Journal of Genetic Counseling, Vol. 14, No.

1, February 2005 (

c 2005)
DOI: 10.1007/s10897-005-1496-5

Professional Issues

Cystic Fibrosis Prenatal Screening in Genetic

Counseling Practice: Recommendations of the
National Society of Genetic Counselors

Elinor Langfelder-Schwind,1,9 Edward Kloza,2 Elaine Sugarman,3 Barbara Pettersen,4

and the NSGC Subcommittee on Cystic Fibrosis Carrier Testing (Trisha Brown,5
Kim Jensen,6 Seth Marcus,7 and Joy Redman8 )

For over a decade, prenatal screening for cystic fibrosis (CF) has been considered a model for
the integration of genetic testing into routine medical practice. Data from pilot studies and
public policy discourse have led to recommendations by some professional organizations that
CF screening should be offered or made available to pregnant women and their partners, and to
couples planning a pregnancy. It is crucial that genetic counselors gain thorough understanding
of the complexities of CF and the implications of positive test results, so that they may serve
as a reliable, educated referral base and resource for health care providers and their patients.
While not all pregnant women will be referred for genetic counseling prior to CF carrier testing,
genetic counselors often will be asked to counsel clients after they have a positive test result,
or who are found to be at increased risk. Genetic counselors can play an important role in
providing accurate and current information as well as support for patients’ informed decisions.
These recommendations were created by a multicenter working group of genetic counselors
with expertise in CF and are based on personal clinical experience, review of pertinent English
language medical articles, and reports of expert committees. The recommendations should
not be construed as dictating an exclusive course of management, nor does the use of such
recommendations guarantee a particular outcome. These recommendations do not displace a
health care provider’s professional judgment based on the clinical circumstances of a particular
client.
KEY WORDS: cystic fibrosis carrier screening; genetic testing; genetic counseling.

PURPOSE DISCLAIMER

To provide practice recommendations for genetic The genetic counseling recommendations of the
counselors whose clients are considering cystic fibro- National Society of Genetic Counselors (NSGC)
sis (CF) carrier testing or seeking information regard- are developed by members of the NSGC to assist
ing CF carrier test results. practitioners and patients in making decisions about

6 FerreInstitute, Binghamton, New York.

1 St.
Vincent Catholic Medical Centers, New York, New York.
2 Foundation for Blood Research, Scarborough, Maine.
3 Genzyme Genetics, Framingham, Massachusetts.
4 Genetic Counseling of Central Oregon, Bend, Oregon.
5 LabCorp, Research Triangle Park, North Carolina.
7 Lutheran General Hospital, Park Ridge, Illinois.
8 Quest Diagnostics, San Capistrano, California.
9 Correspondence should be directed to Elinor Langfelder-
Schwind, The Cystic Fibrosis Center, 36 Seventh Ave., Ste 509,
New York, New York 10011; e-mail: eschwind@svcmcny.org.

1
1068-0667/04/1000-0001/0

C 2005 Springer Science+Media, Inc.
2 Langfelder-Schwind et al.
appropriate management of genetic concerns. Each
practice recommendation focuses on a clinical or
practice issue and is based on a review and analy-
sis of the professional literature. The information and
recommendations reflect scientific and clinical knowl-
edge current as of the submission date and are sub-
ject to change as advances in diagnostic techniques,
treatment, and psychosocial understanding emerge.
In addition, variations in practice, taking into account
the needs of the individual patient and the resources
and limitations unique to the institution or type of
practice, may warrant approaches, treatments, or pro-
cedures alternative to the recommendations outlined
in this document. Therefore, these recommendations
should not be construed as dictating an exclusive
course of management, nor does use of such recom-
mendations guarantee a particular outcome. Genetic
counseling recommendations are never intended to
displace a health care provider’s best medical judg-
ment based on the clinical circumstances of a partic-
ular patient.
OBJECTIVES
The goals of these recommendations are to:
1. Supplement the knowledge and understand-
ing of genetic counselors regarding CF muta-
tion analysis.
2. Compare and contrast approaches to CF pre-
natal screening.
3. Provide a framework for genetic counselors
who are helping clients make decisions about
CF testing, prenatal diagnosis, and pregnancy
management, including pregnancy termina-
tion.
4. Highlight the complexities of CF mutation
testing, pitfalls of genotype/phenotype corre-
lation, and the nuances of interpreting positive
results.
METHOD
The authoring subcommittee consisted of genetic
counselors with expertise in CF testing and counsel-
ing, prenatal genetic counseling as well as experience
working with CF patients and families. Guidelines and
policy statements published by the National Institutes
of Health, U.S. Congressional Office of Technology
Assessment, American Society of Human Genetics,
American College of Medical Genetics, America So-
ciety of Urology, American Society of Reproductive
Medicine, and the American College of Obstetricians
and Gynecologists were also reviewed.
The MEDLINE and PubMed databases were
searched (using the key words CF carrier test-
ing/screening, CF mutations, and CF genotyping),
to locate relevant English language medical papers
published between 1990 and May 2004. Papers were
reviewed with attention to genetic counseling and
screening issues. The literature was reviewed and
evaluated according to the following categories out-
lined by the U.S. Preventive Services Task Force
(1995):
I. Evidence obtained from at least one prop-
erly designed randomized controlled trial.
II-1. Evidence obtained from well-designed con-
trolled trials without randomization.
II-2. Evidence obtained from well-designed co-
hort or case-control analytic studies, prefer-
ably from more than one center or research
group.
II-3. Evidence obtained from multiple time se-
ries, with or without the intervention.
III. The opinions of respected authorities,
based on clinical experience, descriptive
studies, or reports of expert committees.
The rating of supporting literature for this recommen-
dation is Class III.
In addition, the authors recruited a focus group
of practicing genetic counselors with expertise in pre-
natal, infertility, and/or CF newborn screening coun-
seling. The focus group was held at the 2003 NSGC
Annual Education Conference in Charlotte, NC. A
semistructured interview guide was prepared in order
to elicit opinions regarding the need for NSGC guide-
lines and recommendations regarding content. Also,
the authoring subcommittee queried and reviewed all
postings of the archives of the NSGC’s listserve, an on-
line discussion group, regarding CF testing to identify
areas of ongoing uncertainty regarding these issues. In
addition, the authoring committee sought expert re-
view from specialists and consumer groups in North
America. A draft of the document was made available
on the Internet to all members of the NSGC for com-
ment. The NSGC Ethics Subcommittee and an attor-
ney for the NSGC reviewed the revised document.
No conflicts with the NSGC Code of Ethics were
identified in the final document. The NSGC Board
of Directors approved the final document in October
2004.
Cystic Fibrosis Prenatal Screening in Genetic Counseling: Practice Recommendations 3

