Cystic fibrosis population carrier screening: 2004
revision of American College of Medical Genetics
Michael S. Watson, PhD1,*Garry R. Cutting, MD2,*Robert J. Desnick, MD, PhD3, Deborah A. Driscoll, MD4,
Katherine Klinger, PhD5, Michael Mennuti, MD4, Glenn E. Palomaki6, Bradley W. Popovich, PhD7,
Victoria M. Pratt, PhD8, Elizabeth M. Rohlfs, PhD9, Charles M. Strom, MD, PhD10, C. Sue Richards, PhD11,
David R. Witt, MD12, and Wayne W. Grody, MD, PhD*13
In April 2001, the American College of Medical Genetics
(ACMG) Cystic Fibrosis (CF) Carrier Screening Working
Group recommended a panel of mutations and variants that
should be tested to determine carrier status within the CFTR
gene as a part of population screening programs.1,2This was
initially done in response to the recommendations of an NIH
ered by all couples for use before conception or prenatally.3At
that time, the Working Group recognized limitations in our
understanding of the population frequencies of several CF al-
leles and proposed to review mutation distribution data after
the first two years of the program. In 2002, as part of an ongo-
ing effort to ensure that the cystic fibrosis carrier screening
programs are current with respect to the scientific literature
and other available data and practices, we initiated a second
review of data on the distribution of mutations in different
ethnic groups and we began to assess whether providers were
CF Foundation patient mutation database includes nearly
double the number of CF patient chromosomes available for
analysis in 2000. This report summarizes the major recom-
mendations of our Working Group with the supporting justi-
Genetics in Medicine provide some of the data on which our
related to this topic.
The questions addressed in this reevaluation of data were as
(1) Has the observed frequency of any CF mutation
changed significantly since 1999?
(a) Should mutations not meeting the prior standard
of ? 0.1% frequency in CF patients be removed?
(b) Should mutations that now have a frequency of
0.1% or greater but that were ? 0.1% in the initial
analysis be added?
(2) Is the prevalence of CF mutations in the general popu-
(3) Is there evidence of consistent and recurring challenges
with interpretation of some of the mutations in the CF
Multiple databases were used to determine the rates of oc-
patient population data were derived from the Cystic Fibrosis
Foundation (CFF) and the Cystic Fibrosis Consortium. See
Palomaki et al.5for details on these data sets and their limita-
frequencies. Analysis of the rates of CF patient mutations that
were not included in the original ACMG 25 were based exclu-
From the ACMG Cystic Fibrosis Carrier Screening Work Group,1American College of Med-
ical Genetics, Bethesda, Maryland;2McKusick-Nathans Institute of Genetic Medicine, Johns
Hopkins University School of Medicine, Baltimore, Maryland;3Department of Human Ge-
Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,
5Genzyme Corp, Framingham, Massachusetts;6Foundation for Blood Research, Scarbor-
ough, Maine;7Xenon Pharmaceuticals, Burnaby, British Columbia, Canada;8Nichols Inst./
chols Inst./Quest Diagnostics, San Juan Capistrano, California;11Molecular and Medical
Genetics, Oregon Health Sciences University, Portland, Oregon;12Kaiser Permanente, San
Jose, California;13Divisions of Medical Genetics and Molecular Pathology, UCLA School of
Medicine, Los Angeles, California.
*These authors contributed equally to this article.
Mike Watson, ACMG, Executive Director, 9650 Rockville Pike, Bethesda, MD 20814.
Go to www.geneticsinmedicine.org for a printable copy of this document.
ACMG standards and guidelines are designed primarily as an educational resource
for medical geneticists and other health care providers to help them provide quality
medical genetic services. Adherence to these standards and guidelines does not nec-
essarily ensure a successful medical outcome. These standards and guidelines should
not be considered inclusive of all proper procedures and tests or exclusive of other
procedures and tests that are reasonably directed to obtaining the same results. In
determining the propriety of any specific procedure or test, the geneticist should apply
his or her own professional judgment to the specific clinical circumstances presented
by the individual patient or specimen. It may be prudent, however, to document in the
patient’s record the rationale for any significant deviation from these standards and
September/October 2004 ? Vol. 6 ? No. 5
Genetics IN Medicine
(personal communication, Preston Campbell, MD, Medical
Director, CFF, 2004). The CFF data did not include Ashkena-
zim Jewish as an ethnic group.
General population screening data
Genzyme Genetics (data not shown). General population data
are mostly derived from testing that uses the ACMG 25 muta-
tion panel. Hence, general population data for mutations not
included in that panel was limited to information provided by
Genzyme Genetics and Kaiser Permanente.
