HUMAN MUTATION 19:575–606 (2002)

REVIEW ARTICLE

Cystic Fibrosis: A Worldwide Analysis of CFTR

Mutations—Correlation With Incidence Data and
Application to Screening
Joseph L. Bobadilla,1 Milan Macek Jr.,2 Jason P. Fine,3 and Philip M. Farrell1*
1
Department of Pediatrics, University of Wisconsin, Madison, Wisconsin
2
Institute of Biology and Medical Genetics–Cystic Fibrosis Center, Charles University, Prague, Czech Republic
3
Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin

Communicated by Lap-Chee Tsui

Although there have been numerous reports from around the world of mutations in the gene of
chromosome 7 known as CFTR (cystic fibrosis transmembrane conductance regulator), little at-
tention has been given to integrating these mutant alleles into a global understanding of the popu-
lation molecular genetics associated with cystic fibrosis (CF). We determined the distribution of
CFTR mutations in as many regions throughout the world as possible in an effort designed to: 1)
increase our understanding of ancestry–genotype relationships, 2) compare mutational arrays with
disease incidence, and 3) gain insight for decisions regarding screening program enhancement
through CFTR multi-mutational analyses. Information on all mutations that have been published
since the identification and cloning of the CFTR gene’s most common allele, DF508 (or F508del),
was reviewed and integrated into a centralized database. The data were then sorted and regional
CFTR arrays were determined using mutations that appeared in a given region with a frequency of
0.5% or greater. Final analyses were based on 72,431 CF chromosomes, using data compiled from
over 100 original papers, and over 80 regions from around the world, including all nations where
CF has been studied using analytical molecular genetics. Initial results confirmed wide mutational
heterogeneity throughout the world; however, characterization of the most common mutations
across most populations was possible. We also examined CF incidence, DF508 frequency, and
regional mutational heterogeneity in a subset of populations. Data for these analyses were filtered
for reliability and methodological strength before being incorporated into the final analysis. Statis-
tical assessment of these variables revealed that there is a significant positive correlation between
DF508 frequency and the CF incidence levels of regional populations. Regional analyses were also
performed to search for trends in the distribution of CFTR mutations across migrant and related
populations; this led to clarification of ancestry–genotype patterns that can be used to design
CFTR multi-mutation panels for CF screening programs. From comprehensive assessment of these
data, we offer recommendations that multiple CFTR alleles should eventually be included to in-
crease the sensitivity of newborn screening programs employing two-tier testing with trypsinogen
and DNA analysis. Hum Mutat 19:575–606, 2002. © 2002 Wiley-Liss, Inc.

KEY WORDS: cystic fibrosis transmembrane conductance regulator; CFTR; cystic fibrosis; CF; newborn;
mutation screening; incidence; ABCC7

Received 19 June 2001; accepted revised manuscript 1 March
2001.
*Correspondence to: Philip M. Farrell, M.D., Ph.D., Professor
of Pediatrics and Dean, University of Wisconsin Medical School,
Room 1217 MSC, 1300 University Avenue, Madison, WI 53706-
1532. E-mail: pmfarrel@facstaff.wisc.edu
Contract grant sponsors: National Center for Research Re-
sources to the University of Wisconsin Medical School; Academic
Generalist Scholarship Program from the American College of
Physicians-American Society of Internal Medicine, Wisconsin
Chapter; Contract grant sponsor: National Institutes of Health;
Contract grant numbers: DK 34108; M01 RR03186; Contract
grant sponsor: Internal Grant Agency of the Czech Ministry of
Health (IGA MZ CR); Contract grant number: 6250-3; 6464-3;
00000064203; Contract grant sponsor: Ministry of Education of
the Czech Republic; Contract grant numbers: 111300003; LN
00A079; ME451.
DOI: 10.1002/humu.10041
Published online in Wiley InterScience (www.interscience.wiley.
com).

© 2002 Wiley-Liss, Inc.