INTRODUCTION

Cystic fibrosis is inherited in an autosomal reces-

sive manner. Couples in which both members carry a
disease-causing alteration in the CF gene have a 1 in
4 chance, with each pregnancy, of having a child with
CF. When both members of a couple are found to be
CF mutation carriers, several testing options become
feasible. Some couples may opt for prenatal diagnosis
by amniocentesis or chorionic villi sampling to detect
or rule out the parental mutations. For couples who
have not yet conceived a pregnancy, preimplantation
genetic diagnosis and in vitro fertilization (IVF) may
also be an option, although the expense of these pro-
cedures may be a barrier. Adoption and artificial in-
semination by donor are also available to couples who
are concerned about their risk of having a child with
CF but for whom prenatal or preimplantation diag-
nosis may not be consistent with their moral, cultural,
or religious beliefs.

NEED FOR GUIDELINES

Since the gene for CF and several common

disease-causing mutations were identified in 1989,
prenatal screening for CF has been viewed as a model
for the integration of genetic testing into routine med-
ical care (e.g. Caskey et al., 1990; OTA, 1992). In 1997,
a National Institutes of Health Consensus Panel re-
viewed data from pilot studies and suggested that CF
screening should be offered to all patients as part of
routine prenatal care (NIH, 1997). Some professional
organizations have recommended that CF screening
should be offered to persons at highest risk based on
ethnicity, while persons at lower risk should be made
aware of CF screening to facilitate informed deci-
sion making [American College of Obstetricians and
Gynecologists (ACOG), 2001] (Fig. 1). Since the
publication of the ACOG guidelines, the number of
women screened has risen significantly. By early 2003,
an estimated 500,000 women were being screened an-
nually, and that number is expected to increase (Zoler,
2003). Approaches to offering CF testing differ widely
among genetics programs (Schwind et al., 1999).
Genetic counselors may be in a position to offer
CF screening to patients at background risk who are
referred for genetic counseling for a variety of un-
related indications, for example, advanced maternal
age, abnormal maternal serum screening, or abnor-
mal ultrasound findings. They may also be asked to
provide education and counseling to patients who
Fig. 1. Existence of other professional guidelines.
are at higher risk for having offspring with CF based
on family or personal history of CF or CF-related
symptoms. Because most pregnant patients are not
referred to genetic counselors, it follows that most
women who undergo prenatal CF screening will re-
ceive pre- and post-test information from their pri-
mary care providers. Patients may be referred to a
genetic counselor after testing if they are found to be
carriers, or if the prenatal care provider is unable to
interpret the result or provide adequate counseling.
The role of master’s-trained genetic counselors will
depend largely on the referral practices of these pri-
mary care practitioners. It is crucial that genetic coun-
selors gain a thorough understanding of the complex-
ities of CF, and the implications of test results, so that
they may serve as a reliable, educated referral base
for primary care providers and patients.
PILOT STUDIES/INCREASING
PUBLIC AWARENESS
In 1992, the Ethical, Legal, and Social Im-
plications Program of the National Center for
Human Genome Research (now NHGRI), National
4 Langfelder-Schwind et al.
Institutes of Health, responded to a request from the
American Society of Human Genetics and funded
pilot studies to assess the feasibility of CF carrier test-
ing in the general population. Four studies gauged
interest, uptake, and psychosocial sequela of such
testing, and evaluated models for pre- and post-test
counseling and education (e.g., Bernhardt et al., 1996;
Clayton et al., 1996; Grody et al., 1997; Loader et al.,
1996; Tambor et al., 1994). Two studies examined CF
carrier testing issues among relatives of people with
CF (Fanos and Johnson, 1995; Sorenson et al, 1997).
One study modeled CF carrier testing approaches
from an economic standpoint (Asch et al., 1998). The
population-based studies, which focused on testing
in a predominantly Caucasian population, concluded
that interest in testing was far greater in a prenatal
setting than for people who were not pregnant or
planning to become pregnant in the near future. In-
creased anxiety for CF carriers who were waiting for
their partner’s results was also noted. However, once
the partners tested negative, anxiety returned to base-
line levels. No affected fetuses were identified through
these pilot studies. Furthermore, not all those tested
realized that a negative carrier test result did not mean
that their risk to have a child with CF was reduced to
zero (Levenkron et al., 1997).
In 1997, investigators from each of these studies,
along with representatives from several other large-
scale studies funded privately or by other agencies
(Doherty et al., 1996; Eng et al., 1997; Witt, et al., 1996),
presented their data to a diverse NIH Consensus
Panel with expertise in medicine, genetics, economics,
and public health, as well as health care consumer
organizations and the lay public. The panel recom-
mended that all pregnant women and couples plan-
ning a pregnancy, regardless of ethnicity, should be
offered CF carrier testing (Genetic Testing for Cystic
Fibrosis, 1997). This broad-based recommendation
raised additional questions about the use of scarce
health care resources to screen patients from popula-
tions where CF was not common and the sensitivity
of the test was much lower than the reported 85–90%
in Caucasians, (Mennuti et al., 1999; Vintzileos et al.,
