applies to screening results for couples with no personal or family history of CF and no fetal abnormalities associated with CF on ultrasound examination.

Positive screen — Individuals who screen positive should receive genetic counseling. If both partners carry a CFTR mutation, there is a one in four chance that their child will be affected. The severity of clinical disease in offspring varies as a function of the specific genetic mutations present. For mutations other than the F508del-CFTR or W1282X alleles or those associated with CAVD, there is no simple, predictable relationship between genotype and phenotype for CF mutations. (See 'Prediction of phenotype' below and 'Genetic consultation' below.)

It is important to note that if two copies of the same pathogenic variant (eg, F508del) are identified, then this variant will appear in each of the two CFTR alleles. However, if there are two different pathogenic variants or one copy of a pathogenic variant and one copy of a variant of unknown significance, then two possible arrangements with distinctly different clinical implications are possible: each CFTR gene could have one of the variants (individual potentially affected) or both variants could be on the same allele and the other allele could be normal (individual is a CF carrier). Genetic counseling can help distinguish between these two scenarios.

Some patients with otherwise unexplained chronic pancreatitis, chronic rhinosinusitis, or pulmonary disease in adulthood are discovered to have one pathogenic mutation (CF carriers), with disease likely influenced by other genetic and environmental risk factors [14]. However, otherwise healthy, asymptomatic adult carriers discovered through CF screening are unlikely to develop these types of atypical CF manifestations. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'CFTR-related disorder' and "Pancreatitis associated with genetic risk factors".)

Negative screen — Individuals who screen negative do not carry any of the CFTR mutations in the screening panel: A negative result thus reduces the likelihood but does not eliminate the possibility that the individual is a CFTR mutation carrier. When both partners test negative, the risk of having a child with CF is greatly reduced, as shown in the table (table 2).

Using the currently recommended 23 mutation panel, a couple of Ashkenazi Jewish descent with no history of CF who both test negative has a 1 in 490,000 chance of having an affected offspring, and an Asian couple who both test negative has a 1 in 134,000 chance of an affected offspring. Even when one member of the couple tests positive and the other tests negative, the risk of disease is lower than would be estimated from the background risk: 1 in 1540 in offspring of people of Ashkenazi Jewish descent and 1 in 732 in offspring of people of Asian descent.

The degree to which the risk of being a carrier is reduced after a negative test is determined by the number of mutations screened for and the proportion of CF attributable to those mutations. As an example, if a non-Hispanic White person of Northern European descent does not carry the F508del-CFTR mutation (which accounts for 75 percent of all CF cases in this population), the risk of being a CF carrier is reduced from 1 in 25 (the a priori risk based solely on ethnic origin) to 1 in 99. If the person does not carry any of the most common mutations causing 90 percent of CF cases in their ethnic group, the risk is reduced to 1 in 246 (table 5) [13].

Genetic consultation — Genetics professionals can provide complete, accurate information about the features of CF and CF carrier screening, and they can help and support parents in decision making.

Consultation with a geneticist or provider with special expertise in CF screening is recommended when:

Either partner has positive screening test for CF

Either partner has CF

Either partner has a family history of CF

The fetus has been determined to have CF

The male partner is infertile due to congenital bilateral absence or atresia of the vas deferens

A midtrimester prenatal ultrasound shows echogenic/dilated bowel and nonvisualization of the gall bladder

Genetic counselors can also help clarify CF risk in cases in which the standard basic panel is uninformative. Depending on the clinical scenario, analysis of an expanded mutation panel (table 3) or complete analysis of the CFTR gene by DNA sequencing may be indicated.

DOCUMENTATION AND REPEAT TESTING — Once a patient has been screened for CF carrier status, CF screening results should be documented, and this test should not be repeated in most cases. There are exceptions, and those clinical scenarios should be discussed with a health care provider or genetic counselor with expertise in clinical genetics prior to repeating testing [9].