576 BOBADILLA ET AL.
DATABASES:
CFTR – OMIM: 602421; 219700 (CF); GDB: 120584; XM_004980;
http://www.genet.sickkids.on.ca/cftr/ (CFTR Database; HGMD: CFTR)
INTRODUCTION
Cystic fibrosis (CF; MIM# 219700) is one of
the most common life-threatening autosomal re-
cessive disorders in the Western World [Welsh et
al., 1995; Farrell, 2000]. Previous investigators
have generated evidence that CF-causing muta-
tions have existed since the Paleolithic period
(50,000 years) [Morral et al., 1994], and many
are strongly associated with European-derived
populations. CF is caused by mutations in the
cystic fibrosis transmembrane conductance regu-
lator gene (CFTR; MIM# 602421), discovered
in 1989 [Riordan et al., 1989; Rommens et al.,
1989]. The most common mutant allele is the
F508del (∆F508) mutation [Kerem et al., 1989],
which is a three-nucleotide deletion at the 508th
codon causing the deletion of a phenylalanine
residue and subsequent defective intracellular
processing of the CFTR protein that is an impor-
tant chloride channel [Welsh et al., 1995; Mo-
rales et al., 1999]. Worldwide, the ∆F508
mutation is responsible for approximately two-
thirds (66%) of all CF chromosomes; however,
there is great mutational heterogeneity in the re-
maining one-third of all alleles [Cystic Fibrosis
Genetic Analysis Consortium (CFGAC), 1994;
Estivill et al., 1997; Welsh et al., 1995]. Nearly
1,000 CFTR alleles have been identified to date
[Cystic Fibrosis Genetic Analysis Consortium
(CFGAC), 2000] (www.genet.sickkids.on.ca/
cftr). These mutations have been classified into
five categories depending on their functional ef-
fects vis-à-vis the CFTR protein [Zielenski and
Tsui, 1995]. Although these mutations vary
greatly in their frequency and distribution, the
vast majority are either private or limited to a
small number of individuals. A group of CFTR
alleles also exists in non-Caucasian populations
[Macek et al., 1997]. There are about 10 to 20
less common mutations that exist at over 0.1%
worldwide. Some mutations can reach higher fre-
quencies in particular populations due to founder
effect (e.g., M1101K in Hutterites) [Zielenski et
al., 1993] or genetic drift (e.g., G551D in the his-
toric Celts), and other mutations are recurrent
(e.g., R1162X in Zuni and Northwest Italian
populations) which explains their presence in his-
torically unrelated populations [Morral et al.,
1994]. The large number of more common mu-
tations and the association of certain alleles with
ethnic populations, such as African Americans
[Macek et al., 1997], has presented challenges
for screening programs attempting to optimize
sensitivity and encompass minority populations.
In a recent statement publication, the American
College of Medical Genetics (ACGM) has iden-
tified several issues including the “differing preva-
lence of individual CFTR mutations among
various ethnic, demographic, and racial groups;
the extreme ethnic heterogeneity of the U.S.
population and its increasing admixture; and the
absence of guidelines for developing an appropri-
ate mutation test panel” [Grody et al., 2001].
According to the literature on European-de-
rived populations, CF is usually estimated to af-
fect as many as 1 in 2,000–3,000 Caucasian
newborns [Farrell, 2000], with a carrier fre-
quency that averages out to a striking 1 in 26
individuals in such populations [Romeo et al.,
1989; Welsh et al., 1995]. Data on derivative
populations in North America indicate a lower
incidence, namely about 1:3,500 [Kosorok et al.,
1996]. However, CF is still the most prevalent
hereditary metabolic disorder detected through
newborn screening [Allen and Farrell, 1996]. CF
neonatal screening, as a method of early diag-
nosis, has been implemented in many regions
using a two-tier method of immunoreactive
trypsinogen (IRT) analysis first and then, if the
level is high, DNA analysis either for the ∆ F508
mutation or multiple CFTR alleles [Farrell,
2000]. Despite the attractiveness of this diag-
nostic strategy, neonatal screening using the two-
tier, IRT/DNA procedure [Gregg et al., 1997]
cannot achieve 100% sensitivity in most regions
when the DNA interrogation is limited to the
∆F508 allele.
The purpose of this investigation was two-
fold. First, a detailed map of the CFTR muta-
tional spectrum across the world was created by
systematic literature survey. Once these muta-
tional arrays were synthesized, trends were
searched for and analyzed on an ethnic, regional,
and global scale. Secondly, we addressed the
impact of ∆F508 on mutational heterogeneity
and the incidence of classical CF. This was done
 WORLDWIDE ANALYSIS OF
in an attempt to quantify a pattern between the
number of mutations present in a population and
the CF incidence and/or the ∆F508 frequency
of that population. Finding a trend and devel-
oping an algorithm with these variables could
allow for the estimation of CF incidence and
mutational array size in regions where current
data sets are incomplete. Together, the results
of these two investigations should provide help-
ful information for those regions that know the
ethnic origin of their population and wish to
implement CF screening programs. Indeed, the
exhaustive survey and analyses we performed can
serve the need for data allowing determination
of an appropriate mutation panel [Grody et al.,
2001] that could be used in regional CF neona-
tal screening programs.
METHODS AND CRITERIA
This study consisted of two components.
Phase I consisted of identification and geo-
graphic mapping of the mutational arrays for
various countries and regions across the world.
Phase II consisted of searching for global trends
in mutation distribution as well as comparison
of published incidence data with the CFTR
mutational distribution patterns. In order to pre-
serve and enhance data integrity during phase
II, a two-tier filtering protocol was developed.
Mutational Array Determination
Phase I consisted of a comprehensive litera-
ture search, dating back to the identification and
cloning of the CFTR gene in 1989 [Riordan et
at., 1989; Rommens et al., 1989; Kerem et al.,
1989] and extending until December 31, 2000.
The OVID MedLine database was used to gather
initial sources for review. The search protocol
used an initial query of “Cystic Fibrosis” with an
AND Boolean string to include the following
subheadings: “Ethnology” OR “Epidemiology”
OR “Etiology” OR “Genetics” OR “Diagnosis.”
All articles identified by these search parameters
underwent an abstract review, and those perti-
nent to this study were selected for further criti-
cal review. All papers that were identified by
these combined search methods were critically
reviewed, and relevant data were pooled into a
centralized database for further analysis. With
regard to the final data presented in this paper,
studies that included greater than 50 CF chro-
mosomes (nc>50) were represented as mutation
CFTR MUTATIONS 577
percentages of the total number of chromosomes
in the associated studies. These results appear
in parentheses next to the mutations for each
region. For those studies that had fewer than 50
chromosomes (nc<50), but more than 20
(nc>20), mutations were ranked numerically in
the order of most common to least common and
rough estimate percentages appear in parenthe-
ses. For those studies that had fewer than 20
chromosomes (nc<20), mutations were only
ranked in the order of most common to least
common; this was done to prevent percentage
skewing that lower n studies are prone to.
When data from multiple studies were appli-
cable to the same population or geographic re-
gion, several steps were taken to prevent biasing
of the true mutation frequencies. First, attempts
were made to determine if there was overlap in
the populations studied. If there was identifiable
overlap, the study that probed for the greatest
number of mutations was used and the other
discarded, unless significant discrepancies or
novel mutations were noted in the reported re-
sults. If there was no overtly detectable overlap,
the methods used for mutational analysis were
reviewed. If a specific technique used was not
able to detect a certain mutation found in a sec-
ond study, the missing mutation was simply
added to the final list with the percent found in
the second study unmodified. If a mutation was
found at different frequencies in different stud-
ies, the frequencies were averaged to compute a
final mutational prevalence. Finally, if a muta-
tion was found in one study, but not another,
even though the methods used allowed for its
detection in both, a 0% was added into the av-
eraging equation. By using these techniques in
calculating the final mutational frequencies,
potential errors were minimized. In preparing the
final mutational arrays for each country or re-
gion, a cutoff value of 0.5% was used as a lower
limit. This threshold was utilized to minimize
the contribution of “private mutations” and se-
lect for the actual analysis of those mutations
that are common throughout distinct popula-
tions and regions. We focused our study on clas-
sical CF to avoid other conditions associated
with CFTR mutations.
After completing the analyses for 1989–2000
in the initial manuscript, we performed a simi-
lar literature survey for calendar year 2001 and
identified 17 more articles. These were exam-
578 BOBADILLA ET AL.
ined thoroughly and found to be confirmatory
of our conclusions, although many of them were
for isolated regions or included only a few pa-
tients, while others reported population screen-
ing information (rather than CFTR mutational
assessment of aggregated CF patients). Most sig-
nificantly, the quantitative CFTR data con-
firmed our findings and recommendations for
Europe and North America. The implications
of the relevant articles are described in either
Table 1 or the text. In addition, the Central and
Eastern European data presented in Table 1 were
available either from abstracts or the collabora-
tive research of one of the authors (M.M.).
Statistical Methodology
Phase II of the study involved an examina-
tion of trends in mutation distribution as a func-
tion of ethnic and geographic factors. We also
assessed potential correlations of the mutation
arrays determined in phase I with the CF inci-
dence levels of all countries that had such data
reliably determined. Comparisons of CFTR al-
lele percentages and CF diagnoses in different
populations were based on standard two sample
tests for equal proportions. This includes the
analyses of Lac St. Jean-Quebec-Toronto, ∆F508
in South America, and G542X in Brittany and
Southern France. Comparisons of average num-
ber of mutations in Bulgaria/Spain/Turkey/
Greece versus other European countries used the
Wilcoxon rank sum test. Comparison of percent
diagnoses in these regions used an exact rank
sum test. These tests are well suited to the small
number of countries investigated in these mini-
analyses. The potential relationships between
incidence, percentage ∆F508, and the number
of mutations were evaluated via linear regres-
sion. The analyses involving number of muta-
tions were restricted to those countries whose
data satisfied the inclusion criterion listed for
the two filters as described below. Furthermore,
when comparing number of mutations to ∆F508
percentage and CF incidence, these latter two
variables were log transformed to help normal-
ize the data. Comparison of ∆F508 percentage
to CF incidence was done using only filter 1, as
there was no need to control for mutational ar-
ray size with this analysis.
Two filters were employed during the linear
regression analysis of phase II. These filters were
designed to ensure the integrity of the data set
used for analysis, and also to eliminate any in-
ternal methodological biases. Filter 1 was de-
signed to remove weak data sets. In order to pass
through this filter, each country study was re-
quired to meet the following three criteria: 1) a
reliable ∆F508 percentage (nc>50), 2) a pub-
lished CF incidence value, and 3) a CF muta-
tion array large enough to generate percentages
of total CF alleles (determined in phase I,
nc>50). The goal of this filter was to remove
regions with incomplete data sets and lower n
studies. This filter was used when linear regres-
sion analysis was done with regard to ∆F508 per-
centage versus incidence. Filter 2 was designed
to remove those studies that were using allele
specific mutation detection methods that could
bias the results. During this filter implementa-
tion, the original methods of mutation detec-
tion were reviewed. Only those studies that used
a gene scanning technique (e.g., single strand
conformation polymorphism (SSCP), denatur-
ing gradient gel electrophoresis (DGGE), etc.),
or those that probed for greater than 200 muta-
tions by comprehensive allele specific methods,
were selected to pass through filter 2. The goal
of this filter was to prevent the downward skew-
ing of mutational arrays size by selecting only
those studies that could, in theory, detect 100%
of the present CFTR mutations, or a large por-
tion thereof. When doing linear regression analy-
sis of the total number of mutations present at
greater than 0.5% versus ∆F508 percentage or
CF incidence, both filters 1 and 2 were employed
and both ∆F508 percentage and CF incidence
were log transformed (Fig. 1).
HISTORICAL PERSPECTIVES AND
STATISTICAL IMPLICATIONS
Worldwide, the ∆F508 allele, which presum-
ably arose from a single origin, ranks as the most
common CFTR mutation [Cystic Fibrosis Ge-
netic Analysis Consortium (CFGAC), 1994].
Although ∆F508 is the most prevalent mutation
for most populations, there are some, such as
certain Jewish groups and many Middle Eastern
populations, in which other mutations show a
higher frequency (Table 1). Examining the
∆F508 allele across European countries illus-
trates how variable the CFTR mutation frequen-
cies are as ancestry varies. Indeed, ∆F508
frequencies vary from a maximum of 100% in
the isolated Faroe Islands of Denmark [Schwartz
 WORLDWIDE ANALYSIS OF CFTR MUTATIONS 579

FIGURE 1. Flow chart of study methods. This figure graphically illustrates the methods used to sort and analyze the
individual studies incorporated into this work. Filter 1 is marked by a country fulfilling all of the following three criteria:
1) having and available ∆F508 percentage; 2) having a published CF incidence value; and 3) having an nc>50. Filter 2
is marked by fulfilling the following criteria: 1) passing filter 1; and 2) mutation identification via a gene scanning methods
(DGGE, SSCP, etc.), or probing greater than 200 allele specific mutation loci.

et al., 1995a] to a minimum of 24.5% in Turkey
(Table 1). There is a clear northwest to south-
east gradient in ∆F508 frequency across Europe
[European Working Group on CF Genetics,
1990; Lucotte et al., 1995].
There are several other CFTR mutations that
are common throughout the entire world. His-
torically, these alleles appear to be the oldest,
other than ∆F508, and therefore have had the
longest time to spread throughout different
populations [European Working Group on CF
Genetics, 1990; Morral et al., 1994; Loirat et al.,
1997]. Mutations that fall into this category in-
clude: 1) G542X, of single origin, associated with
the ancient Phoenicians [Loirat et al., 1997], 2)
N1303K, also of single origin, and linked to an-
cient Mediterranean populations, and 3) G551D,
also of single origin [Cashman et al., 1995], hav-
ing been associated with the ancient Celtic tribes
[Macek et al., 1991].
There are also a multitude of other interest-
ing regions or populations such as Reunion Is-
land, which shows its distinct ancestral founder
effect by having both high rates of G551D and
 580
TABLE 1. Mutational Arrays, Detection Rates and Methods by Region*
Estimated
Projected detection of Number of Number of
Country/ allele two CFTR mutations chromosomes
detectiona mutationsb includedc (max/min)d