1998). It also led to the current standard of care set
forth by the ACOG/ACMG statement.
NATURAL HISTORY/CLINICAL
DESCRIPTION
Cystic fibrosis is a chronic, life-shortening condi-
tion that affects approximately 30,000 children and
adults in the United States [Cystic Fibrosis Foun-
dation (CFF), 2002]. Mutations in the cystic fibrosis
transmembrane conductance regulator gene (CFTR)
lead to aberrant chloride conductance across the api-
cal cell membrane. While CFTR is expressed through-
out the body, CFTR abnormalities predominantly
impact the pulmonary, digestive, and male reproduc-
tive systems, as well as the sinuses and sweat glands.
Chronic pulmonary infections and progressive dete-
rioration of lung function are the major causes of
morbidity and mortality in people with CF. Children
and adolescents with CF often maintain normal lung
function or have mild pulmonary disease. However,
the lung disease progresses over time, so that most
adults with CF have moderate or severe pulmonary
obstruction, which makes breathing more difficult.
Pancreatic insufficiency occurs in approximately 85%
of people with CF, causing failure to thrive in in-
fants, and chronic malabsorption and poor weight gain
throughout the lifetime (CFF, 2002). A small percent-
age of people are diagnosed with CF in adulthood and
tend to have milder lung disease than adults who were
diagnosed as children (Yankaskas et al., 2004).
GENETIC/MEDICAL DIAGNOSTIC OPTIONS
Analysis of sweat chloride concentrations ob-
tained after the sweat glands are stimulated with pilo-
carpine iontophoresis—known as the “sweat test”—
is the gold standard for CF diagnosis (normal values
for sweat chloride: <40: negative; 40–59: borderline;
and >60: positive). The sweat test is not an appro-
priate test for determining CF carrier status. A few
patients (1–2%) with symptoms consistent with CF
will have sweat chloride levels in the borderline or
even normal range (CFF, 2002). In these individu-
als, identification of two disease-causing mutations in
the CFTR gene is also sufficient to make a CF diag-
nosis. However, some people with CF will not have
mutations that are identifiable with current technol-
ogy (Table I). A third diagnostic method, currently
investigational, is a nasal potential difference (NPD)
study, available on a limited basis through CF research
Table I. CF Patient Genotypes
(17,836 CF Patients Genotyped)
52.6%
F508 homozygotes
36% heterozygous
F508
11% no
F508 or both unidentified
(CFF, 2002)
Cystic Fibrosis Prenatal Screening in Genetic Counseling: Practice Recommendations
facilities. NPD may be of particular use in confirm-
ing a CF diagnosis in symptomatic individuals whose
sweat chloride levels are below diagnostic values, and
who do not have two identifiable CFTR mutations
(Rosenstein and Cutting, 1998). Studies indicate that
a CF diagnosis is likely to be confirmed by CFTR
sequencing in symptomatic individuals whose sweat
chloride levels are borderline and who have only one
mutation on the ACMG panel of 25 (Groman et al.,
2002).
MEDICAL MANAGEMENT
Treatment for CF involves airway clearance
therapies to loosen and expectorate secretions,
antibiotics to treat acute infections and chronic col-
onization with microorganisms such as Pseudomonas
aeruginosa, as well as aerosolized mucolytic agents
(e.g., Pulmozyme), bronchodilators, aerosolized an-
tibiotics (e.g., Tobi) and maintenance of good nu-
tritional status through a high calorie diet and pan-
creatic enzyme supplementation. Airway clearance
is achieved through manual chest physical therapy
performed by another person, or via mechanical de-
vices such as the Flutter or vest-based systems that
promote independence. Each prescribed treatment
regimen can take 30 minutes a day to several hours.
Cystic Fibrosis Foundation Guidelines state that peo-
ple with CF should be seen in a CF treatment center
at least 4 times a year for well checkups (CFF, 1997).
The need for hospitalizations and/or intravenous an-
tibiotics varies widely but generally increases with
disease severity. Improvements in the treatment of
CF have led to significant increases in survival age,
which is presently 32 years (CFF, 2002). Median sur-
vival is predicted to be more than 40 years for pa-
tients born in the last decade (Elborn et al., 1991).
Lung transplantation is a consideration when lung
function has fallen below 30% of normal values (Kere
et al., 1992), but the procedure is accompanied by sig-
nificant morbidity and mortality. In addition, malab-
sorption and other CF-related problems persist after
transplant and some symptoms may be worsened by
immunosuppressive regimens (Yankaskas and Aris,
2000).
Although gene therapy is not currently a clinical
option, it receives a great deal of media attention, and
is widely touted as a cure for CF. The CFF has created
a therapeutic development network to streamline the
process of phase I and II clinical trials for gene therapy
modalities and other treatments under investigation.
5
QUALITY OF LIFE
Cystic fibrosis does not affect intelligence. Many
people with CF maintain a high quality of life in terms
of professional and personal achievements such as ed-
ucation, hobbies, marriage, and having children. Pul-
monary exacerbations have been found to be the most
significant predictor of decreased perceptions of qual-
ity of life (Britto et al., 2002). Men with CF are almost
always (98%) infertile due to congenital absence of
the vas deferens (Taussig et al., 1972), but techniques
such as microsurgical epididymal sperm aspiration
(MESA) with IVF have improved prospects for fa-
thering children (Schlegel et al., 1995). Adoption and
artificial insemination by donor sperm are also avail-
able to men with CF and their partners. Women with
