Cystic fibrosis: Carrier screening

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 1 in 24 to 1 in 25 and birth prevalence of 1 in 2500 in this population. 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".)

SYNOPSIS OF THE GENETIC BASIS OF CF — CF is caused by pathogenic variants in a single large gene on chromosome 7 called the CF transmembrane conductance regulator (CFTR) gene. This gene encodes the 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 pathogenic variants in the CFTR gene have been identified [1], but the vast majority 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 pathogenic variant, modulation of the phenotype by other genes, and variation in susceptibility to environmental factors. The genetic basis of CF and pathogenesis of the disease are reviewed in detail separately. (See "Cystic fibrosis: Genetics and pathogenesis".)

PREVALENCE OF CFTR PATHOGENIC VARIANTS — CF transmembrane conductance regulator (CFTR) pathogenic variant frequencies vary among populations, as shown in the table (table 1). Of note:

●Populations with high CFTR carrier frequency rates include non-Hispanic White individuals and individuals of Ashkenazi Jewish descent, of whom 1 in 29 carries a CFTR pathogenic variant. Other ancestry groups with high CFTR pathogenic variant carrier rates include Greek, Bulgarian, Georgian, and Libyan individuals, in whom carrier rates range from 1 in 24 to 1 in 29. For individuals with ancestry origins from Iran or Iraq, the carrier rate is 1 in 90.

●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.

●Although some Native American populations, specifically Pueblo and Zuni people, carry CFTR pathogenic variants (1 in 3970 and 1 in 1580, respectively), their pathogenic variants do not involve delta F508 deletion.

●Among individuals of Ashkenazi Jewish ancestry, the most common pathogenic variant is W1282X (accounting for 46 percent of all CF cases); other common pathogenic variants 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].

BENEFITS AND LIMITATIONS OF SCREENING

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

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

Although CF is a life-limiting disease, the prognosis for affected individuals is improving, especially with the development of newer therapies, such as CF transmembrane conductance regulator (CFTR) modulators, which target the underlying genetic abnormality to increase the deficient CFTR protein. The median survival is >50 years for affected individuals born after 2000 [5]. (See "Cystic fibrosis: Treatment with CFTR modulators" and "Cystic fibrosis: Overview of the treatment of lung disease".)

●Parental preparation and antenatal intervention – Parents who have been educated about CF before the birth of an affected child 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.

One exception is when evidence of meconium ileus is present in the fetus based on bowel dilation on ultrasound. Two case reports have described successful use of maternal therapy with elexacaftor-tezacaftor-ivacaftor (ETI) during pregnancy for treating fetal meconium ileus; however, this remains investigational [6,7].

It is possible that, in the future, early detection of the CF pathogenic variant may provide an opportunity for in utero therapy, either medical or gene altering. For example, CRISPR gene editing tools are under investigation to permanently correct the genetic abnormality [8].

●Appropriate newborn management – 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. Newborn screening is less costly than prenatal diagnosis and avoids the small risk of a 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'.)

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

●Incomplete information about pathogenic variants – Prenatal risk assessment is less robust in some ancestral groups because the specific pathogenic variants responsible for CF in these groups are incompletely understood or unknown [9]. In the United States, recognition that many people are of mixed ancestry has resulted in changes in selection of the pathogenic variants in carrier panels.

●Parental anxiety – Although CF screening provides an opportunity to obtain important information about a current or future pregnancy, uncertainty can provoke significant and prolonged anxiety. For example, genotype:phenotype classifications and databases are growing, but remain incomplete; therefore, a negative screen does not exclude a chance of clinical disease.

●Undesired genetic information – Once an individual is identified as carrying a CF pathogenic variant, the individual is responsible for notifying family members 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 ancestry, in accordance with guidelines from several professional organizations [2,9-12]. Counseling and screening are ideally performed before conception but can be done in the first or early second trimester.

Risk factors for carrying a CF pathogenic variant include:

●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 higher risk of carrying a CF pathogenic variant. A directed screening strategy may be appropriate for these couples. (See 'Couples with a personal or family history of CF' 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 [13], 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".)

●Higher risk ancestry – Non-Hispanic White individuals and individuals of Ashkenazi Jewish descent have a relatively high carrier rate (1 in 29) (table 1).

Other ancestries, such as 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 CF transmembrane conductance regulator (CFTR) pathogenic variants than the most common pathogenic variants included in the traditional 23-variant panel. The use of an ancestry approach to genetic carrier screening is decreasing in regions where mixed and often unknown ancestry is common, such as the United States [2]. A 100-variant panel was introduced in 2023 in an effort to be more inclusive across diverse ancestries in the United States [12].