BOBADILLA ET AL.
Region Mutation array Reference
Europe
Albania ∆F508 (72.4%) C276X (0.7%) 74.5 55.5 4 270/146 CFGAC [1994]; Macek et al.
G85E (0.7%) R1070Q (0.7%) [2002]
Austria ∆F508 (62.9%) 457TAT→G (1.2%) 76.6 58.7 11 1516/580 Estiville et al. [1997]; Dörk et al.
(total) G542X (3.3%) 2183AA→G (0.7%) [2000]; Macek et al. [2002]
CFTRdele2,3 (2.1%) N1303K (0.6%)
R1162X (1.9%) I148T (0.5%)
R553X (1.7%) R117H (0.5%)
G551D (1.2%)
Austria ∆F508 (74.6%) 2183AA→G (2.4%) 95.3 90.8 8 126 Stuhrmann et al. [1997]
(tyrol) R1162X (8.7%) G551D (1.6%)
G542X (2.4%) R347P (1.6%)
2789+5G→A (2.4%) Q39X (1.6%)
Belarus ∆F508 (61.2%) R553X (0.5%) 75.2 56.6 9 278/188 Dörk et al. [2000]; Macek et al.
G542X (4.5%) R334W (0.5%) [2002]
CFTRdele2,3 (3.3%) R347P (0.5%)
N1303K (3.2%) S549N (0.5%)
W1282X (1.0%)
Belgium ∆F508 (75.1%) 622-1A→C (0.5%) 100.0 100.0 27 1504/522 Cuppens et al. [1993]; Mercier et
G542X (3.5%) G458V (0.5%) al. [1993]; CFGAC [1994];
N1303K (2.7%) 1898+G→C (0.5%) Estivill et al.[1997]
R553X (1.7%) G970R (0.5%)
1717-1G→A (1.6%) 4218insT (0.5%)
E60X (1.6%) 394delTT (0.5%)
W1282X (1.4%) K830X (0.5%)
2183A→G+2184delA (1.2%) E822K (0.5%)
W401X (1.0%) 3272-1G→A (0.5%)
A455E (1.0%) S1161R (0.5%)
3272-26A→G (1.0%) R1162X (0.5%)
S1251N (1.0%) 3750delAG (0.5%)
S1235R (0.8%) S1255P (0.5%)
∆I507 (0.6%)
Bulgaria ∆F508 (63.6%) R75Q (1.0%) 93.0 86.5 21 948/432 Angelicheva et al. [1997];
(total) N1303K (5.6%) 2183AA→G (0.9%) Estivill et al. [1997]; Macek
G542X (3.9%) G1244V+S912L (0.9%) et al. [2002]
R347P (2.2%) G85E (0.9%)
1677delTA (2.1%) 2184insA (0.9%)
R1070Q (1.8%) L88X+G1069R (0.8%)
Q220X (1.2%) 2789+5G→A (0.8%)
3849+10KbC→T (1.1%) G1244E (0.8%)
W1282X (1.0%) 1717-1G→A (0.8%)
2176insC (1.0%) Y919C (0.7%)
G1069R (1.0%)
Bulgaria 1) DF508 4) 1677delTA — — 6 13 Angelicheva et al. [1997]
(ethnic 2) R347P 5) Q493R
Turks) 3) G542X 6) L571S — — 1 30 Angelicheva et al. [1997]
Bulgaria 1) DF508 (100.0%)
(Gypsy)
Croatia ∆F508 (64.5%) G551D (1.1%) 72.5 52.6 5 276 Macek et al. [2002]
G542X (3.3%) 3849+10KbC→T (0.7%)
N1303K (2.9%)
Czech ∆F508 (70.0%) 1898+1G→T (2.0%) 89.6 80.3 10 2196/628 CFGAC [1994]; Estiville et al.
Republic CFTRdele2,3 (5.5%) 2143delT (1.2%) [1997]; Dörk et al. [2000];
G551D (3.8%) R347P (0.8%) Macek et al. [2002]
N1303K (2.9%) 3849+10KbC→T (0.6%)
G542X (2.2%) W1282X (0.6%)
Denmark ∆F508 (87.5%) G542X (0.7%) 92.3 85.2 6 1888/678 CFGAC [1994]; Schwartz et al.
(excluding 394delTT (1.8%) 621+1G→T (0.6%) [1994]; Estiville et al. [1997]
Faroe) N1303K (1.1%) 3659delC (0.6%)
Estonia ∆F508 (51.7%) R117C (1.7%) 80.2 64.3 10 165/80 Estivill et al. [1997]; Klaassen et
394delTT (13.3%) E217G (1.7%) al. [1998]; Macek et al.
S1235R (3.3%) R1066H (1.7%) [2002]
359insT (1.7%) 3659delC (1.7%)
I1005R (1.7%) S1169X (1.7%)
Finland ∆F508 (46.2%) G542X (1.9%) 78.8 62.1 4 132/52 CFGAC [1994]; Kere et al.
394delTT (28.8%) 3372delA (1.9%) [1994]; Estivill et al. [1997]

WORLDWIDE ANALYSIS OF
France ∆F508 (67.7%) 2789+5G→T (0.79%) 79.7 63.6 12 17854/7420 Chevalier-Porst et al. [1994];
(total) G542X (2.94%) 2184delA+2183A→G (0.77%) Estivill et al. [1997]; Claustres
et al. [2000]; Guilloud-Bataille
N1303K (1.83%) G551D (0.74%) et al. [2000]
1717-1G→A (1.35%) 1078delT (0.63%)
W1282X (0.91%) ∆I507 (0.62%)
R553X (0.86%) Y122K (0.59%)
France ∆F508 (75.8%) R297Q (0.8%) 98.7 97.4 18 599/365 Férec et al. [1992]; Scotet et al.
(Brittany) 1078delT (4.0%) R347H (0.8%) [2000]
G551D (3.6%) I1234V (0.8%)
N1303K (3.0%) R553X (0.8%)
R117H (1.7%) 2789+5G→A (0.8%)
3272-26A→G (1.3%) 4005+1G→A (0.7%)

CFTR MUTATIONS
G542X (1.1%) 621+1G→T (0.6%)
1717-1G→A (1.0%) ∆I507 (0.6%)
G1249R (0.8%) W846X (0.5%)
France ∆F508 (70.0%) N1303K (0.8%) 90.4 81.7 16 250 Claustres et al. [1993]
(southern) G542X (6.4%) 3737delA (0.8%)
1717-1G→A (1.6%) R1162X (0.8%)
L206W (1.2%) Y1092X (0.8%)
R334W (1.2%) S945L (0.8%)
∆I507 (1.2%) K710X (0.8%)
2184delA (1.2%) 1078delT (0.8%)
R1158X (1.2%) Y122X (0.8%)

581
(Continued)
 582
TABLE 1. Continued.
Estimated
Projected detection of Number of Number of