CF may have reduced fertility and a higher incidence
of preterm labor and complications, but they are able
to bear children (Fiel, 1996). Pregnancy may have a
detrimental impact on the disease course of women
with CF, which correlates with their pulmonary and
nutritional status prior to pregnancy. However, the
impact of CF on a person’s ability to live a productive
life into adulthood is largely dependent on disease
severity (CFF, 2002).
Genetic counselors should be familiar with the range
of severity of 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 CORRELATION
The relationship between mutations in the CFTR
gene and CF symptoms has proven to be more com-
plex and variable than was anticipated with the dis-
covery of the most common CF mutation,
F508, in
1989 (Kere et al., 1989). While the CFTR gene was dis-
covered as a result of studying patients with classic CF,
mutations in this same gene have been identified in pa-
tients with nonclassic CF and other phenotypes such
as congenital bilateral absence of the vas deferens
(CBAVD) (Claustres et al., 2000; Lissens et al., 1996),
idiopathic chronic pancreatitis (Noone and Knowles,
2001) and disseminated bronchiectasis (Girodon et al.,
1997; Pignatti et al., 1996). Polymorphisms in CFTR
are associated with many of these often isolated, CF-
related symptoms. In addition, a number of appar-
ently healthy individuals referred for carrier testing
have tested positive for two CFTR mutations (Rohlfs
et al., 2001). The identification of increasing numbers
6 Langfelder-Schwind et al.
of mutations along with the appreciation of the highly
variable clinical symptoms of CF introduced the
possibility of genotype/phenotype relationships that
could be prognostically useful. Here too, the situa-
tion is more complex than might have been initially
anticipated.
Certain clinical features of classic CF, such as
pancreatic insufficiency, show a strong association
with genotype. Others, such as pulmonary disease,
cannot be predicted reliably from genotype (The CF
genotype-phenotype consortium, 1993). In addition,
mutations such as R117H and I148T have been found
at unexpectedly high frequencies in healthy popula-
tions, suggesting that they are not completely pene-
trant (Rohlfs et al., 2002; Strom et al., 2002; Witt et al.,
1996). Further evidence for a variable phenotypic
effect of these and other mutations is found by the
observation of the same genotype (
F508/R117H) in
individuals with and without disease. All of these ob-
servations suggest that other genetic and/or environ-
mental factors play a role in modifying clinical expres-
sion of the CFTR mutations.
FACTORS INFLUENCING PHENOTYPE IN CF
Three factors appear to influence the clinical ex-
pression of CF: CFTR mutations, modifying factors-
either within the CFTR gene or in other genes, and
environment.
CFTR mutations have been classified based on
the nature of the molecular defect and impact on
chloride channel function (Fig. 2). Class I, Class II,
Fig. 2. Molecular consequences of CFTR mutations. Reprinted with permission from
Lap-Chee Tsui, PhD.
and Class III mutations such as W1282X,
F508,
and G551D result in little or no functional CFTR
channel activity, and are usually associated with the
classic CF phenotype of pulmonary disease, elevated
sweat chlorides, pancreatic insufficiency, and male in-
fertility. In contrast, class IV and V mutations, for
example, R117H and R334W, result in decreased chlo-
ride conductance with retained residual functional ac-
tivity. These latter mutations tend to be associated
with a pancreatic sufficient phenotype and later on-
set of symptoms (Mickle and Cutting, 1998; Zielenski,
2000).
The role of the CFTR genotype, genetic back-
ground and environment in phenotypic expression
further appears to be tissue dependent. The vas defer-
ens seems to be most sensitive to CFTR dysfunction
since most men with two CFTR mutations, regard-
less of class, are infertile due to CBAVD (Zielenski
et al., 2000). Expression in the pancreas is closely cor-
related with the CFTR genotype as demonstrated by
concordance among individuals with the same geno-
type (The cystic fibrosis genotype-phenotype consor-
tium, 1993). In contrast, the severity of lung disease
has not been strongly linked to genotype, and signif-
icant variability exists among patients with the same
genotype. Pulmonary disease, which is the primary
cause of morbidity and mortality in CF, appears to be
influenced significantly by environmental factors, e.g.,
exposure to bacterial pathogens and cigarette smoke,
as well as by modifier genes at other loci. Several can-
didate loci have been identified (Garred et al., 1999).
A modifier locus for meconium ileus, present in 15–
20% of affected CF patients, has been identified at
Cystic Fibrosis Prenatal Screening in Genetic Counseling: Practice Recommendations
the q13 region of chromosome 19 (Zielenski et al.,
1999). The identified region at 19q13 is large, which
complicates the search for a specific causative gene.
GENOTYPE/PHENOTYPE COUNSELING
There is no simple one-to-one relationship between
genotype and phenotype and many modifying fac-
tors likely exist. Conveying complex information in
a sensitive and supportive manner is a necessary skill
when counseling about CF.
The CF literature often describes mutations with
value-laden terms such as “severe” or “mild” with-
out appropriate clinical context, resulting in confusion
for patients and providers. Mutations described as
“severe,” for example,
F508,
I507, G542X, G551D,
W1282X, N1303K, R553X, 621 + 1G>T, and 1717-
1G>A, are usually categorized as Class I, II, or III,
and the expected pancreatic insufficient phenotype
occurs when one of these mutations is inherited in
trans with a second mutation, of Class I, II, or III.