Organization of data
Data were stratified by self-reported race/ethnicity when
available. CF patients self-identified as either non-Hispanic
were 37,263 non-Hispanic Caucasian CF chromosomes, 1,350
from African Americans, 2,718 from Hispanics, 125 from
Asians, and 108 from others (American Indians and Aleu-
tians). An additional 1,173 CF chromosomes were from indi-
viduals of unknown ethnicity. A subset of patients from the
general population study self-identified as either non-His-
Mutation selection standards
As in the initial recommendations of a CF mutation screen-
in at least 0.1% of CF patient chromosomes. Further, the mu-
tations chosen should be associated with classical CF rather
than with milder phenotypes because the decision-making
process largely impacts reproductive decisions.
Revising the CF carrier screening panel
Table 1 lists the mutations found in CF patient chromosomes
in descending order of their occurrence in a pan-ethnic popula-
tion. Mutation frequencies are listed by ethnic group to provide
laboratories testing local populations with data to determine an
Has the observed frequency of any CF mutation changed
significantly since 1999?
1078delT was found to occur in 0.03% of CF cases in the
the perspective of assay platform development, are thought to
be minimal. Although there may be other issues associated
with changing a “standard,” it was felt that changes should be
available to the Working Group. It was decided that any mu-
on the benefits and costs of incremental gain in the perfor-
mance characteristics of the screening test as defined here.
Thus, the ACMG recommends that 1078delT be removed
from the panel.
frequencies ranging from 0.1% to 0.17% in CF patients in the
2003 data (Table 2). Together the six could account for ap-
proximately 0.77% of CF alleles.
Several issues arise when considering adding mutations to a
we focused on improved clinical utility and have previously ad-
dressed issues of analytical quality.6We also weighed the incre-
changes.7The Working Group recommends no additions to the
general population screening panel be made at this time. Addi-
able for different ethnic groups or as new technologies emerge.
press the panel to an ethnic-specific subset as was stated in the
able. These 14 mutations occurred in 0.01% to 0.09% of CF pa-
groups. However, their relationship to disease severity was not
Is the prevalence of CF mutations in the general population the
same as that predicted from their frequency in CF patients?
The mutation/variant I148T occurs at rates 50 to 100 times
higher than in the general population being tested for carrier
status than in patients.8,9It was shown that CFTR genes bear-
ing I148T in CF patients have a second mutation termed
3199del6. The vast majority of individuals in the general pop-
lines of evidence indicate that 3199del6 is the disease causing
mutation. One, CF patients have been described who lack
I148T but have 3199del6 in association with another CF caus-
ing mutation.10Two, unaffected individuals have been de-
I148T but lacking 3199del6.7–11
Because the frequency of I148T alone is 0.05% and I148T
with 3199del6 in this analysis is considerably lower than 0.1%
and because I148T does not cause classical CF by itself, we
recommend removing I148T from the CF carrier screening
panel. The rarity of 3199del6 does not support its addition to
the panel as a disease associated mutation and we recommend
against it being added as a reflex test for carrier testing.
Is there evidence of consistent and recurring challenges with
interpretation of some of the mutations in the CF panel?
have suggested that it may not be appropriate for carrier screen-
Watson et al.
Genetics IN Medicine
ing.12Based on assessment of this situation, the Working Group
at risk of having offspring with CF if their partner is also a CF
from genetic counseling to discuss the risk and prenatal testing
options. Because the frequency of R117H-5T is appreciable, the
sizing the need to perform a screening test for 5T only as a reflex
In addition to the issues already discussed, several related
is inappropriate to screen for mutations such as R117H for
which a definitive prediction of clinical outcome can not be
provided. With appropriate informed consent, the limitations
inherent in predicting specific phenotypes resulting from any
mutations in a CF carrier screening panel should be discussed.
Although our recommendations are pertinent to classical CF
risk rather than the milder phenotypes discussed, there are
some mutations that may be associated with mild or severe
forms of CF depending on the mutations with which they are
panels. A goal of informed consent for CF carrier testing is to
make couples aware that there is a range of clinical outcomes
that cannot be predicted, and that that, in and of itself, consti-
tutes informed consent.