BOBADILLA ET AL.
Country/ allele two CFTR mutations chromosomes
Region Mutation array detectiona mutationsb includedc (max/min)d Reference
Germany ∆F508 (71.8%) 1789+5G→A (0.9%) 87.6 76.7 17 5662/1316 Dörk et al. [1992]; Dörk et al.
R553X (2.0%) 3272-26A→G (0.9%) [1994]; Tümmler et al. [1996];
N1303K (1.8%) W1282X (0.7%) Estivill et al. [1997]; Dörk et
G542X (1.2%) 2143delT (0.7%) al. [2000]
R347P (1.2%) 1078delT (0.6%)
CFTRdele2,3 (1.2%) 2183AA→G (0.6%)
3849+10KbC→T (1.0%) 2184insA (0.6%)
G551D (0.9% 3659delC (0.6%)
1717-1G→A (0.9%)
Greece ∆F508 (52.9%) 3272-26A→G (0.8%) 82.2 67.6 22 2097/718 Kanavakis et al. [1995]; Estivill
621+1G→T (5.0%) R1070Q (0.8%) et al. [1997]; Tzetis et al.
G542X (4.1%) W496X (0.7%) [1997]; Macek et al. [2002]
N1303K (3.3%) 621+3A→G (0.7%)
2183AA→G (1.8%) ∆I507 (0.7%)
2789+5G→A (1.7%) W1282X (0.7%)
E822X (1.6%) 574delA (0.7%)
R117H (1.2%) 1677delTA (0.7%)
R334W (1.1%) A46D (0.6%)
R1158X (1.0%) 3120+1G→A (0.6%)
G85E (1.0%) G551D (0.5%)
Hungary ∆F508 (54.9%) W1282X (1.8%) 68.3 46.6 9 1133/976 CFGAC [1994]; Estivill et al.
1717-1G→A (1.9%) G542X (1.7%) [1997]; Macek et al. [2002]
R553X (2.1%) N1303K (1.3%)
Y1092X (1.8%) G551D (1.0%)
S1196X (1.8%)
Ireland ∆F508 (70.4%) G542X (1.0%) 82.1 67.4 7 801/509 CFGAC [1994]; Estivill et al.
G551D (5.7%) 621+1G→T (0.8%) [1994]
R117H (2.4%) 1717-1G→A (0.6%)
R560T (1.2%)
Italy ∆F508 (50.9%) ∆I507 (0.65%) 60.3 36.4 9 3524 Estivill et al. [1997]
(total) G542X (3.1%) W1282X (0.62%)
1717-1G→A (1.6%) Y122K (0.59%)
N1303K (1.4%) G551D (0.53%)
R553X (0.94%)
Italy ∆F508 (47.6%) R553X (1.3%) 87.1 75.9 15 225 Bonizzato et al. [1995]
(Northeast) R1162X (9.8%) 2789+G→A (1.3%)
2183AA→G (9.3%) Q552X (1.3%)
N1303K (4.0%) 621+1G→T (0.9%)
G542X (2.7%) W1282X (0.9%)
711+5G→A (2.7%) 3132delTG (0.9%)
1717-1G→A (2.2%) 2790-2A→G (0.9%)
G85E (1.3%)
Italy ∆F508 (56.4%) 711+1G→T (1.3%) 85.7 73.4 13 660/396 Castaldo et al. [1996]; Castaldo
(southern) N1303K (6.8%) G1244E (1.3%) et al. [1999]
G542X (5.7%) R1185X (1.3%)
W1282X (3.8%) L1065P (1.3%)
1717-1G→A (2.3%) R553X (1.1%)
2183AA→G (1.9%) I148T (0.7%)
4016insT (1.8%)
Latvia 1) DF508 (58.3%) 4) CFTRdele2,3 (2.8%) — — 6 36 Dörk et al. [2000]; Macek et al.
2) 3849+10KbC®T (8.3%) 5) W1282X (2.8%) [2002]
3) N1303K (5.6%) 6) 394delTT (2.8%)
Lithuania ∆F508 (31.0%) N1303K (2.0%) 39.0 15.2 4 94 Dörk et al. [2000]; Macek et al.
R553X (4.0%) CFTRdele2,3 (2.0%) [2002]
Macedonia ∆F508 (54.3%) 711+3A→G (1.0%) 69.2 47.9 12 559/226 Petreska et al. [1998]; Dörk et
G542X (4.2%) 3849G→A (1.0%) al. [2000]; Macek et al.
N1303K (2.0%) 2184insA (0.9%) [2002]
CFTRdele2,3 (1.3%) 457TAT→G (0.7%)
621+1G→T (1.3%) V139E (0.7%)
611-1G→T (1.2%) 1811+1G→C (0.6%)
Netherlands ∆F508 (74.2%) R1162X (0.9%) 86.8 75.3 9 3167/1442 Gan et al. [1995]; Estiville et al.
A455E (4.7%) S1251N (0.9%) [1997]; Collee et al. [1998]
G542X (1.8%) N1303K (0.9%)
1717-1G→A (1.5%) W1282X (0.7%)
R553X (1.2%)
Norway ∆F508 (60.2%) G551D (1.2%) 69.8 48.7 6 410/242 Schwartz et al. [1994]; Estivill

WORLDWIDE ANALYSIS OF
394delTT (4.2%) G542X (0.6%) et al. [1997]
R117H (3.0%) N1303K (0.6%)
Poland ∆F508 (57.1%) CFTRdele2,3 (1.8%) 73.5 54.0 11 4046/1726 CFGAC [1994]; Estivill et al.
3849+10Kb C→T (2.7%) R560T (1.5%) [1997]; Dörk et al [2000];
G542X (2.6%) W1282X (0.7%) Macek et al. [2002]
1717-1G→A (2.4%) ∆I507 (0.5%)
R553X (1.9%) G551D (0.5%)
N1303K (1.8%)
Portugal ∆F508 (44.7%) R334W (0.7%) 49.7 24.7 5 739/454 CFGAC [1994]; Estivill et al.
G542X (1.6%) N1303K (0.7%) [1997]
R1066C (2.0%)
Romania ∆F508 (36.6%) G542X (1.4%) 51.5 26.5 11 224/74 CFGAC [1994]; Estivill et al.

CFTR MUTATIONS
2043delG (2.0%) R553X (1.4%) [1997]; Popa et al. [1997];
W1282X (1.7%) G576X (1.4%) Macek et al. [2002]
1717-2A→G (1.4%) 1898+1G→A (1.4%)
I148T (1.4%) 2183AA→G (1.4%)
621+1G→T (1.4%)
Russia ∆F508 (54.4%) 552insA (0.9%) 70.7 50.0 12 5073/2562 CFGAC [1994]; Estivill et al.
CFTRdele2,3 (5.0%) G542X (0.9%) [1997]; Dörk et al. [2000];
R553X (3.5%) R334W (0.9%) Macek et al. [2002]
2183AA→G (1.3%) 1677delTA (0.8%)
W1282X (1.0%) Y122X (0.5%)
394delTT (1.0%) 1367del5 (0.5%)

583
(Continued)
 584
TABLE 1. Continued.
Estimated
Projected detection of Number of Number of

BOBADILLA ET AL.
Country/ allele two CFTR mutations chromosomes
Region Mutation array detectiona mutationsb includedc (max/min)d Reference
Slovakia ∆F508 (57.3%) CFTRdele2,3 (1.2%) 82.7 68.4 14 908/254 CFGAC [1994]; Estivill et al.
G542X (6.8%) 3849+10KbC→T (1.0%) [1997]; Dörk et al. [2000];
R553X (4.0%) S42F (0.9%) Macek et al. [2002]
N1303K (3.4%) R75X (0.9%)
2143delT (1.8%) G85E (0.9%)
R347P (1.4%) 605insT (0.9%)
W1282X (1.3%) 1898+1G→A (0.9%)
Slovenia ∆F508 (57.8%) R347P (1.1%) 79.7 63.5 16 455/132 CFGAC [1994]; Dörk et al.
2789+5G→A (4.1%) S4X (0.8%) [2000]; Macek et al. [2002]
R1162X (3.2%) 457TAT→G (0.8%)
G542X (1.9%) D192G (0.8%)
Q552X (1.5%) R553X (0.8%)
Q685X (1.5%) A559T (0.8%)
3905insT (1.5%) 2907delTT (0.8%)
CFTRdele2,3 (1.5%) 3667ins4 (0.8%)
Spain ∆F508 (52.7%) G85E (0.8%) 80.2 64.3 21 3608/1356 Chillón et al. [1994]; Casals et
G542X (8.0%) R1066C (0.8%) al. [1997]; Estivill et al. [1997]
N1303K (2.5%) 2789+5G→A (0.7%)
3601-111G→C (2.0%) 2869insG (0.7%)
1811+1.6Kb A→G (1.7%) ∆I507 (0.6%)
R1162X (1.6%) W1282X (0.6%)
711+1G→T (1.3%) L206W (0.5%)
R334W (1.2%) R709X (0.5%)
Q890X (1.0%) K710X (0.5%)
1609delCA (1.0%) 3272-26A→G (0.5%)
712-1G→T (1.0%)
Sweden ∆F508 (66.6%) E60X (0.6%) 85.9 73.8 10 1357/662 Schwartz et al. [1994]; Estivill et
394delTT (7.3%) Y109C (0.6%) al. [1997]; Schaedel et al.
3659delC (5.4%) R117H (0.6%) [1999]
175insT (2.4%) R117C (0.6%)
T338I (1.2%) G542X (0.6%)
Switzerland ∆F508 (57.2%) K1200E (2.1%) 91.3 83.4 9 1268/1173 Estivill et al. [1997];
R553X (14.0%) N1303K (1.2%) Hergersberg et al. [1997]
3905insT (9.8%) W1282X (1.1%)
1717-1G→A (2.7%) R347P (0.6%)
G542X (2.6%)
Ukraine ∆F508 (65.2%) CFTRdele2,3 (1.1%) 74.6 55.7 6 1055/580 Estivill et al. [1997]; Dörk et al.
R553X (3.6%) G551D (1.8%) [2000]; Macek et al. [2002]
N1303K (2.4%) W1282X (0.5%)
United ∆F508 (75.3%) 621+1G→T (0.93%) 81.6 66.6 5 19622/9815 Schwartz et al. [1995b];
Kingdom G551D (3.1%) 1717-1G→A (0.57%) Estivill et al. [1997]
(total) G542X (1.7%)
United ∆F508 (56.6%) 621+1G→T (1.8%) 69.1 47.7 7 456 CFGAC [1994]
Kingdom G551D (3.7%) R117H (1.5%)
(N. Ireland) R560T (2.6%) ∆I507 (0.9%)
G542X (2.0%)
United ∆F508 (19.2%) 621+2T→C (3.8%) 84.4 71.2 11 52 Malone et al. [1998]
Kingdom Y569D (15.4%) 2184insA (3.8%)
(Pakistani) Q98X (11.5%) R560S (1.9%)
1525-1G→A (9.6%) 1898+1G→T (1.9%)
296+12T→C (7.7%) R709X (1.9%)
1161delC (7.7%)
United ∆F508 (71.3%) 1717-1G→A (1.0%) 86.4 74.6 9 1236/730 Shrimpton et al. [1991];
Kingdom G551D (5.5%) 621+1G→T (0.6%) Gilfillan et al. [1998]
(Scotland) G542X (4.0%) ∆I507 (0.6%)
R117H (1.4%) R560T (0.6%)
P67L (1.4%)
United ∆F508 (71.6%) 1717-1G→A (1.1%) 98.7 97.4 17 183 Cheadle et al. [1993]
Kingdom 621+1G→T (6.6%) 3659delC (0.5%)
(Wales) 1898+1G→A (5.5%) R117H (0.5%)
G542X (2.2%) N1303K (0.5%)
G551D (2.2%) E60X (0.5%)
1078delT (2.2%) S549N (0.5%)
R1283M (1.6%) 3849+10KbC→T (0.5%)
R553X (1.1%) 4016insT (0.5%)
∆I507 (1.1%)
Yugoslavia ∆F508 (68.9%) 3849G→A (1.0%) 82.2 67.6 11 709/398 Dabovic et al. [1992]; Estivill et