Mutations described as “mild”, for example, R117H,
R334W, R347P, and A455E (Kristidis et al., 1992; The
CF genotype-phenotype consortium, 1993), are more
likely to be associated with pancreatic sufficiency re-
gardless of the class of the second mutation. These
mutations, usually Class IV and V, are also associated
with borderline or negative sweat chloride values and
later onset of symptoms. While genotype information
has some prognostic value for predicting pancreatic
status, correlation with severity of lung disease can-
not be made reliably for individuals.
Significant phenotypic differences have been re-
ported among cohorts of CF patients when they were
grouped according to functional class, with Class IV
and V generally associated with better clinical pa-
rameters and lower mortality (McKone et al., 2003).
Of note, there is substantial variability in phenotype
among patients with the same genotype (McKone
et al., 2003). This underscores the importance of fac-
tors other than genotype on predicting phenotype
yet provides useful counseling information regarding
possible range of clinical presentation.
For the majority of the >1000 CFTR mutations
identified to date, genotype/phenotype counseling be-
yond predictions of pancreatic status is not possi-
ble. As sequencing or related technologies allow for
the identification of rare mutations in both affected
and unaffected individuals, the phenotypic conse-
quences of these mutations (or variants) may remain
uncertain.
7
Genotype alone does not explain the variability of
CF clinical presentation. In response to patient re-
quests for prognostic information, genetic counselors
should be cautious about estimating clinical sever-
ity based on limited data. Genetic counselors should
avoid using individual patient experiences or pub-
lished case reports as a basis for predicting the clin-
ical course of a person or fetus with CF, even when
the genotype is similar. General discussions of pan-
creatic status or prospect for classic versus nonclassic
presentation may be appropriate.
COMPLEX ALLELES
While phenotypic expression of autosomal reces-
sive disorders typically results from the presence of
a causative mutation in each allele of the pair, for
example,
F508 mutation on one chromosome and
W1282X on the other, CF screening has unmasked
a diagnostic and counseling challenge in the form of
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 pres-
ence or absence of that variant affects phenotype—
characterize two common CFTR mutations, I148T
and R117H.
With an allele frequency of 0.1% among affected
CF patients, I148T is included in the ACMG/ACOG
recommended panel (Grody et al., 2001). After test-
ing for I148T in the general population, it has become
apparent that its frequency among apparently healthy
individuals is 60–100 times that expected based on
the CF affected population (Buller et al., 2004). In
addition, several asymptomatic individuals (including
fertile males) were identified as compound heterozy-
gotes for I148T and other CF mutations (Rohlfs et al.,
2002; Strom et al., 2002). These observations led to the
identification of the 3199del6 allele whose presence in
cis with the I148T allele influences phenotype (Rohlfs
et al., 2002). Among 8 apparently healthy adults who
were compound heterozygotes or homozygotes for
I148T, all were negative for 3199del6. In contrast, 7 of
8 individuals with a suspected or confirmed clinical di-
agnosis of CF had the 3199del6 allele in cis with I148T
and a second CF mutation on the other chromosome.
I148T in the absence of 3199del6 appears to
be a polymorphism, given its presence in apparently
healthy adults who are compound heterozygotes. Fur-
ther studies would be required to determine whether
I148T alone with a CFTR mutation on the other chro-
mosome is associated with single-organ or late onset
expression of disease. Counseling for I148T positive
individuals is therefore best done with knowledge of
8 Langfelder-Schwind et al.
3199del6 status. The ACMG Cystic Fibrosis Working
Group has recommended the removal of I148T from
the ACMG panel because 3199del6 is the pathogenic
finding (Watson et al., 2004). Genetic counselors re-
viewing 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, oc-
curring on different intron 8 polythymidine (“polyT”)
backgrounds: 5T or 7T (Kiesewetter et al., 1993). As
with I148T, the background contributes to the phe-
notypic expression. Therefore, identifying the intron
8 statuses for this mutation provides significant infor-
mation for counseling purposes (Grody et al., 2001;
Watson et al., 2002).
The R117H mutation has been reported to occur
on the same chromosome as the 5T or 7T intron 8 vari-
ants. Individuals with a disease-causing CF mutation
on one chromosome (such as
F508) and an R117H
mutation on the other have been reported with a va-
riety of clinical presentations: no symptoms (Massie
et al., 2001), congenital absence of the vas deferens in
males (Dork et al., 1997), chronic pancreatitis (Noone
et al., 2001), and nonclassic and pancreatic sufficient
CF (Kiesewetter et al., 1993; Massie et al., 2001). The
likelihood of each of the possible clinical outcomes of
a given genotype is currently unknown as there is con-
siderable overlap in clinical presentation among indi-
viduals with the same genotype. However, individuals
with
F508 (or another CF mutation) on one chromo-
some, and R117H/5T in cis on the other chromosome,
would be expected to have cystic fibrosis (likely pan-
creatic sufficient), whereas an individual with a CF
mutation on one chromosome and R117H in cis with
7T or 9T on the opposite chromosome (Massie et al.,
2001; Chu et al., 1993) is more likely to be asymp-
tomatic or have milder symptoms, e.g. 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