CARRIER PANEL SELECTION

General principles — Because over 2100 different pathogenic variants in the CF gene have been identified, it is not possible to screen for all known pathogenic variants. The key to effective CF screening is determining which pathogenic variants should be included in the screening panel. As discussed above, this requires knowledge of the most common CF transmembrane conductance regulator (CFTR) pathogenic variants in the population being tested (table 1) and assuring equity is achieved across different ancestries. Additionally, robust phenotype information is required for variant inclusion [12].

For individuals with an affected or known carrier family member, if the specific variant(s) involved are known, these variants should be considered first by sequencing the individuals as opposed to a general population screen. For individuals with a prior pregnancy or livebirth diagnosed with CF, the pathogenic variants of the affected child should be confirmed as a carrier state in each parent.

Standard panel — In 2023, The American College of Medical Genetics (ACMG) published a minimum pathogenic variant list of 100 variants in an effort to be more inclusive across diverse races and ethnicities in the United States [12]. Before 2023, ACMG recommended use of a selected 23-pathogenic-variant panel (table 2) based on non-Hispanic White and Ashkenazi populations, but this approach was reconsidered in light of more robust genotype:phenotype databases and accessibility to low-cost, high-throughput sequencing. Although variant panels of 23 or more CF pathogenic variants are commercially available and commonly used, the publication of the 2023 ACMG 100-pathogenic variant panel will likely influence and expand commercial laboratory offerings.

The 100 CFTR variants were chosen by a working group with inclusion of the original 23 variants recommended by ACMG in conjunction with the Clinical and Functional Translation of CFTR (CFTR2) database as a reference database given its large sample size, ethnic diversity, and extensive phenotype:genotype information. The group of pathogenic and likely pathogenic CTFR variants then underwent automatic and manual exclusion of variants that were not causing CF, complex alleles, or absent from gnomAD data set (a reference database of frequency estimates of CF alleles in the United States with information from multiple ancestral populations). The gnomAD dataset was selected as a reference database to obtain carrier frequency estimates of CF alleles in the US with information from multiple ancestral populations [14]. This approach ensured that at least 95 percent of the total carrier frequency in each population is represented in the final variant set.

Laboratories are not limited to these 100 variants in their standard panel if their panels are more comprehensive. An important principle is that any variant panel requires continued reassessment and potentially revision as databases continue to increase in their depth with regard to phenotype information and ethnicities included.

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

●F508del-CFTR or F507del – 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 CF pathogenic variant and thus the full CF phenotype. Identification of a variant suggests a false positive.

●R117H – If the test identifies the R117H pathogenic variant, this pathogenic variant can cause classic CF if it is on the same chromosome as a pathogenic variant 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 pathogenic variant on the other chromosome. The outcome of the R117H with other poly-T sizes (7T, 9T) and a second disease-causing CFTR pathogenic variant can be quite variable, ranging from no symptoms to mild lung disease. However, if an R117H pathogenic variant 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 3). 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.

SCREENING STRATEGIES — Historically, guidance from professional societies for genetic carrier screening often has been dissimilar, likely reflecting each group's unique perspective on generalizability, resource utilization, and assimilation of technological advances. Importantly, however, there is consensus that providers should establish and be knowledgeable of a systematic screening approach most applicable to their own reproductive populations, both preconception and prenatal.

The following items should be considered:

Couples with no personal or family history of CF

●Single-person screening – The concept of screening is rapidly changing based on the broader knowledge of genotype:phenotype correlations, cost efficacy of sequencing, and the low inclusion of paternal samples after identification of a maternal sample during pregnancy. The least expensive and probably currently most widely used screening strategy is to offer a 23 CF pathogenic variant (and soon a 100-variant) testing panel to the person who will be or is pregnant. Laboratories should report the tested person's residual risk incorporating their specific CF transmembrane conductance regulator (CFTR) variant panel and the indicated ancestry. To reach a theoretic risk for a couple, the individual's residual risk can be combined with the untested partner's risk based on ancestry and include a 25 percent risk of autosomal recessive transmission.

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. However, as technologies are changing rapidly and continually updated, genetic counselling is recommended for situations in which one partner is identified as a carrier of a CFTR pathogenic variant and a donor gamete was used, as it is important to review the details of the testing done on the donor.

●Serial screening – The next least expensive screening strategy is to first screen the person who will be or is pregnant ("serial screening"). 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 with a sequencing-based approach [12].