WORLDWIDE ANALYSIS OF
G542X (4.0%) N1303K (0.8%) al. [1997]; Macek et al.
R1162C (3.0%) 525delT (0.5%) (submitted for publication)
457TAT→G (1.0%) 621+1G→T (0.5%)
I148T (1.0%) G551D (0.5%)
Q552X (1.0%)
Middle East/Africa
Algeria 1) DF508 (20.0%) 4) 1812-1G®A (5.0%) — — 5 20 Loumi et al. [1999]
2) N1303K (20.0%) 5) V754M (5.0%)
3) 711+1G®T (10.0%)
Jewish W1282X (48.0%) 3849+10KbC→T (6.0%) 95.0 90.3 6 261 Kerem et al. [1995]
(Ashkenazi) ∆F508 (28.0%) N1303K (3.0%)
G542X (9.0%) 1717-1G→A (1.0%)

CFTR MUTATIONS
Jewish 1) N1303K — — 1 6 Kerem et al. [1995]
(Egypt)
Jewish 1) Q359K/T360K — — 1 8 Kerem et al. [1995]
(Georgia)
Jewish 1) DF508 2) 405+1G®A — — 2 11 Kerem et al. [1995]
(Libya)
Jewish 1) DF508 (72.0%) 3) D1152H (6.0%) — — 3 33 Kerem et al. [1995]
(Morocco) 2) S549R (6.0%)
Jewish ∆F508 (35.0%) W1282X (2.0%) 43.0 18.5 4 51 Shoshani et al. [1992]
(Sepharadim) G542X (4.0%) S549I (2.0%)

585
(Continued)
 586
TABLE 1. Continued.
Estimated
Projected detection of Number of Number of
Country/ allele two CFTR mutations chromosomes
detectiona mutationsb includedc (max/min)d

BOBADILLA ET AL.
Region Mutation array Reference
Jewish 1) 405+1G®A (48.0%) 3) W1282X (17.0%) — — 4 23 Kerem et al. [1995]
(Tunisia) 2) DF508 (31.0%) 4) 3849+10KbC®T (4.0%)
Jewish 1) G85E 4) G542X — — 6 10 Kerem et al. [1995]
(Turkey) 2) DF508 5) 3849+10KbC®T
3) W1282X 6) W1089X
Jewish (Yemen) None — — 0 5 Kerem et al. [1995]
Lebanon 1) DF508 (35.0%) 6) 4096-28G®A (2.5%) — — 9 40 Desgeorges et al. [1997]
2) W1282X (20.0%) 7) 2789+5G®A (2.5%)
3) 4010del4 (10.0%) 8) M952I (2.5%)
4) N1303K (10.0%) 9) E672del (2.5%)
5) S4X (5.0%)
Reunion ∆F508 (52.0%) 1717-1G→A (0.7%) 90.4 81.7 9 138 Cartault et al. [1996]
Island Y122X (24.0%) G542X (0.7%)
3120+1G→A (8.0%) A309G (0.7%)
A455E (2.2%) 2789+5G→A (0.7%)
G551D (1.4%)
Saudi North: 3) H139L — — North 1 49 families El-Harith et al. [1997];
Arabia 1) 1548delG 4) L1177X Central 3 Kambouris et al. [1997];
Central: 5) DF508 South 4 Banjar et al. [1999]
1)I1234V 6) 3120+1G®A West 9
2)1548delG 7) 425del42 East 6
3)DF508 8) R553X
South: 9) N1303K
1) I1234V East:
2) 1548delG 1) 3120+1G®A
3) 711+1G®T 2) H139L
4) 3120+1G®A 3) 1548delG
West: 4) DF508
1) I1234V 5) S549R
2) G115X 6) N1303K
Tunisia ∆F508 (17.6%) G85E (2.6%) 58.7 34.5 11 78 Messaoud et al. [1996]
G542X (8.9%) W1282X (2.6%)
711+1G→T (7.7%) Y122X (1.3%)
N1303K (6.4%) T665S (1.3%)
2766del8NT (6.4%) R47W+D1270N (1.3%)
R1066C (2.6%)
Turkeye ∆F508 (24.5%) 1066L (1.3%) 80.6 65.0 36 1067/670 Yilmaz et al. [1995]; Estivill et al.
1677delTA (4.1%) E822X (1.3%) [1997]; Onay et al. [1998];
2789+5G→A (3.9%) 2183+5G→A+2184insA (1.3%) Macek et al. [2002]
2181delA (3.8%) D110H (0.8%)
R347H (3.6%) P1013L (0.8%)
N1303K (2.9%) 3172delAC (0.8%)
621+1G→T (2.6%) 1259insA (0.8%)
G542X (2.6%) M1028I (0.8%)
 E92K (2.6%) 4005+1G→A (0.7%)
A96E (2.6%) W1282X (0.7%)
M152V (2.6%) I148T (0.6%)
2183AA→G (2.5%) R1162X (0.6%)
296+9A→T (1.6%) D1152H (0.6%)
2043delG (1.4%) W1098X (0.6%)
E92X (1.4%) E831X (0.6%)
K68N (1.4%) W496X (0.6%)
G85E (1.3%) F1052V (0.5%)
R1158X (1.3%) L571S (0.5%)
United Arab S549R (61.5%) ∆F508 (26.9%) 88.4 78.1 2 86/52 Frossard et al. [1988];
Emirates Frossard et al. [1999]
North/Central/South Americas
Argentina ∆F508 (58.6%) N1303K (1.8%) 69.1 47.7 5 326/228 CFGAC [1994]; Chertkoff et al.
W1282X (3.9%) 1717-1G→A (0.9%) [1997]
G542X (3.9%)
Brazilf ∆F508 (47.7%) W1282X (1.3%) 66.8 44.6 10 820/500 CFGAC [1994]; Cabello et al.
(total) G542X (7.2%) G85E (1.3%) [1999]; Raskin et al. [1999];
R1162X (2.5%) R553X (0.7%) Bernardino et al. [2000]
R334W (2.5%) L206W (0.6%)
N1303K (2.4%) 2347delG (0.6%)
South East: >∆F508, G542X
South: >N1303K

Brazil ∆F508 (31.7%) N1303K (2.5%) 42.5 18.1 3 120 Parizotto and Bertuzzo [1997]

WORLDWIDE ANALYSIS OF
(Sao Paulo) G542X (8.3%)
Canada ∆F508 (59.0%) G542X (0.5%) 98.5 97.0 13 381/200 Rozen et al. [1992];
(Lac St. Jean) 621+1G→T (24.3%) N1303K (0.5%) De Braekeleer et al. [1998]
A445E (8.2%) Q890X (0.5%)
Y1092X (1.2%) S489X (0.5)
711+1G→T (1.0%) R117C (0.5%)
I148T (1.0%) R1158 (0.5%)
G85E (0.8%)
Canada ∆F508 (71.4%) ∆I507 (1.3%) 90.9 82.6 7 77 Rozen et al. [1992]
(Quebec City) 711+1G→T (9.1%) Y1092X (1.3%)
621+1G→T (5.2%) N1303K (1.3%)
A455E (1.3%)

