Quality of Life
Genetic counselors should be familiar with the range of severity of cystic fibrosis (CF) symptoms and the basic approach to medical management of CF patients. Clients seeking additional information may be referred to consumer organizations such as the Cystic Fibrosis Foundation.
Genotype/Phenotype Counseling
There is no simple one-to-one relationship between genotype and phenotype and many modifying factors likely exist. Conveying complex information in a sensitive and supportive manner is a necessary skill when counseling about CF.
Genotype alone does not explain the variability of CF clinical presentation. In response to patient requests for prognostic information, genetic counselors should be cautious about estimating clinical severity based on limited data. Genetic counselors should avoid using individual patient experiences or published case reports as a basis for predicting the clinical course of a person or fetus with CF, even when the genotype is similar. General discussions of pancreatic status or prospect for classic versus non-classic presentation may be appropriate.
Complex Alleles
Complex CFTR genotypes--where more than one CFTR mutation or variant is present in the same copy of the gene (in cis) and the presence or absence of that variant affects phenotype--characterize two common CFTR mutations, I148T and R117H.
I148T in the absence of 3199del6 appears to be a polymorphism, given its presence in apparently healthy adults who are compound heterozygotes. Further studies would be required to determine whether I148T alone with a CFTR mutation on the other chromosome is associated with single-organ or late onset expression of disease. Counseling for I148T positive individuals is therefore best done with knowledge of 3199del6 status. The American College of Medical Genetics (ACMG) Cystic Fibrosis Working Group has recommended the removal of I148T from the ACMG panel because 3199del6 is the pathogenic finding. Genetic counselors reviewing test results issued prior to the implementation of this recommendation may be called upon to clarify older results with patients and/or providers.
The R117H mutation is also a complex allele, occurring on different intron 8 polythymidine ("polyT") backgrounds: 5T or 7T. As with I148T, the background contributes to the phenotypic expression. Therefore, identifying the intron 8 statuses for this mutation provides significant information for counseling purposes.
The R117H mutation has been reported to occur on the same chromosome as the 5T or 7T intron 8 variants. Individuals with a disease-causing CF mutation on one chromosome (such as delta F508) and an R117H mutation on the other have been reported with a variety of clinical presentations: no symptoms, congenital absence of the vas deferens in males, chronic pancreatitis, and non-classic and pancreatic sufficient CF. The likelihood of each of the possible clinical outcomes of a given genotype is currently unknown as there is considerable overlap in clinical presentation among individuals with the same genotype. However, individuals with delta F508 (or another CF mutation) on one chromosome, and R117H/5T in cis on the other chromosome, would be expected to have cystic fibrosis (likely pancreatic sufficient), whereas an individual with a CF mutation on one chromosome and R117H in cis with 7T or 9T on the opposite chromosome is more likely to be asymptomatic or have milder symptoms, e.g., congenital bilateral absence of the vas deferens (CBAVD) in males. As asymptomatic people with these genotypes are followed over time, the risks for development of CF-related symptoms later in life may be clarified. Current carrier testing recommendations therefore include performing polyT variant analysis reflexively for individuals identified as R117H positive.
Poly T
As CFTR variants of variable consequence or unknown significance continue to be identified and reported, genetic counselors should emphasize the distinction between known disease-causing mutations such as delta F508 that lead to classic CF, and CFTR variants such as the 5T allele that are not expected to result in classic CF.
Prenatal Ultrasound Findings
Fetal echogenic bowel (FEB) is visualized in approximately 0.6 to 1.4% of pregnancies during routine fetal anatomy scans. An estimated 2% of FEB can be attributable to CF, depending on the brightness of the bowel, the presence of CFTR mutations in one or both parents, ethnicity and whether other fetal anomalies have been identified. Thus, CF appropriately remains in the differential diagnoses for fetuses with FEB. Given that there may be time constraints for couples who would consider pregnancy termination, parental carrier testing and/or fetal CF mutation analysis should be discussed when FEB has been identified.