Both single-person and serial screening face the obstacle of timeliness of results as well as a high rate (60 percent) of nonparticipation by the nonpregnant partner. Approaches to address this situation are to offer an amniocentesis for diagnostic genetic testing or, alternatively, noninvasive testing of a maternal blood sample for cell-free DNA early in pregnancy with determination of both the maternal carrier state and the fetal genotype, which is a recent innovation. (See 'Chorionic villus sampling and amniocentesis' below and 'Noninvasive prenatal diagnosis' below.)

●Couple screening – The most expensive, but also most sensitive, 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 in whom time constraints may limit options, for couples who want to achieve the lowest risk assessment of having an affected child, and for those persons who want 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 tested by the same laboratory that performed the analysis of the affected relative [2]. If this is not possible, laboratory reports from the affected individuals can be requested with medical release and supplied to a new testing laboratory.

If a specific pathogenic variant has not yet been identified in the affected family member, then testing the affected individual with sequencing is the first step. If the affected family member 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 offered testing. Recommendations vary but inclusion of the ACMG 2023 approach of 100 pathogenic variants will provide the most robust coverage across the diversity of ethnicities in the United States [2,12].

TEST REQUISITION — The laboratory requisition should include information about the indication for the test, the ancestry 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 pathogenic variant(s), if known.

INTERPRETATION OF SCREENING RESULTS

General principles — The screening test report should list the pathogenic variants in the screening panel and provide a posttest interpretation of the individual's residual carrier frequency based on ancestry. The residual carrier frequency indicates the fetal risk based on the screening test results, the incidence of CF in the patient's ancestral group, and consideration that the panel does not include all CF transmembrane conductance regulator (CFTR) pathogenic variants. As panels vary between laboratories, the risk assessment provided by the laboratory should be discussed rather than risk obtained from older published tables, which may not reflect the breadth or depth of the specific panel utilized and may be influenced by personal report of ancestry.

The possibility of de novo fetal CFTR pathogenic variants is not considered because they have never been reported. When neither partner has the detectable pathogenic variant but they have a fetus/child with a detectable CFTR pathogenic variant, misassigned paternity should be considered.

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 single CFTR pathogenic variant, there is a one in four chance that their child will inherit the variant from each parent and be affected. The severity of clinical disease varies as a function of the specific variants present. For pathogenic variants other than the F508del-CFTR or W1282X alleles or those associated with congenital absence of vas deferens (CAVD), the relationship between genotype and phenotype is more complex and the expertise of a CF geneticist is often appropriate. As genotype:phenotype databases continue to grow, this information may become more readily available. (See 'Prediction of phenotype after prenatal diagnosis' below and 'Genetic consultation' below.)

●Interpretation when a partner carries two or more CF variants requires an additional level of analysis. If two copies of the same pathogenic variant are identified, this represents an aberration at the same site within the CFTR gene. This variant must be present on each of that partner’s two CFTR alleles, some impairment of the partner’s CFTR gene function is likely, and one copy of the variant must be passed down to all offspring.

By comparison, when two different pathogenic CF variants (or one pathogenic variant and one variant of unknown significance) are identified in one partner, then two possible arrangements with distinctly different clinical implications are possible. Each of this partner's CFTR alleles could contain one of the variants (ie, trans configuration: compound heterozygote, one variant was inherited from one parent and the other variant inherited from the other parent). Alternatively, both variants could be on the same allele (ie, cis configuration: compound heterozygote, both variants were inherited from one parent) and the other allele could be normal. Genetic counseling with further testing (eg, genotyping the variants in informative relatives, ideally both parents) can help distinguish between these two scenarios and the implications for offspring.

Some patients with otherwise unexplained chronic pancreatitis, chronic rhinosinusitis, or pulmonary disease in adulthood are discovered to have one pathogenic variant (CF carrier), with disease likely influenced by other genetic and environmental risk factors [15]. 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 pathogenic variants in the screening panel. A negative result thus reduces the likelihood but does not eliminate the possibility that the individual is a CFTR pathogenic variant carrier. When both partners test negative, the risk of having a child with CF is greatly reduced but not eliminated.

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, genetic counselor, 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

DOCUMENTATION AND REPEAT TESTING — CF screening results should be documented in the patient's medical record. As databases improve, individuals who tested negative with a 23-variant panel can consider retesting using the expanded 100-pathogenic variants panel. If the patient is a carrier and changes their partner, then the new partner will need to be tested to revise any estimates of CF risk in the couple's offspring.

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 for monogenic disorders (PGT-M) of embryos 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 CF transmembrane conductance regulator (CFTR) pathogenic variant may choose to use an egg or sperm from a noncarrier donor to reduce the risk of conceiving an affected offspring [16]. 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 pathogenic variant. Consultation with a genetic counselor should assist in determining the extent of testing of the donor and the residual risk. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?' and "Donor insemination".)