CFTR MUTATIONS
Canada ∆F508 (70.9%) W1282X (0.9%) 82.0 67.2 10 632 Kristidis et al. [1992]
(Toronto) G551D (3.1%) R117H (0.9%)
G542X (2.2%) 1717-1G→A (0.6%)
621+1G→T (1.3%) R560T (0.6%)
N1303K (0.9%) ∆I507 (0.6%)
Chile ∆F508 (29.2%) R553X (4.2%) 33.4 11.2 2 72 Rios et al. [1994]
Columbia 1) DF508 (35.4%) 3) N1303K (2.1%) — — 4 48 Restrepo et al. [2000]
2) G542X (6.3%) 4) W1282X (2.1%)
Ecuador 1) DF508 (25%) — — 1 20 Paz-y-Mino et al. [1999]

587
(Continued)
 588
TABLE 1. Continued.
Estimated
Projected detection of Number of Number of
Country/ allele two CFTR mutations chromosomes
detectiona mutationsb includedc (max/min)d

BOBADILLA ET AL.
Region Mutation array Reference
Mexico ∆F508 (41.6%) G551S (0.5%) 75.5 57.0 35 374/194 Orozco et al.[1993]; Villalobos-
G542X (5.6%) 1078delT (0.5%) Torres et al. [1997]; Liang et al.
∆I507 (2.5%) Y1092X (0.5%) [1998]; Orozco et al. [2000]
S549N (1.9%) R117H (0.5%)
N1303K (1.7%) G85E (0.5%)
R75X (1.5%) 1716G→A (0.5%)
406-1G→A (1.5%) W1204X (0.5%)
I148T (1.5%) W1098C (0.5%)
3849+10KbC→T (1.5%) 846delT (0.5%)
621+1G→T (1.2%) P750L (0.5%)
2055del9→A (1.0%) V754M (0.5%)
935delA (1.0%) R75Q (0.5%)
I506T (1.0) W1096X (0.5%)
3199del6 (1.0%) L558S (0.5%)
2183AA→G (1.0%) 4160insGGGG (0.5%)
G551D (0.5%) 297-1G→A (0.5%)
R553X (0.5%) H199Y (0.5%)
1924del7 (0.5%)
United States ∆F508 (68.6%) R553X (0.9%) 79.7 63.5 10 25048 Cystic Fibrosis Foundation
(total) G542X (2.4%) 621+1G→T (0.9%) [1998]
G551D (2.1%) 1717-1G→A (0.7%)
W1282X (1.4%) 3849+10KbC→T (0.7%)
N1303K (1.3%) R117H (0.7%)
United States ∆F508 (48.0%) S1255X (1.4%) 77.3 59.8 16 160/148 Carles et al. [1996]; Macek et al.
(African 3120+1G→A (12.2%) 444delA (0.7%) [1997]; Dörk et al. [1998];
American) 2307insA (2.0%) R334W (0.7%) Friedman et al. [1998]
A559T (2.0%) ∆I507 (0.7%)
R553X (2.0%) 1717-1G→A (0.7%)
∆F311 (2.0%) G542X (0.7%)
G480C (1.4%) S549N (0.7%)
405+3A→C (1.4%) G551D (0.7%)
United States 1) L1093P — — 1 2 Yee et al. [2000]
(Cherokee)
United States Non-French: French: Non- Non- Non- Non- Bayleran et al. [1996]
(Maine) ∆F508 (82.0%) ∆F508 (58%) French: French: French: French:
G542X (2.6%) 711+1G→T (8.3%) 95.3 90.8 11 191
G551D (2.6%) I148T (4.2%) French: French: French: French:
N1303K (2.1%) A455E (4.2%) 80.3 64.5 8 72
R560T (1.0%) 1717-1G→A (1.4%) Total:
621+1G→T (1.0%) G85E (1.4%) 263
711+1G→T (1.0%) 621+1G→T (1.4%)
R117H (1.0%) Y1092X (1.4%)
1717-1G→A (1.0%)
G85E (0.5%)
W1282X (0.5%)
United States ∆F508 (46.0%) R334W (1.6%) 58.5 34.2 7 129 Grebe et al. [1994]
(SW Hispanic) G542X (5.4%) W1282X (0.8%)
3849+10KbC→T (2.3%) R553X (0.8%)
R1162X (1.6%)
United States 1) R1162X — — 3 17 Mercier et al. [1992]
(SW Native 2) D648V
American) 3) G542X
United States 1) R1162X 3) G542X — — 4 16 Mercier et al. [1994]
(Zuni Pueblo) 2) 3849+10KbC®T 4) D648V
Venezuela ∆F508 (29.6%) G542X (3.7%) 33.3 11.1 2 54 Restrepo et al. [2000]
Other Regions
Australia ∆F508 (76.9%) 621+1G→T (1.1%) 88.7 78.7 8 761/464 CFGAC [1994]
G551D (4.5%) N1303K (0.9%)
G542X (2.8%) W1282X (0.6%)
R553X (1.3%) R117H (0.6%)
East Asia 1) 1898+1G®T 2) 1898+5G®T — — 2 28 Suwanjutha et al. [1998]
Hutterite 1) M1101K (69.0%) 2) DF508 (31.0%) — — 2 32 Zielenski et al. [1993]
Brethren
New Zealand ∆F508 (78.0%) N1303K (1.9%) 87.4 76.4 5 636 CFGAC [1994]
G551D (4.4%) 621+1G→T (1.1%)
G542X (2.0%)

WORLDWIDE ANALYSIS OF
*This table presents the mutation panels for all regions investigated in this study. Countries and regions are sorted by geographic location and appear in alphabetical order within their
geographical divisions. Overall mutation detection rates, as well as theoretical projections of screening diagnosis rates, appear in columns 3 and 4. Those regions with an nc<50 appear in italics.
It should be noted that the R117H mutation is only associated with classical CF when associated with the 5T variation. Therefore, identification of the R117H mutation should prompt investigation
for the 5T variant as well, R117H (IVS8-5T), and this combination should be regarded as a single CF causing allele.
a
This column presents the total percent of CF chromosomes that have been completely genotyped with identifiable mutations.
b
Using data from column 3, the estimated CF diagnosis based solely on genetic analysis was calculated. Assuming Hardy-Weinberg equilibrium.
c
Listed here are the total number of mutations that account for the percentages reported in columns 3 and 4.
d
This column gives the number of chromosomes that the arrays and detection/diagnosis rates are based on. They are presented in a maximum/minimum format. In those regions where only one
study was performed, only the absolute chromosome number appears, as there is no possibility of sample overlap.
e
Onay et al. [2001] confirm the aggregated database calculated from previous publications, revealing nearly identical percentages and strengthening conclusions regarding CFTR heterogeneity
in Turkey.
f
Cabello et al. [2001] also reported 3120+G→A in five patients with African ancestry living in Rio de Janeiro.