The poly T tract in intron 8 poses counseling
challenges, regardless of the presence of R117H. It is
most commonly comprised of 5, 7, or 9 thymidines at
the splice branch acceptor site. Alternative splicing at
this acceptor site results in aberrantly spliced mRNA
lacking exon 9, and this exon9-mRNA produces a
nonfunctional protein. The length of the polyT tract
modifies the amount of normal mRNA produced.
9T is associated with >90% normal mRNA, 7T with
50–100%, and 5T with 5–30% normal mRNA (Chu
et al., 1993). The 5T variant is fairly common, having
a 5% allele frequency and ∼10% carrier frequency
among Caucasians (Kiesewetter et al., 1993). Recently
there have been case reports of individuals with a 6T
allele (Kraus et al., 2002; Rohlfs et al., 2003).
Since a CFTR gene with only a 5T variant
produces about 5–30% functional protein, it may
have clinical significance when paired with a CFTR
mutation or 5T variant on the other chromosome.
The presence of a CF mutation on one chromosome
with a 5T variant on the other has been reported
with a number of clinical presentations: no symptoms
(Rave-Harel et al., 1997), congenital absence of the
vas deferens in males (Chillon et al., 1995; Lissens
et al., 1996), chronic pancreatitis (Noone et al., 2001),
and nonclassic CF (Kere et al., 1997). Homozygosity
for the 5T variant has been reported in healthy in-
dividuals (Rave-Harel et al., 1997), men with CAVD
(Dork et al., 1997), an adult with CF-like lung disease
(Noone et al., 2000) and in persons with bronchiec-
tasis (Pignatti et al., 1996). Again, most information
about individuals with these genotypes comes from
case reports rather than population-based studies.
The ability to predict phenotypic frequency based on
genotype may follow the analysis of data from com-
prehensive prospective studies and identification of
additional modifiers.
An additional polymorphic region of CFTR con-
sisting of TG repeats may be of use in further de-
termining whether a male with one CFTR mutation
and 5T is likely to be asymptomatic or exhibit CF
symptoms, which could range from isolated CBAVD
to nonclassical CF (Cuppens et al., 1998; Groman et al.,
2004). Until more is learned about females with atyp-
ical or nonclassic CF who also have a 5T/CF mutation
genotype, TG typing does not aid in predicting the
likelihood of CF symptoms in females. In addition,
TG typing does not reliably distinguish between males
likely to have isolated CBAVD and males likely to
be affected with nonclassic CF (Groman et al., 2004).
Testing for the 5T allele may help to identify the eti-
ology of CBAVD or nonclassic CF symptoms (Kere
et al., 1997; Richards et al., 2002), in addition to its
use in reflex testing for R117H. However, nonreflex-
ive testing for the 5T allele is not recommended at
this time as part of population-based carrier testing
protocols since the intent of CF screening programs
Cystic Fibrosis Prenatal Screening in Genetic Counseling: Practice Recommendations
is to identify classic CF (ACMG CF Working Group,
submitted for publication; Strom et al., 2002; Watson
et al., 2002).
As CFTR variants of variable consequence or un-
known significance continue to be identified and re-
ported, genetic counselors should emphasize the dis-
tinction between known disease-causing mutations
such as
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 0.6–1.4% of pregnancies during rou-
tine fetal anatomy scans (Al-Kouatly, 2002; Bromley,
1994; Hill, 1994). An estimated 2% of FEB can be
attributable to CF (Bosco, 1999), depending on the
brightness of the bowel (Al-Kouatly, 2001), the pres-
ence of CFTR mutations in one or both parents
(Bosco, 1999), ethnicity (Ogino, 2004) 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 con-
straints 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 con-
dition prior to onset of symptoms, or to identify per-
sons at sufficiently high risk to justify further testing
procedures. The term “carrier testing” refers to car-
rier detection in an individual, whereas “CF screen-
ing” refers to the identification of affected individuals
(or fetuses) within a population (Haddow, 1997).
Sequential testing (also called two-step, or
step-wise testing) (Haddow et al., 1999), 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
(Vintzileos et al., 1998). 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 (resid-
ual) risk for having an affected child is provided
(Palomaki, 2004). An alternative couple-based model
described by Wald et al. (2003) involves collecting
9
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 recommen-
dations have endorsed the couple-based approach as
long as the results are given to both members of the
couple (Grody et al., 2001).
Concurrent testing of both partners simultane-
ously is available for couples in which extenuating
circumstances dictate a need to accelerate the test-
ing process. This is the least cost-effective method of
screening (Asch et al., 1998). 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 depen-
dent 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 ap-
proach to population screening (Ormond et al., 2003;
Super et al., 1994), but this method may have value
in identifying some carrier relatives of motivated in-
dividuals themselves identified as carriers through
population screening programs (Roberts et al., 2003).
While discussion of the implications of a positive car-
rier test for blood relatives is an important component
of post-test counseling for carriers, genetic counselors
must adhere to ethical obligations and legal require-
ments by respecting patients’ wishes regarding notifi-
cation of relatives.
The suitability of the above-described ap-
proaches 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
Cystic fibrosis occurs throughout the world in
