Cystic Fibrosis Carrier Screening

Roger A. Williamson, M.D.
University of Iowa Hospitals and Clinics

First Published: Fall 2002
Last Revised: August 2003
Peer Review Status: Internally Peer Reviewed

Cystic fibrosis (CF) carrier screening is beginning in Iowa. This is the first widespread pregnancy screening program in which testing is at the DNA level and is couple-based. The program will feature the elements which have characterized the expanded MSAFP testing program, including genetic counseling support, medical consultation, educational materials, and laboratory expertise.

Cystic fibrosis is the most common fatal autosomal recessive disorder in Caucasian populations. The disorder is caused by mutations in a gene which encodes the protein controlling the transport of chloride ions in and out of cells. These mutations disrupt chloride transport, producing thick secretions in the lungs and pancreas, the organs most affected by this disease. Improved treatments have permitted average survival into the 30s. However, persistent lung infections continue to be the major source of morbidity and mortality.

What has been the process leading to a cystic fibrosis carrier screening program in Iowa?

In 1997, a National Institutes of Health Consensus Conference, after review of multiple pilot CF screening studies and other relevant considerations, concluded that there were public health benefits to be realized from widespread CF testing. This was followed by another NIH workshop that included representatives of the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG). A Steering Group began to formulate recommendations and to develop the needed materials for 1) provider education, 2) patient education and informed consent documents, 3) laboratory testing and interpretation, and 4) genetic counseling.

In the latter part of 2001, CF screening materials were sent to practitioners (Preconception and Prenatal Carrier Screening for Cystic Fibrosis: Clinical and Laboratory Guidelines). This represented the final phase of an extended process, and was the signal that CF screening now needs to be offered not only to patients with a family history of CF, but to couples considering a pregnancy or seeking prenatal care. After a similarly extended process, the Iowa Department of Public Health, through its widely representative Birth Defects Advisory Committee, has approved a statewide CF screening program. This article will provide background on the decisions that have been made for the provision of this service in Iowa and the importance of the pretest information your patients receive.

What do we know about the genetics of CF?

CF is an autosomal recessive condition, If both parents are carriers (heterozygotes), they have a 1-in-4 chance of having an affected child. The gene for CF was discovered (cloned) in 1989. Since that time, over 900 mutations which produce the disease have been revealed. This genetic heterogeneity is only one of multiple, complex factors which have required consideration prior to the establishment of widespread CF screening. These mutations are not distributed equally in all population groups, and the carrier frequency varies among these groups. As noted in Table 1, there is a wide carrier frequency range among different ethnic populations.

Tables 1 and 2 have been adapted from the ACOG/ ACMG publication Preconception and Prenatal Carrier Screening for Cystic Fibrosis: Clinical and Laboratory Guidelines.

Table 1
Ethnicity*	Disease Incidence	Carrier Frequency
Caucasian	1/3,300	1/29**
Ashkenazi Jewish	1/3,300	1/29
Hispanic	1/8,100	1/46
African American	1/15,300	1/65
Asian	1/32,000	1/90

*Approximately 1 in 29 Caucasians is a carrier for CF. The 2000 census revealed that 93.9% of the Iowa population is Caucasian. Other groups in Iowa include: 2.8% Hispanic and Latino, 2.1% African American, 1.3% Asian, and 0.3% American Indian.

**In Caucasians, the most prevalent mutation is termed delta F508. This DNA change, which results in deletion of a phenylalanine from the encoded protein, represents 70% of all mutations in this population. This mutation is significantly less common in other ethnic groups.

With so many mutations, which ones should we screen for?

We will follow the guidelines issued by the Steering Committee representing ACOG, ACMG, and NIH. They have recommended a 25-mutation pan-ethnic panel. This will include the 25 most common CF mutations encountered in the United States, or those which represent at least 0.1% of all disease alleles. This strategy will avoid the necessity of tailoring the mutation panel to best match a patient's ethnicity, which would be difficult given the increasing ethnic admixture in the U.S. population. Table 2 displays the carrier risk after a negative test based on the utilization of this mutation panel and its detection rate in different ethnic groups.