REPRODUCTIVE OPTIONS FOR CARRIER COUPLES — Reproductive strategies for carrier couples include:

Using noncarrier gametes to reduce the risk of conceiving an affected child

Using preimplantation genetic testing (PGT) to reduce the risk of implantation of an affected embryo

Using prenatal diagnosis to determine fetal status, followed by preparation for an affected child or pregnancy termination

Newborn screening only

Deciding to forgo future pregnancy

Noncarrier gamete donor — Couples in whom both partners carry a CFTR mutation may choose to use an egg or sperm from a noncarrier donor to reduce the risk of conceiving an affected offspring [15]. The possibility of an affected child cannot be completely eliminated as a donor with a negative family history of CF and a negative CF panel could still have an unidentified CF mutation. Donors are usually matched for ethnicity. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?' and "Donor insemination".)

Preimplantation genetic testing — PGT is a good option when both partners are carriers of known CF mutations and want to have an unaffected child but would not undergo pregnancy termination. PGT requires in vitro fertilization: DNA isolated from the blastomere (preimplantation embryo) is analyzed for the CF mutation and only mutation-negative embryos are transferred. Not all insurance programs cover this procedure, so insurance coverage should be clarified. (See "Preimplantation genetic testing".)

If one parent of an affected child is screen-positive and the other is screen-negative, and nonpaternity and uniparental isodisomy (inheriting both copies of the gene from the same parent) have been ruled out, the affected child and the screen-negative partner should be tested with an expanded mutation panel (table 3) or undergo complete analysis of the CFTR gene by DNA sequencing. If the second CF mutation still cannot be identified, only embryos that do not have the identified CF mutation are transferred, recognizing that some of them may be heterozygous (carriers) for the unknown CF mutation.

Prenatal diagnosis

Chorionic villus sampling and amniocentesis — Couples with known CFTR mutations who choose to conceive naturally may undergo prenatal diagnosis using chorionic villus cells (obtained at 11 to 14 weeks of gestation by chorionic villus sampling) or amniocytes (obtained at ≥15 weeks of gestation by amniocentesis) to determine fetal CFTR gene status. Fetal blood can also be tested, but this procedure is performed at ≥18 weeks of gestation and has a higher risk of procedure-related pregnancy loss, so it is rarely performed.

As discussed above, if one parent of an affected child is screen-positive and the other is screen-negative, prenatal diagnosis will not be able to distinguish a carrier fetus with an unidentifiable CF mutation from an unaffected fetus. Although this circumstance is unlikely to alter pregnancy management, the child should receive preconception genetic counseling upon reaching adulthood. Because of expected advances in CF screening, the child, now an adult, may wish to be tested before conceiving.

Noninvasive prenatal diagnosis — With advances in molecular technology, noninvasive screening for CF using cell-free DNA from maternal plasma has become available commercially and has been described in the literature; however, the American College of Gynecologists (ACOG), the Society for Maternal-Fetal Medicine (SMFM), or the American College of Medical Genetics and Genomics (ACMG) have not recommended its use [16,17].

Cell-free DNA extracted from maternal blood contains a mixture of DNA fragments from both maternal and placental (fetal) cells; maternal DNA must be distinguished from placental (fetal) cell-free DNA reliably in order to achieve accurate results. If both parents were CFTR mutation carriers and each carried a different mutation, or if the maternal and paternal mutations were the same but were closely linked to polymorphisms that could distinguish the two, then excluding the paternal mutation in the cell-free DNA sample would indicate that the fetus was not affected (would either be a heterozygote carrying the mother's mutation or would be mutation-free). If the paternal mutation was present in the sample, techniques to determine if the fetus also inherited the maternal mutation would have to be employed. This would require documentation that the cell-free DNA sample contained a significant excess of DNA fragments containing the maternal mutation, with the extra allele-containing fragments presumed to come from the fetus.