people of every race and ethnicity (Bobadilla et al.,
10
2001). Although CF is often described as a disease
of Northern European Caucasians, the incidence in
some nonwhite populations is significantly greater
than in some Northern European populations. For
example, CF has an estimated disease frequency of 1
in 333 among Zuni Native Americans (Kessler et al.,
1996), while the incidence of CF in Finland is 1 in
25,000 (Kere et al., 1994).
Incorporating patient ethnicity into genetic
counseling is complicated by imprecise definitions of
ethnicity or nationality, as well as the varying eth-
nic composition of patient populations. For exam-
ple, reported CF frequencies vary significantly among
subsets of people identified as “Hispanic,” and pop-
ulations labeled “Asian” by CF databases include
Sephardic Jews, Pakistanis, Indians, and S. East Asians
(www.genet.sickkids.on.ca). 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 stud-
ies within several ethnic populations. These data rep-
resent “best estimates” and are considered reliable
(Table II).
The concept of residual risk should be included as
part of any discussion of negative CF carrier testing
results.
In the context of prenatal screening, residual risk
is the chance that, despite a negative test, the fetus
might still have CF. The residual risk will differ if
one partner tests negative versus both partners test-
ing negative, and is influenced by ethnicity and family
history of CF. Laboratories that offer carrier testing
may define residual risk as the chance that an individ-
ual with a negative test may still carry an undetected
CF mutation. Sensitivity and residual risk data can
vary depending upon the laboratory used and/or the
number of ethnic specific mutations tested. Given the
multiethnic mixture prevalent in the United States, it
Table II. Cystic Fibrosis Incidence Carrier Frequencies and Detection Rates by Ethnicity
Incidence Carrier
Ethnic group of CF 1 in frequency 1 in
Caucasian 2,500 25
Ashkenazi Jewish 2,300 24
African American 15,100 61
Hispanic 13,500 58
Asian American 35,100 94
Note: Detection rate and residual risk pertain to the ACMC, ACOG, NIH-recommended 25-mutation panel (from Palomaki et al., 2004).
Langfelder-Schwind et al.
is often difficult to provide an ‘exact’ residual risk and
test sensitivity to an individual.
Given the dearth of ethnic-specific risk data, at this
time it is appropriate for genetic counselors to use
general published guidelines such as the chart above,
or specific figures provided by the laboratory, when
counseling patients about pre- and posttest CF car-
rier 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
(Bobadilla et al., 2002; Sugarman et al., 2004). Genetic
counselors should also keep in mind that even if a mu-
tation is reported to be ‘ethnic specific’, its frequency
may not have been studied in the unaffected popula-
tion of that ethnic group (see previous discussion of
“Complex Alleles”).
Genetic counselors should work with their genetic
and OB/GYN colleagues as well as their institutional
legal department to develop a consistent approach
for actively offering CF screening or making infor-
mation available to patients of certain ethnicities who
are at lower risk to be CF carriers or for whom test-
ing is not very sensitive. Genetic counselors should
consider “ethnic specific” mutation testing as one fac-
tor in selecting a laboratory to send patient samples.
Other factors may include insurance reimbursement,
institutional contractual arrangements, and state reg-
ulatory issues.
SIGNIFICANCE OF FAMILY HISTORY
The approach to carrier testing differs signifi-
cantly 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
Approximate risk
of affected fetus after
Proportion of mutations Prenatal detection negative test in one
identified (%) rate (%) parent ∼1 in
88 78 21,000
94 89 83,000
65 42 54,000
72 52 18,000
49 24 75,000
Cystic Fibrosis Prenatal Screening in Genetic Counseling: Practice Recommendations
and, whenever possible, the affected person’s geno-
type, 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 reassur-
ing. The process of obtaining proper releases may de-
lay 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 link-
age analysis may be necessary before the risk to the
pregnancy can be clarified and informative prenatal
diagnosis can be offered.
PSYCHOSOCIAL AND COUNSELING ISSUES
Psychosocial and counseling issues pertaining to
genetic counseling, providing genetic risk assessment,
and offering DNA-based tests have been delineated
in the NSGC practice guidelines regarding cancer
risk counseling (Trepanier et al., 2004), Fabry testing
(Bennett et al., 2002a), Fragile X testing (McIntosh
et al., 2000), and counseling consanguineous couples
(Bennett et al., 2002b). These issues are not unique
to CF.
Careful attention to and emphasis on the emotional
component of the genetic counseling process are crit-
ical to the provision of quality genetic counseling for
CF.
SPECIAL CIRCUMSTANCES
CF carrier testing is optional for patients in the
prenatal setting, and some patients will decline to be
tested (Vintzileos et al., 1998). In addition, not all
prenatal providers are offering CF screening to their
patients (Zoler, 2003). In contrast, newborn screen-
ing for CF is routinely performed in several states.
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 set-
ting. In this situation, one of the parents is an ob-
11
ligate CF carrier, and additional genetic counseling
is indicated, so that the parents may reconsider car-
rier testing in light of the new, albeit unsolicited
information.
Several laboratories offer and market expanded
CF mutation panels, CFTR sequencing or gene scan-
ning techniques. 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 pro-