Preimplantation genetic testing — PGT-M is an option when both partners are carriers of known CF pathogenic variants and want to have an unaffected fetus. PGT-M requires in vitro fertilization: DNA isolated from the blastocyst (preimplantation embryo) is analyzed for the CF pathogenic variant and only pathogenic variant-negative embryos are transferred. Not all insurance programs cover this procedure. (See "Preimplantation genetic testing".)

PGT-M is more complicated of one parent of an affected child is screen positive and the other is screen negative, and nonpaternity and uniparental isodisomy of chromosome 7 (inheriting both copies of the gene from the same parent) have been ruled out. In such cases, the affected child and the screen-negative parent should be tested with a panel with a larger number of variants or undergo complete analysis of the CFTR gene by DNA sequencing. In rare instances, only genomic sequencing will reveal the second deleterious change in the CFTR region or surrounding regions. If the second CF pathogenic variant still cannot be identified, only embryos that do not have the identified CF pathogenic variant are transferred, recognizing that heterozygotic carriers for the unknown CF pathogenic variant may be transferred or, similarly, heterozygotic unaffected carriers of the identified variant discarded. Both will significantly limit the availability of embryos for transfer.

Prenatal diagnosis

Diagnostic criteria — The diagnosis of fetal CF is based on the presence of two CFTR variants known to cause CF on separate fetal alleles.

Chorionic villus sampling and amniocentesis — Couples with known CFTR pathogenic variants who conceive using their own gametes and without PGT-M may undergo prenatal diagnosis using chorionic villus cells (obtained at 11 to 14 weeks of gestation by chorionic villus sampling [CVS]) or amniocytes (obtained at ≥15 weeks of gestation by amniocentesis) to determine fetal CFTR gene status [17,18]. Alternatively, a fetal blood sample can be tested at ≥18 weeks of gestation, but the procedure carries a higher risk of procedure-related pregnancy loss than CVS or amniocentesis; therefore, it is rarely performed for this purpose.

Noninvasive prenatal diagnosis — Noninvasive screening for CF using cell-free DNA from maternal plasma has become available commercially and studies have been described in the literature [17-21]. Cell-free DNA extracted from maternal blood contains a mixture of DNA fragments from both maternal and placental (fetal) cells; maternal DNA must be reliably distinguished from placental (fetal) DNA to prove that the fetoplacental unit is being evaluated and achieve accurate results.

If both parents are CFTR pathogenic variant carriers but carry different pathogenic variants, or if the maternal and paternal pathogenic variants are the same but closely linked to polymorphisms that could distinguish the two, then not finding the paternal pathogenic variant in the cell-free DNA sample would indicate that the fetus was not affected (ie, would either be a heterozygote carrying the mother's pathogenic variant or would be pathogenic variant-free).

If the paternal pathogenic variant is present in the cell-free DNA sample, techniques to determine if the fetus also has inherited the maternal pathogenic variant will have to be employed. This would require documentation that the cell-free DNA sample contained a significant excess of DNA fragments containing the maternal pathogenic variant, with the extra allele-containing fragments presumed to come from the fetus. If both parents carry the same pathogenic variant and they cannot be distinguished by nearby polymorphisms, it will be more difficult to establish that the fetus did or did not inherit two mutant alleles.

Recent advances in single-gene noninvasive prenatal diagnosis enable detection of maternal single-gene carrier status with reflex to assess the fetal gene status (carrier or affected) from the same sample, and does not require a paternal sample [17,18]. Continued evaluation of this new technique in larger cohorts with more complete collection of fetal outcomes is needed to inform clinical implementation.

Prediction of phenotype after prenatal diagnosis — If prenatal diagnosis determines that the fetus carries two CFTR pathogenic variants 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.

●Common CF pathogenic variants and an affected family member – In the setting of a family history of CF in which at least one of the CF pathogenic variants 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 pathogenic variants (F508del-CFTR or W1282X), which are associated with the classic CF phenotype [22-24], or the R117H pathogenic variant 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 pathogenic variant 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'.)

●Less common pathogenic variants and limited information about an affected member – If the fetus inherits other, less common pathogenic variants, 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 pathogenic variants 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 pathogenic variants is of prime importance, but is not currently possible [23].

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 pathogenic variants inherited. Several CF pathogenic variants 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) [22-25]. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatic disease' and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Infertility'.)

Resources — The Cystic Fibrosis Foundation provides information on specific phenotypic aspects of several hundred CFTR pathogenic variants for clinicians or the general public.