CFTR MUTATIONS
589
590 BOBADILLA ET AL.
3120+1G→A. This correlates to the 27% Eu-
ropean and 40% African origins of the original
founders of this isolated island [Cartault et al.,
1996].
A theoretical maximum number of CF chro-
mosomes analyzed in this study is 119,257, as-
suming 0% overlap in regions with multiple
studies where overlap could not be definitively
excluded. The absolute minimum total number
of distinct CF chromosomes reviewed in this
study consisted of 72,431; this number is derived
assuming 100% chromosome overlap in regions
where multiple studies have been conducted.
Table 1 presents a listing of all regions that
had CFTR genotype information available. In
those regions with a low number of chromo-
somes, less than 50 (nc<50), the results appear
in italics. These data were compiled and the rela-
tive number of CFTR alleles detected were de-
termined on a regional basis. The detection rates
ranged from a maximum of 100% in Belgium and
98.7% in Brittany, France, and Wales, to a mini-
mum of 33.3% in Venezuela. When these results
are ranked, seven regions had detection rates of
95% or greater, using mutations present at
greater than 0.5% in the CF patient pool. By
decreasing the threshold to 90%, we found that
six more regions could be included, for a total of
13. In addition, 21 more regions were identified
with detection rates above 80%. These results
listed in Table 1 are estimates based solely on
those mutations that have been identified at
0.5% or greater. Actual detection rates could be
higher; however, in most cases, this would re-
quire the screening of many more mutations
present at very low prevalence.
European Spectrum
Central, northern, western, and northeastern
Europe (including Austria, Belarus, Belgium,
Denmark, Estonia, Finland, France, Germany,
Lithuania, the Netherlands, Norway, Poland,
Russia, Sweden, Switzerland, and the Ukraine)
show a large degree of homogeneity among
CFTR mutations (Table 1). On average, 10.2
(95% CI, 7.4–13.0) mutations per country ac-
count for 78.9% (95% CI, 72.1–85.7) of the to-
tal number of CF chromosomes in these regions.
This is largely attributable to the high prevalence
of ∆F508 in these regions. Spain, Bulgaria,
Greece, and Turkey have some of the most di-
verse mutational arrays in Europe. On average,
25.0 (95% CI, 17.7–32.3) mutations account for
84.0% (95% CI, 77.9–90.1) of the CF alleles in
these regions. This is most likely due to their
geographic situation, serving as historic “gate-
ways” into Europe from the Middle East, Africa,
and associated waterways.
We performed a comparative analysis of these
four European countries (Turkey, Bulgaria,
Greece, and Spain) that are situated with coastal
territories that enabled them to function as
“gateways” to the continent over long periods of
ancient Neolithic migration. This revealed a sig-
nificantly higher total number of mutations
present in the gateway countries when evalu-
ated against the remaining European countries.
When comparing the number of mutations
present in this group of gateway countries ver-
sus the others (25.0 mutations vs. 10.2 muta-
tions), a statistically significant difference was
observed with a p-value = 0.001; however, the
total percentage of CFTR mutations identified
is not significantly different (p = 0.48). While it
may be possible to account for the 5.1% detec-
tion discrepancy by evoking a theory of multiple
mutations present at a very low frequency (on
average, 15 mutations at ∼0.34% each), it seems
unlikely that this is the case due to the vast varia-
tion in mutation array size (2.5 times larger in
the gateway regions) and the exceedingly well
investigated genomes of the non-gateway na-
tions. This discrepancy is more likely explained
by the presence of a few unidentified mutations
present at relatively higher frequency and/or
rounding artifact in the non-gateway regions. In
all, these data tend to support the concept that
these countries did indeed serve as “gateways”
into Europe. Over the centuries, CFTR muta-
tions have fluxed into and out of Europe through
these regions, and the effects of this migration
can be seen in the high mutational heterogene-
ity of the current CF patient population. This
diverse panel of CFTR mutations further com-
plicates the ability of molecular tests to detect
CF patients confidently with any screening pro-
gram. Therefore, these regions are prime candi-
dates for the implementation of screening
protocols that can detect a wide range of unre-
lated mutations.
G542X is most common in the Mediterranean
regions of Europe and Africa. Italy and France
(Table 1) show a gradient of diffusion that is seen
commonly across southern Europe. Regions such
 WORLDWIDE ANALYSIS OF
as extreme northwest France (Brittany) have a
greater than five-fold decrease in this mutation
frequency when compared to the Mediterranean
coastal part of southern France (Brittany, 1.1%;
Southern France, 6.4%; p = 0.001). Spain also
displays this trend (Mediterranean Coastal
Spain, 14.4%; all other regions of Spain, 5.7%; p
<0.001) [Casals et al., 1993]. This gradient of
decreasing G542X prevalence can be seen on
both the international and intranational levels
as the distance from the Mediterranean Sea in-
creases. Some countries, however, like Hungary,
Slovakia, and Austria, tend to show a more
Mediterranean mutation panel. This can be par-
tially attributed to the retrograde colonization
of many portions of Europe via waterways like
the Danube river [Serre et al., 1990]. Early colo-
nization of Europe via the branching waterways
carried these Mediterranean mutations up into
the continent of Europe, where they now are
present at unexpectedly higher incidences.
G542X has been implicated as a mutation that
was introduced into the Mediterranean region
by the migration of Phoenicians [Loirat et al.,
1997]. Across Europe, G542X is found in sig-
nificantly higher proportions in countries, and
in regions of countries, which border the Medi-
terranean Sea (Table 1). Not surprisingly, G542X
has its highest rates of prevalence in the south
of Spain and in the north of Africa (South Spain,
14.4%; Tunisia, 8.9%). Interestingly enough,
these two regions correspond to two major an-
cient Phoenician cities, Carthagène and Carthage,
respectively [Loirat et al., 1997]. The genetic re-
sults of the introduction of this mutation into such
a busy trade and trafficking center as the Medi-
terranean can still be observed today. When one
studies CF chromosomes in those populations
of the New World that were heavily influenced
by such countries as Spain and Italy, the G542X
mutation frequencies are virtually identical. The
mutation N1303K is another CFTR allele that
has a similar distribution patterns as G542X, and
may also have been introduced via the Mediter-
ranean route (Table 1).
Another mutation that seems to have a clear
history is the G551D allele. This allele has char-
acteristically been associated with populations
that are of a Celtic descent, and is seen at its
highest prevalence in regions such as Ireland and
Brittany. This mutation has also diffused across
the remainder of Europe, and can be seen in di-
CFTR MUTATIONS 591
minishing frequencies as one moves to the south-
ern and the eastern portions of Europe. One ini-
tially puzzling phenomenon uncovered by CFTR
mutation analysis is the relatively high incidence
of this mutation in the Czech Republic (3.8%,
Table 1). In order to explain this variance, it is
necessary to analyze the migration of early Celtic
and Germanic tribes and the development of the
Roman Empire. In the Neolithic period, Celts
once inhabited a large band of land spanning
across much of western, central and eastern
Europe, just north of the Alps. During the last
century BCE, both the Roman Empire and the
Germanic tribes expanded and displaced or ab-
sorbed Celtic tribes. This expansion eventually
resulted in the expulsion of the Celts into what
are now present-day Ireland, UK, and northwest
France. However, a few tribes (e.g., the Boii)
maintained a relatively small region just north
of the Alps, and assimilated with incoming popu-
lations [James, 1993]. This region was eventu-
ally known as Bohemia, which now corresponds
to the Czech Republic and some portions of
southeast Germany and northern Austria
[Macek et al., 1991]. The effects of this move-
ment can be seen today by the nearly three times
higher than expected frequency of G551D in the
Czech Republic.
W1282X is a mutation of single origin that
has historically been associated with the
Ashkenazi Jews. This mutation’s frequency has
been amplified to almost double that of the
∆F508 mutation in this distinct population
[Kerem et al., 1995]. As with all other popula-
tion specific mutations, the W1282X mutation
is seen within the mutational arrays of the mul-
titude of countries that have had a significant
Ashkenazi Jewish influence.
394delTT, referred to as the “Nordic muta-
tion” [Schwartz et al., 1994], has been found to
be present at a high frequency in the countries
bordering the Baltic Sea and associated water-
ways (Sweden, Norway, Denmark, Finland, Es-
tonia, Russia, etc.). 394delTT is associated
almost exclusively with a single chromosomal
haplotype, which suggests a single origin, cen-
tered in this region [Schwartz et al., 1994]. Many
of the present day populations in this region have
a common ancestry, and therefore, this muta-
tion is rare outside these populations.
Another CFTR mutation that is common in
central and eastern Europe is the CFTR dele2,3
592 BOBADILLA ET AL.
(21kb) [Dörk et al., 2000]. To date it has been
found in many regions of Europe with a strong
Eastern Slavic origin, including the Czech Re-
public, Russia, Belarus, Austria, Germany, Po-
land, Slovenia, Ukraine, and Slovakia. It has also
been found in a few other regions of Europe, but
is absent in the vast majority of the remaining
countries.
North American Spectrum
Table 1 also shows the data from North
America. In the United States, the CFTR alle-
les reflect the geographic origin of the current
population with a strong relationship to Euro-
peans. The results from analysis of 25,048 chro-
mosomes indicate that there are at least 10
CFTR alleles found at greater than 0.5% fre-
quency in CF chromosomes of patients resid-
ing in the United States. These 10 mutations
account for 79.7% of the identified CFTR mu-
tations. The top 10 list for the United States
(Table 1) includes five CFTR alleles found in
populations with distinct ethnic ancestries, i.e.,
G542X, G551D, W1282X, N1303K, and
3849+10KbC→T.
The CFTR mutation 3120+1G→A is the
second most prevalent allele in African Ameri-
can populations of CF patients and is second
only to the ∆F508 mutation, which presumably
emerged via ethnic admixture with Caucasians
(Table 1). This mutation has also been found
in Native African and Arab populations [El-
Harith et al., 1997; Kambouris et al., 1997;
Banjar et al., 1999]. For instance, CF chromo-
somes from black CF patients of South Africa
show an estimated frequency of 46%, making
3120+1G→A the most common mutation in
that population where ∆F508 was not found
[Goldman et al., 2001]. With only a few ex-
ceptions—mainly regions that had early con-
tributions of African founder genes—this
mutation is rarely seen outside the African mu-
tation array [Macek et al., 1997]. 3120+1G→A
is a prime example of the impact that a single
rare mutation can have on the efficiency of a
screening program. This mutation, which is tra-
ditionally isolated to African descended gene
pools, will account for over 12% of the total
CFTR alleles in African American CF patients,
and overlooking it when screening newborns
for CF could lead to lower sensitivity and po-
tentially delayed diagnosis for many of these
patients. The top 10 list for the United States
(Table 1) clearly does not include this muta-
tion, further stressing the importance of com-
plete characterization of a population prior to
implementing multi-mutation screening pro-
grams. We include 3120+1G→A in our rec-
ommended panel of mutations for the United
States in 2001 (Table 2).
Eastern Canada shows a wide variability in
CF-causing mutations spread over a relatively
small geographic region (Table 1). With an ap-
parent average incidence of 1 per 914 births, the
Lac St. Jean (LSJ) region of Quebec Canada has
the highest CF incidence of all the populations
assessed in this study [Rozen et al., 1992; De
Braekeleer et al., 1998]. LSJ also presents with a
relatively low ∆F508 level (59%), a high
621+1G→T prevalence (24.3%), and the sec-
ond highest CF allele detection rate identified
in this study (98.5%). Historically, the LSJ re-
gion of Canada was isolated geographically, and
had a small founder population [Rozen et al.,
1992]. These factors most likely account for the
large deviation noted when compared to other
nearby Canadian cities.
When compared to Toronto and Quebec City,
LSJ has a statistically lower ∆F508 percentage
(p =0.002 for Toronto vs. LSJ; p = 0.047 for
Quebec vs. LSJ; Quebec vs. Toronto p = 0.93)
and a statistically higher 621+1G→T percent-
age (p = 0.00001 for Toronto vs. LSJ; p =
0.00001 for Quebec vs. LSJ; Quebec vs. Toronto
p = 0.12). The total percentage of CF muta-
tions identified is also higher in LSJ compared
to Toronto or Quebec City (98.5% vs. 82.0% (p
= 0.00001) and 90.9% (p = 0.026), respec-
tively). The investigation of Toronto utilized a
25 mutation reverse dot blot panel, yielding a
total detection rate of 82.0% [Kristidis et al.,
1992]; and a study by Rozen et al. [1992] com-
pared LSJ and Quebec with a 10 mutation panel.
Results of this study revealed mutation identifi-
cation rates of 93% and 91%, respectively. Newer
techniques such as DDGE have been applied to
the LSJ region recently [De Braekeleer et al.,
1998], and this has allowed for the statistically
significant increase in mutation detection rates
identified in this study. LSJ serves a prime ex-
ample of how thorough characterization of mu-
tational diversity can help increase overall
population detection rates, and strengthen po-
tential screening panels.
 WORLDWIDE ANALYSIS OF CFTR MUTATIONS 593