vide additional reassurance to clients if the test results
are negative. These methodologies have not been en-
dorsed as appropriate for routine CF carrier testing
(Grody, 2001). Genetic counselors should be aware of
the possibility of identifying a new sequence variant
or result for which clinical predictions cannot be reli-
ably 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 find-
ing a CF mutation if it is there, these methodologies
do not detect all CF mutations. In addition, CFTR se-
quencing results may raise unanswerable questions,
increase patient anxiety, and possibly lead to termi-
nation 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 situa-
tion, 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
DNA technology when carrier testing is offered.
Therefore, patient education plays a vital role in
informed decision making. In preparing patients for
12
Table III. Web-Based Resources
CFTR mutation database www.genet.sickkids.on.ca: Searchable
by mutation name. The purpose is to collect information on
each mutation as it is identified - there usually is only one case
report per mutation. Clinical information is not always
available or relevant. Contains links to published reports.
Submitting authors are responsible for providing updates
such as an association with a complex allele, but not required.
GeneReviews www.geneclinics.org: Contains a comprehensive
overview of classic cystic fibrosis and atypical presentations.
Provides details regarding CF diagnosis. Several years may
lapse between updates.
Cystic Fibrosis Foundation www.cff.org: Designed for
individuals who have been diagnosed with CF and their
families, but contains a question and answer sheet about
carrier testing http://www.cff.org/living with cf/. Provides
information about CFF-funded research trials and the
network of accredited Care Centers which provide specialized
care for people with CF.
Cystic-L www.cysticL.org: A popular Listserv for CF patients
and their families, it contains searchable archives. Most of the
discussion is among laypersons. Not recommended for
persons seeking information about population-based carrier
testing.
the range of test results, CF education may also help
clients to anticipate their responses.
Genetic counselors should become familiar with
the two ACOG patient education pamphlets that have
been distributed to all ACOG members, and which
OB/GYNs may be purchasing for use with CF screen-
ing. These are Cystic Fibrosis Carrier Testing: The
Decision is Yours, and Cystic Fibrosis Testing: What
Happens if Both My Partner and I Are Carriers?
The NSGC has produced two brochures, “Genetic
Testing for CF: A Handbook for Professionals” and
“Genetic Testing for CF: A Handbook for Families”
(both currently under revision), and also has a CF car-
rier testing pamphlet that is part of a larger brochure
for Ashkenazi Jewish carrier testing.
Genetic programs or institutions may choose to
design their own patient material describing the spe-
cific characteristics of their screening approach. Oth-
ers may use patient education materials provided by
the testing laboratory or an independent source. Sev-
eral commercial laboratories and universities/private
institutions have created CF carrier testing literature,
and many of these materials are available on-line.
Some non-English resources are also available.
RESOURCES, PRINTED AND ON-LINE
Information about CF is available on many web-
sites, including general health care websites, e.g.,
Langfelder-Schwind et al.
WebMD, About.com, National Institutes of Health.
Not all websites are updated regularly and some may
contain information that is not relevant to the patient.
As with any disease-specific website, in attempts to
be comprehensive the descriptions may also be con-
strued as insensitive or alarming to patients. A num-
ber of pharmaceutical companies (Solvay, Chiron,
Genentech) that market products to CF patients also
have information on their websites. Several popu-
lar sites for obtaining information about CF are de-
scribed in Table III.
EXCEPTIONS/SPECIAL CASES
Genetic counselors should use their best clinical
judgment regarding situations when it may not be ap-
propriate to offer CF carrier testing within the scope
of a particular genetic counseling session. For exam-
ple, a woman who is referred for genetic counseling
to discuss abnormal ultrasound findings that are not
suggestive of CF (e.g. anencephaly) may consider in-
formation about CF screening to be distracting or
insignificant. Patients who are counseled regarding
increased risk to the pregnancy based on maternal
serum screening may also find it difficult to “shift
gears” and process the risks, benefits and limitations
of CF screening in the context of increased risks
for birth defects or mental retardation, and this is
an area for further study. If CF testing is not of-
fered, 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 screen-
ing recommendations and the reason that screening
was not offered.
CONCLUSIONS
To some patients, CF screening may provide an
opportunity that can give them important informa-
tion 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.
ACKNOWLEDGMENTS
We would like to thank the following indi-
viduals for their thoughtful review and input into
Cystic Fibrosis Prenatal Screening in Genetic Counseling: Practice Recommendations
this document: Barbara Bernhardt, M.S., University
of Pennsylvania, Barbara Karzeceski, M.S., Johns
Hopkins University, Ana Stenzel, M.S., Stanford Uni-
versity, Suzanne Patee, J.D., The Cystic Fibrosis Foun-
dation, Leslie Hazel, M.S., R.N., The Cystic Fibrosis
Foundation, Glenn Palomaki, B.S., B.A., Founda-
tion for Blood Research, and Wayne Grody, M.D.,
U.C.L.A. School of Medicine.
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