If both parents carried the same mutation and they could not be distinguished by nearby polymorphisms, it would be more difficult to establish that the fetus did or did not inherit two mutant alleles. Research publications have reported that this kind of analysis has been achieved for other autosomal recessive disorders, using digital PCR and sequencing [18].

Newer methods using relative haplotype dosage analysis using target-enriched next-generation sequencing can be used for detection of monogenic conditions such as cystic fibrosis [17].

Prediction of phenotype — If prenatal diagnosis determines that the fetus carries two CFTR mutations that are known to cause CF, parents should be counseled about the likely CF phenotype so that they can make an informed decision about the future of the pregnancy.

In the setting of a family history of CF in which at least one of the CF mutations inherited by the fetus is identical to that carried by the affected family member, the fetus can be predicted to have a phenotype similar to that of the affected relative. This is especially true if the fetus has inherited at least one of the two most common CF mutations (F508del-CFTR or W1282X), which are associated with the classic CF phenotype [19-21], or the R117H mutation and the 5T or 7T allele or 5T/5T homozygosity, which are associated with congenital absence of the vas deferens (CAVD) in a male fetus. However, a different mutation from a carrier parent without an affected family member can also have important effects on phenotype. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Cystic fibrosis'.)

If the fetus inherits other, less common mutations, or if only limited medical information about the affected relative is available, phenotype prediction is difficult. For individual fetuses who do not inherit the F508del-CFTR or W1282X alleles or those associated with CAVD, there is no simple, predictable relationship between genotype and phenotype; such fetuses may have "nonclassic" or "atypical" CF. The terms nonclassic and atypical CF have been used to describe patients who fulfill diagnostic criteria for CF but have a normal or intermediate sweat chloride result. These terms have also been used to describe patients with clinical disease limited to only one organ system: pancreatitis, liver disease, nasal polyps, or bilateral CAVD.

Because of the wide spectrum of severity in CF, in part due to the inherited mutations and in part resulting from different treatment regimens and environmental factors, accurate prenatal prediction of the postnatal phenotype is not possible for fetuses who do not inherit the F508del-CFTR or W1282X alleles or those associated with CAVD. Because 95 percent of the morbidity and mortality of CF is attributable to pulmonary disease, predicting pulmonary function in fetuses homozygous for CF mutations is of prime importance, but is not currently possible [20].

Similarly, prenatal prediction of the age at which CF symptoms will occur, the fetus' risk of eventually developing liver disease or diabetes mellitus, or its adult weight/height ratio cannot be done at the present time. (See "Cystic fibrosis: Hepatobiliary disease" and "Cystic fibrosis-related diabetes mellitus".)

However, some information about the potential phenotype may be provided to the family, depending on the mutations inherited. Several CF mutations are fairly consistently associated with pancreatic insufficiency (F508del-CFTR, W1282X, G542X, 1717GA, N 1 303K), pancreatic sufficiency (R1 17H, R334W, T3381, R347P, etc), and CAVD (F508del-CFTR, R1 17H, 5Tvar, 7Tvar) [19-22]. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatic disease' and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Infertility'.)

Resources — Information on specific phenotypic aspects of several hundred CFTR mutations is available and is presented in separate searchable formats for clinicians or the general public. (See "Cystic fibrosis: Genetics and pathogenesis".)

PREGNANCY AND PERIPARTUM MANAGEMENT — Parents of an affected fetus can benefit from counseling by a geneticist or a genetic counselor with expertise in CF and a pediatrician who can discuss newborn issues and follow-up. Additionally, efforts should be made to bring the parents together with parents of children with CF or individuals with CF within their community [8]. The Cystic Fibrosis Foundation offers information and support for families and individuals with CF.

Prenatal sonography near term may be useful so that newborn’s providers can be alerted to suspected meconium ileus, if present.

There are no prenatal therapeutic interventions for CF. In utero gene therapy is investigational [23].