CF Testing Models
One of the basic tenets of medical screening is that its objective be to identify a serious medical condition prior to onset of symptoms, or to identify persons at sufficiently high risk to justify further testing procedures. The term "carrier testing" refers to carrier detection in an individual, whereas "CF screening" refers to the identification of affected individuals (or fetuses) within a population.
Sequential testing (also called two-step, or step-wise testing), is a common approach in which initially one member of the couple is tested, and only if a CF mutation is identified is the partner then tested. This method is reported to be cost-effective for the Caucasian population. Sequential testing is best applied within the context of a screening program, which can assure that samples from both members are tested at the same laboratory, and that a (residual) risk for having an affected child is provided. An alternative couple-based model involves collecting samples from both members of the couple but testing the second sample only if a mutation is identified in the first. Only couples in which both partners carry mutations are reported as positive. Professional organizations in the United States have favored the sequential screening approach over the couple-based model, because CF carriers are routinely identified, allowing results to be transferred to new relationships and enabling patients to inform family members of their carrier testing results. United States recommendations have endorsed the couple-based approach as long as the results are given to both members of the couple.
Concurrent testing of both partners simultaneously is available for couples in which extenuating circumstances dictate a need to accelerate the testing process. This is the least cost-effective method of screening. However, concurrent testing may be useful for couples anxious about risk due to a family history of CF, following identification of echogenic bowel on ultrasound, or for a couple who is offered CF carrier testing in the second trimester.
Cascade testing describes an approach to testing of additional family members after the identification of an affected individual or CF carrier. It is dependent upon communication of test results to family members, as well as the willingness of these informed family members to pursue testing themselves. Studies have not supported cascade testing as a useful approach to population screening, but this method may have value in identifying some carrier relatives of motivated individuals themselves identified as carriers through population screening programs. While discussion of the implications of a positive carrier test for blood relatives is an important component of post-test counseling for carriers, genetic counselors must adhere to ethical obligations and legal requirements by respecting patients' wishes regarding notification of relatives.
The suitability of the above-described approaches to CF screening needs to be assessed for a given practice. Genetic counselors should work within their institutions to develop approaches to offering CF screening consistent with local/regional practices and customs and the needs of the individual family.
Significance of Ethnic Background
Because it is difficult to determine precisely which ethnic subgroup to assign a patient, and reliable risk data is not available for many populations, genetic counselors are urged to use prevalence and detection rate tables based on studies within several ethnic populations. These data represent "best estimates" and are considered reliable.
The concept of residual risk should be included as part of any discussion of negative CF carrier testing results.
Given the dearth of ethnic-specific risk data, at this time it is appropriate for genetic counselors to use general published guidelines such as Table II in the original guideline document, or specific figures provided by the laboratory, when counseling patients about pre- and posttest CF carrier risks.
The ACMG standard panel of CF disease causing mutations, comprised of mutations with >0.1% frequency among patients with CF, may not include particular mutations known to occur with relatively high frequency in certain populations. Genetic counselors should also keep in mind that even if a mutation is reported to be "ethnic specific," its frequency may not have been studied in the unaffected population of that ethnic group (see previous discussion of "Complex Alleles").
Genetic counselors should work with their genetic and obstetrician/gynecologist (OB/GYN) colleagues as well as their institutional legal department to develop a consistent approach for actively offering CF screening or making information available to patients of certain ethnicities who are at lower risk to be CF carriers or for whom testing is not very sensitive. Genetic counselors should consider "ethnic specific" mutation testing as one factor in selecting a laboratory to send patient samples. Other factors may include insurance reimbursement, institutional contractual arrangements, and state regulatory issues.