For programs that are establishing CF testing, it is helpful to assess the relative frequencies of the individual mutations in the population to determine if a mutation may be over-represented and should therefore be included in the screening mutation panel. The frequency of the genotypes (individual mutations) of 167 patients cared for at the University of Iowa Hospitals and Clinics CF Clinic did not suggest that the Iowa program should deviate from the above recommendations.

What are my responsibilities related to CF screening?

Accurate pretest counseling is a critical element that will help to avoid later misunderstandings. One key recommendation is that CF screening be offered to individuals in the high risk groups, i.e., Caucasian and Ashkenazi Jewish. This implies a discussion of screening in sufficient detail that the decision to be tested is truly informed. Those in the other ethnic groups with a lower risk and a lower detection rate should be made aware of screening options. This means that written material should be provided, and a thorough discussion should follow if the patient raises the issue. It also has been recommended that preconception testing be encouraged whenever possible, although as a practical matter, testing will often occur in the prenatal setting. This should be done as early as feasible in pregnancy.

At the conclusion of a successful pilot program, those of you providing prenatal care have been sent test request forms, shipping information, contact numbers, and patient education materials. The test request forms require ethnic background and family history of CF. If this history is positive, the individual with a negative family history will be tested initially. Several sources of cells for DNA extraction can be used, including a buccal smear. However, to enhance the ability of the laboratory to obtain a result, blood will be requested. The issue of couple vs. sequential screening has been widely debated. The Iowa CF Screening Program will perform sequential screening. A specimen from both partners is required. The female partner will be tested initially. If she is negative, the male will not be tested. If positive, the male sample will be screened. Some have advised calling a couple screen-negative if one is a CF carrier and the other is not. This will not be the policy in Iowa. If an individual is screen-positive, he/she will be informed. This will allow other family members to know their risk status.

What are some of the facts I should be aware of when offering CF testing?

Because the majority of Iowa residents are Caucasian, several figures that relate to this group may help illustrate the complexities of screening of which patients and practitioners should be aware. Some of these facts are similar to those associated with other screening tests such as triple marker screening, but some are unique because CF testing necessarily involves couples. First, approximately 1 in 3,300 Caucasian infants is born with CF. If the screening test for both partners is negative, about 77% of their risk has been eliminated (0.88 x 0.88). For approximately 1 in 15 couples, one partner will be positive and one negative. In this case, the couple's residual risk to have an affected child will remain in the intermediate range, about a 1-in-600 chance.

Some couples with a 1-in-4 risk will request prenatal diagnosis, which can be performed by chorionic villus sampling between 10-12 weeks' gestation or by amniocentesis. If a fetus is affected, all options will be discussed. However, counseling a couple after determining a fetus is affected will be complex for several reasons. In contrast to many other autosomal recessive conditions, there is a poor genotype-phenotype correlation for CF, meaning the mutation or mutations an individual possesses does not predict disease severity. Related to this counseling dilemma, there is considerable variability in the manifestations of CF even among those with the same genotype. Lastly, a couple may question whether there is any form of prenatal treatment for CF. At the present time there is none. However, there are numerous studies that suggest a nutritional benefit if a presymptomatic diagnosis of CF is made. Also, if a prenatal diagnosis of CF is made and the pregnancy continues, this will help the family cope and make adjustments for the birth of a child with a chronic illness. The information also will benefit physicians caring for the child after birth.

See related Provider Textbooks about Obstetrics and Gynecology.

See related Provider Topics Cystic Fibrosis, Genetics/Birth Defects, Laboratory Tests, Lungs and Breathing, Obstetrics, Obstetrics and Gynecology or Procedures and Therapies.

See related Patient Textbooks about Obstetrics and Gynecology.

See related Patient Topics Genetics/Birth Defects, Laboratory Tests, Lungs and Breathing, Obstetrics, Obstetrics and Gynecology or Procedures and Therapies.

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