consent process is the reporting of results. It has been ar-
CFTR mutation frequency among individuals with clinically diagnosed cystic fibrosis by racial/ethnic group and in a pan-ethnic U.S. population
Mutation frequency among individuals with clinically diagnosed cystic fibrosis (%)
delF508 72.4254.3844.0738.95 31.4166.31
G542X 2.285.10 1.45 0.007.552.64
W1282X 1.50 0.630.24 0.0045.92 2.20
G551D2.25 0.56 188.8.131.52 1.93
621?1G?T1.570.26 1.11 0.000.00 1.30
N1303K1.27 1.660.35 0.762.781.27
R553X0.87 2.81 2.320.760.00 1.21
dell5070.88 0.68 1.87 0.000.220.90
3849?10kbC?T 0.58 1.570.175.31 4.770.85
3120?1G?T 0.080.169.57 0.00 0.100.86
R117H 0.700.110.06 0.000.00 0.54
1717-1G?T 0.48 0.270.37 0.000.670.44
2789?5G?A 0.480.160.00 0.000.100.38
R347P 0.450.160.06 0.000.00 0.36
711?1G?T0.43 0.23 0.00 0.000.100.35
R334W0.141.78 0.490.00 0.000.37
R560T0.38 0.000.170.00 0.000.30
3569delC0.340.130.06 0.00 0.000.28
A455E0.340.05 0.000.00 0.000.26
G85E 0.29 0.230.12 0.000.000.26
1898?1G?A0.16 0.050.060.00 0.100.13
CF population carrier screening
policystatement ? Vol. 6 ? No. 5
gued that a laboratory is obligated to report any and all
information that is gleaned from a test system, however,
there is no regulatory requirement and practice varies. Be-
cause the CF mutation testing platforms included the reflex
tests this led to the reporting of the 5T allele in the absence
of R117H by some laboratories. It is not an uncommon
practice for clinical chemistry testing platforms to bundle
many analytes into a single test but it poses a dilemma for
laboratories. Laboratories using existing reagents and tests
may be uncomfortable not reporting the 5T/7T/9T alleles
and sequences that are no longer considered appropriate for
CF carrier screening. The informed consent process should
emphasize that CF carrier screening is not designed to de-
tect all of the mutations that cause classical CF or the milder
phenotypes. As a result of this process, specification of
which results would be reported may help laboratories de-
cide to only report the test results that comprise the recom-
CF carrier screening is among the first general population
ing offers a potential prototype for the development of other
genetic screening programs. Recent experience with I148T
serves to demonstrate the importance of evaluating distribu-
tion among both affected and carrier screening populations to
discern discrepancies before inclusion in a screening panel.
Approved by the Board of Directors of the American College of
Medical Genetics on March 3, 2004.
© AMERICAN COLLEGE OF MEDICAL GENETICS, 2004.
1.Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ. Lab-
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American College of Obstetricians and Gynecologists, and American College of
Medical Genetics. Preconception and prenatal carrier screening for cystic fibrosis.
Clinical and Laboratory Guidelines. American College of Obstetricians and Gyne-
cologists, Washington, DC; 2001.
NIH Consensus Development Conference Statement. Genetic testing for cystic fi-
brosis. April 14–16, 1997. Arch Intern Med 1999;159:1529–1539.
Watson MS, Grody WW, Mennuti MT, Popovich BW, Richards CS. Cystic fibrosis
carrier screening: Issues in Implementation. Genet Med 2003;4/6:407–409.
Palomaki GE, Fitzsimmons S, Haddow JE. Clinical sensitivity of prenatal screening
Genet Med (in press in this issue)
Richards CS, Bardley LA, Amos J, Allitto B, Grody WW, Maddalena A et al. Technical
Distribution of additional mutations not in original ACMG 25 now appearing in ?0.1% CF patient chromosomes (%)
Q493X 0.19 0.070.04000.17
S549N 0.050.8 0.663.2 0.600.14
3905insT 0.13 0.07 0.0400 0.12
E60X0.130 0.1100 0.12
Y1092X 0.110.15 0.2600 0.12
2183delAA-?G 0.110000 0.10
Distribution of additional mutations not in original ACMG 25 appearing in 0.01%–0.1% of CF patient chromosomes (%)
R1158X0.07 0.740.1500 0.09
V520F 0.0900.04 0.80 0.09
R1066C0.02 0.07000 0.03
D1152H 0.0300.11 000.03
1812-1G-?A00.44 0.0400 0.02
Watson et al.
Genetics IN Medicine
8. Rohlfs EM, Zhou Z, Sugarman EA, Heim EI, Pace RG, Knowles MR et al. I148T
CFTR mutation confers a variable phenotype and occurs on multiple haplotypes.
Am Jour Hum Genet Suppl 2001:69A.
fibrosis. Genet Med 2002;4:319–323.
Strom CM, Huang D, Buller A, Redman J, Crossley B, Anderson B et al. Cystic
from the first 20,000 samples. Genet Med 2002;4:289–296.
Buyse IM, McCarthy SE, Lurix P, Pace RA, Vo D, Bartlett GA et al. Use of MALDI-
TOF mass spectrometry in a 51-mutation test for cystic fibrosis: evidence that
3199del6 is a disease causing mutation. Genet Med 2004;6:426–430.
an appropriate antenatal screening mutation. Unpublished data, 2004.
CF population carrier screening
policystatement ? Vol. 6 ? No. 5