Significance of Family History
The approach to carrier testing differs significantly from the general population approach when the client reports a family history of the condition. Interpretation of a negative CF carrier test result is dependent on knowing which specific mutations have been identified in a blood relative who has CF or is a carrier. Medical records to confirm the diagnosis and, whenever possible, the affected person's genotype, are best obtained prior to meeting with a relative of a person with CF or CF carrier. If familial mutations have been identified, then it is important to make sure that the panel used for testing the client includes those mutations. If the affected relative does not have two identifiable mutations, then a negative CF test result on the client may be misleading or falsely reassuring. The process of obtaining proper releases may delay access to the information, and on some occasions, such clinical information may not be available in a timely fashion. When documentation of mutations is not available, it is appropriate to consider testing for a panel of clinically significant mutations to determine if the patient carries a common CF mutation. Testing the partner may provide adequate reassurance to the couple if the partner's result is negative. If the partner is a carrier, additional family studies, including linkage analysis may be necessary before the risk to the pregnancy can be clarified and informative prenatal diagnosis can be offered.
Psychosocial and Counseling Issues
Careful attention to and emphasis on the emotional component of the genetic counseling process are critical to the provision of quality genetic counseling for CF.
Special Circumstances
Children who are born in a state in which newborns are routinely screened for CF may subsequently be identified as CF carriers even if their parents had previously declined to be tested in the prenatal setting. In this situation, one of the parents is an obligate CF carrier, and additional genetic counseling is indicated, so that the parents may reconsider carrier testing in light of the new, albeit unsolicited, information.
In some circumstances, such as for couples who express a great deal of anxiety about residual risk, or partners of known carriers or affected individuals who are from ethnic groups that have a low detection rate using the standard panel, offering an expanded panel, scanning, or sequencing may provide additional reassurance to clients if the test results are negative. These methodologies have not been endorsed as appropriate for routine CF carrier testing. Genetic counselors should be aware of the possibility of identifying a new sequence variant or result for which clinical predictions cannot be reliably made, and include this possibility in their pretest counseling.
Genetic counselors should inform patients interested in CF carrier testing that they will be tested for a panel of disease-causing mutations. While expanded panels or CFTR sequencing may improve the odds of finding a CF mutation if it is there, these methodologies do not detect all CF mutations. In addition, CFTR sequencing results may raise unanswerable questions, increase patient anxiety, and possibly lead to termination of unaffected pregnancies, if a novel mutation or polymorphism is identified.
On rare occasions, individuals with CF will be identified through carrier testing. CF carrier testing may also reveal more than one mutation or sequence variant in an asymptomatic individual. In this situation, data from published case reports may be helpful in predicting whether mutations are in cis or trans, but phase should be determined through CFTR analysis of the patient's parents or children whenever possible. Genetic counselors should obtain clinical information from the patient, including personal or family history of infertility, asthma and sinus disease, malabsorption, nasal polyps, etc. When mutations are found to be in trans, genetic counselors should also recommend referral to an accredited CF care center for further evaluation.
Patient Education
Patients may be unfamiliar with either CF or deoxyribonucleic acid (DNA) technology when carrier testing is offered. Therefore, patient education plays a vital role in informed decision making. In preparing patients for the range of test results, CF education may also help clients to anticipate their responses.
Genetic counselors should become familiar with the two American College of Obstetricians and Gynecologists (ACOG) patient education pamphlets that have been distributed to all ACOG members, and which OB/GYNs may be purchasing for use with CF screening.
Exceptions/Special Cases
Genetic counselors should use their best clinical judgment regarding situations when it may not be appropriate to offer CF carrier testing within the scope of a particular genetic counseling session. If CF testing is not offered, it is appropriate to recommend to the primary care provider that CF screening be considered at a future visit, and include a notation in the patient record/summary letter regarding current CF screening recommendations and the reason that screening was not offered.
Conclusions
To some patients, CF screening may provide an opportunity that can give them important information about a current or future pregnancy. To others, it may provoke unwelcome anxiety or require a painful decision about the pregnancy. Genetic counselors will play an important role in providing information and support sufficient to allow people to make choices that are consistent with patient values and based on the best available information.