After birth, a variety of therapies are available, which are not curative. (See "Cystic fibrosis: Overview of the treatment of lung disease" and "Cystic fibrosis: Overview of gastrointestinal disease" and "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prenatal genetic screening and diagnosis" and "Society guideline links: Cystic fibrosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Cystic fibrosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Goal of screening – The goal of preconception or prenatal carrier screening is to identify couples at increased risk of having a child with cystic fibrosis (CF). Some couples will use their screening results to prevent the birth of an affected infant, while others will use the information to plan for the birth of an affected child. Because obstetric management is not changed by the prenatal diagnosis of CF, couples who would not terminate an affected pregnancy may elect to wait and have newborn CF screening. (See 'Benefits and limitations of screening' above.)

Candidates – Carrier screening for CF should be offered to all people who are considering a pregnancy or who are in the first or early second trimester, if not previously performed. (See 'Candidates for screening' above.)

Pretest counseling should explain that sensitivity of this screening test varies among ethnic groups and the standard screening is most efficacious in non-Hispanic White individuals and people of Ashkenazi Jewish descent. (See 'Standard panel' above.)

For individuals of non-White, non-Ashkenazi Jewish ethnicities, an expanded screening panel could theoretically provide a higher carrier detection rate than the standard panel. The limitations and residual risks of standard CF carrier screening should be discussed. (See 'Expanded panel' above.)

Screening strategies

Couples without a positive history of CF – Only one partner may be tested, or testing may be sequential (the pregnant person is tested first; the partner is tested only if the pregnant person is a carrier), or testing may be couple-based (both partners are tested at the same time). (See 'Couples with no personal or family history of CF' above.)

Couples with a positive history of CF – Carrier screening for CF entails a different approach for individuals and reproductive partners who have a personal history of CF or family history of CF. Health providers or genetic counselors with expertise in genetics should be involved in the counseling and decision-making for these patients. (See 'Couples with a personal or family history of CF' above.)

Test panel – CF testing laboratories will screen for a specific panel of the 23 most common CF mutations in the United States (table 3). The panel of 23 mutations accounts for almost 90 percent of detectable mutations in non-Hispanic White individuals (see 'Standard panel' above). In two situations, additional "reflex" testing will also be done. (See 'Reflex testing' above.)

In cases in which the standard screening panel has identified a CF mutation in one partner, some clinicians offer the expanded panel to the other partner to improve identification of couples at risk of having an affected child. (See 'Expanded panel' above.)

Screen-positive results – If the CF screen is positive, the individual should receive genetic counseling. If both partners carry a CF mutation, there is a one in four chance that their child will be affected. The severity of clinical disease in offspring varies as a function of the specific genetic mutations present. However, except when the fetus inherits the CF mutations F508del-CFTR or W1282X (which are associated with classic CF), or a male fetus inherits the CF mutations associated with congenital absence of the vas deferens (CAVD), there is no direct relationship between genotype and phenotype, making the phenotype difficult to predict. (See 'Interpretation of screening results' above.)

Screen-negative results – A negative screening test means only that the individual does not carry any of the CF mutations in the screening battery; a negative result thus reduces the likelihood, but does not eliminate the possibility, that the individual is 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 for and the proportion of CF attributable to those mutations. (See 'Interpretation of screening results' above.)

Prenatal (fetal) diagnosis – If both members of a couple are determined to be CF carriers, the next step is to test the fetus. If the fetus inherits the F508del-CFTR or W1282X mutations or those associated with CAVD, phenotype prediction is possible. In the setting of a family history of CF in which at least one of the CF mutations inherited by the fetus is identical to that carried by the affected family member, the fetus may be predicted to have a phenotype similar to that of the affected relative. If the fetus inherits other, less common mutations, or if limited medical information about the affected relative is available, phenotype prediction is difficult. (See 'Reproductive options for carrier couples' above.)

Should screening be repeated in successive pregnancies? – CF carrier screening results should be documented in the medical chart and only be performed once for an individual in most cases. (See 'Documentation and repeat testing' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Katharine Wenstrom, MD, who contributed to an earlier version of this topic review.

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