PREGNANCY AND PERIPARTUM MANAGEMENT

●Counseling and support – 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 [10]. The Cystic Fibrosis Foundation offers information and support for families and individuals with CF.

There are no prenatal therapeutic interventions for CF. In utero medical and genomic therapy (eg, CF transmembrane conductance regulator [CFTR] modulators, CRISPR gene editing) is progressing but remains investigational.

●Ultrasound examination near term – Prenatal sonography near term may be useful so that the newborn’s providers can be alerted to suspected meconium ileus, if present. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Meconium ileus'.)

●Pediatric care – 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 5^th to 6^th 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 10^th to 12^th 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. Obstetric and newborn management are generally not changed by the prenatal diagnosis of CF, with the exception of some cases of meconium ileus. (See 'Benefits and limitations of screening' above.)

However, a negative screening test means only that the individual does not carry any of the CF pathogenic variants in the screening panel; a negative result thus reduces the likelihood, but does not eliminate, the possibility that the individual is a CF carrier. (See 'Negative screen' above.)

●Candidates – We offer CF screening to all couples actively planning pregnancy and all pregnant people regardless of personal or family history or ancestry, in accordance with guidelines from several professional organizations. Alternatively, if a risk factor-based approach is used (see 'Candidates for screening' above):

•Couples in whom one or both partners have a personal or family history of CF are at higher risk of carrying a CF pathogenic variant. A directed screening strategy may be appropriate for these couples.

•Visualization of echogenic fetal bowel in the second trimester, particularly with dilated bowel and a nonvisualized gallbladder, is a nonspecific marker of CF. It is an indication for offering carrier screening and, for carrier couples, fetal diagnostic testing.

•Non-Hispanic White individuals and individuals of Ashkenazi Jewish descent have a relatively high carrier rate (1 in 29) (table 1).

●Carrier screening panels – Over 2100 different pathogenic variants in the CF gene have been identified, thus it is not possible to screen for all known pathogenic variants. The sensitivity of the standard 23-variant screening panel (table 2) varies among ancestral groups and performs best in non-Hispanic White individuals and people of Ashkenazi Jewish ancestry. Additional “reflex” testing will be done in F508del-CFTR, F507del, and R117H carriers. (See 'Standard panel' above and 'Reflex testing' above.)

The more contemporary 100-variant panel incorporates variants from a more diverse population and thus is expected to perform better. Assimilation of these 100 variants into a single commercial panel is pending. (See 'Standard panel' above.)

●Screening strategies

•Couples without a positive history of CF – Only one partner may be tested, or testing may be serial (the pregnant person or person planning to become pregnant is tested first; the partner is tested only if the person is a carrier), or testing may be couple-based (both partners are tested at the same time). The choice depends on factors such as time, cost, and partner availability. (See 'Couples with no personal or family history of CF' above.)

•Couples with a positive history of CF – Carrier screening for individuals and reproductive partners who have a personal history or family history of CF ideally tests for the specific pathogenic variant of the affected individual. 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.)

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

Interpretation when an individual carries two or more different CF variants requires an additional level of analysis and genetic counseling to discuss the implications for the individual and offspring. (See 'General principles' above and 'Positive screen' above and 'Genetic consultation' above.)

●Screen-negative results – The degree to which the risk of being a carrier is reduced after a negative test is determined by the number of pathogenic variants screened for and the proportion of CF attributable to those pathogenic variants. (See 'General principles' above and 'Negative screen' above and 'Genetic consultation' above.)

●Prenatal (fetal) diagnosis – If both parents are CF carriers, the next step is to test the fetus. The diagnosis of fetal CF is based on the presence of two CF transmembrane conductance regulator (CFTR) variants known to cause CF on separate fetal alleles. (See 'Diagnostic criteria' above.)

•Test options – Diagnostic testing is typically based on tests on amniocytes or chorionic villi, but cell-free DNA tests on maternal blood are becoming available. (See 'Chorionic villus sampling and amniocentesis' above and 'Noninvasive prenatal diagnosis' above.)

•Interpretation of results – If the fetus inherits the F508del-CFTR or W1282X pathogenic variants 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 pathogenic variants 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 pathogenic variants, or if limited medical information about the affected relative is available, phenotype prediction is difficult. (See 'Prediction of phenotype after prenatal diagnosis' above.)

●Should screening be repeated in successive pregnancies? – CF carrier screening results should be documented in the medical chart. For those in whom the initial screen was performed using a 23-pathogenic-variant panel, repeat screening in a subsequent pregnancy with a 100-variant panel can be considered. A change in partner can also prompt repeat carrier testing. (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.