TABLE 2. Ideal Recommended CFTR Mutation Screening Panel for 2001 Neonatal Screening in the USA*
Location Estimated
Mutation in CFTRa percentageb Reason for inclusion
DF508 Exon 10 68.6% CFF registry, >1%, Pan-European
G542X Exon 11 2.4% CFF registry, >1%, Mediterranean
G551D Exon 11 2.1% CFF registry, >1%, Celtic
W1282X Exon 20 1.4% CFF registry, >1%, Ashkenazi Jew
N1303K Exon 21 1.3% CFF registry, >1%, Mediterranean
R553X Exon 11 0.9% CFF registry, >0.5%, Hispanic
621+1G®T Intron 4 0.9% CFF registry, >0.5%, multi-ethnic
1717-1G®A Intron 10 0.7% CFF registry, >0.5%, Italian
3849+10KbC®T Intron 19 0.7% CFF registry, >0.5%, Hispanic
R117Hc Exon 4 0.7% CFF registry, >0.5%
1898+1G→T Intron 12 0.4% CFF registry, >0.1%, East Asian
DI507 Exon 10 0.3% CFF registry, >0.1%, Hispanic
2789+5G®A Intron 14b 0.3% CFF registry, >0.1%
G85E Exon 3 0.3% CFF registry, >0.1%
R347P Exon 7 0.2% CFF registry, >0.1%
R334W Exon 7 0.2% CFF registry, >0.1%, multi-ethnic
R1162X Exon 19 0.2% CFF registry, >0.1%, multi-ethnic
R560T Exon 11 0.2% CFF registry, >0.1%
3659delC Exon 19 0.2% CFF registry, >0.1%
A455E Exon 9 0.2% CFF registry, >0.1%
2184delA Exon 13 0.1% CFF registry, >0.1%
S549N Exon 11 0.1% CFF registry, >0.1%, multi-ethnic
711+1G®T Intron 5 0.1% CFF registry, >0.1%
R75X Exon 3 0.2% Hispanic
406-1G→A Intron 3 0.2% Hispanic
I148T Exon 4 0.2% Hispanic, French
2055del9→A Exon 13 0.1% Hispanic
935delA Exon 6b 0.1% Hispanic
I506T Exon 10 0.1% Hispanic
3199del6 Exon 17a 0.1% Hispanic
2183AA→G Exon 13 0.1% Hispanic
3120+1G®A Intron 16 1.5% African American, Arabian
2307insA Exon 13 0.2% African American
A559T Exon 11 0.2% African American
∆F311 Exon 7 0.2% African American
G480C Exon 10 0.2% African American
405+3A→C Intron 3 0.2% African American
S1255X Exon 20 0.2% African American
L1093P Exon 17b Undetermined Native American
D648V Exon 13 Undetermined Native American
I1234V Exon 19 Undetermined Arabian linkage
S549R Exon 11 Undetermined Arabian linkage
1898+5G→T Intron 12 Undetermined East Asian linkage
CFTRdele2,3 Exons 2,3 Undetermined Eastern European linkage (Slavic)
Y1092X Exon 17b Undetermined French linkage
394delTT Exon 3 Undetermined Nordic linkage
Y569D Exon 12 Undetermined Pakistani linkage
3905insT Exon 20 Undetermined Swiss linkage (also: Amish, Acadian, Mennonite)
1898+1G®A Intron 12 Undetermined Welsh linkage
M1101k Exon 17b Undetermined Hutterite ancestry
*This table presents the top 50 mutations in the USA based on the Cystic Fibrosis Foundation CF Registry data from 1997
[Cystic Fibrosis Foundation, 1998], and data generated during our investigation. Mutations that are highly prevalent in certain
ethnic populations are included to help boost the overall detection rate and help guard against internal screening biases. Those
mutations that are bolded are included in the ACOG/ACMG recommendations; note that 1078delT was excluded from the list
above because of its low frequency in the USA [Cystic Fibrosis Foundation, 1998].
a
This column indicates the location of the mutation within the introns and exons of the CFTR gene.
b
This column presents the estimated contribution of the individual mutations to the total US CF mutation pool. Those mutations
listed from the CFF Registry are absolute percentages based on the 1997 CF population. For those mutations assigned to a
particular ethnic population, values were estimated based on the prevalence of the mutation within the group and the fraction
that that group contributes to the total US population, as listed by the 2000 census [US Census Bureau, 2000b].
c
The mutation R117H is only associated with classical CF when associated with the 5T variation; therefore, identification of the
R117H mutation should prompt investigation for the 5T variant as well, R117H(IVS8-5T).
594 BOBADILLA ET AL.
Central and South American Spectrum
CFTR mutation characterization in the Cen-
tral and South American countries to date has
been quite sparse. Generally, there have been
very few studies that examined the CFTR mu-
tation spectrum in Central and South America.
In those studies that have assessed this region of
the world, the results were limited, and a major-
ity of mutations went unidentified. During the
course of this study, we were able to generate
enough data to examine CFTR mutational dis-
tributions across South America, as shown in
Table 1. For comparative analysis, South
America was divided into “mountainous” and
“highland” regions. By dividing South America
arbitrarily into two components, the west coast
“mountainous” (Colombia, Ecuador, and Chile)
region and east coast “highlands” (Venezuela,
Brazil, and Argentina) region, we found a sig-
nificant (p=0.00001) difference in the ∆F508
frequencies, namely 29.9% (nc=140 chromo-
somes) vs. 45.3% (nc=782 chromosomes), re-
spectively. This variation may be attributable to
early colonization patterns of South America.
The east coast highland nations of South
America typically have a greater tie to European
colonization, with major contributions from Por-
tuguese, Spanish, and Jewish peoples. Not sur-
prisingly, the mutational arrays of the “highland”
region mimic those of the major southern Euro-
pean exploratory nations. In those regions that
are isolated by the Andes mountain ranges (Co-
lumbia, Ecuador, and Chile), CFTR allele
characterization is more difficult, despite several
efforts (see Table 1 references). This is presum-
ably due to the greater association with
Amerindian gene pools and their typical CFTR
mutations. This hypothesis is further strength-
ened by the relative absence of the ∆F508 mu-
tation from the mutations listed for the three
Native American tribes that have thus far been
studied (Table 1).
REGRESSION ANALYSES
Scatter plot and regression analysis of ∆F508
versus incidence and number of mutations pro-
vided interesting results, which may help to close
a gap that has been not yet been fully resolved
in the literature. Currently, there has been some
dispute as to the impact of ∆F508 on the total
CF mutational diversity and CF prevalence. It
is obvious that in some regions the ∆F508 allele
can account for at least half the CF patients (e.g.,
North America).
After all the regional data were gathered and
sorted, we performed scatter plot analysis with
linear regression extrapolation. Filter 1 was used
for the ∆F508 percentage vs. CF incidence analy-
sis and filters 1 and 2 were used for the remain-
ing two analyses. Table 3 presents the filtered
data used in the regression analysis section of
this study. The remaining regions are ranked by
incidence wherein the incidence is represented
as one case per x live births. This table presents
the ∆F508 frequency, the total number of muta-
tions that are present at a frequency of 0.5% or
greater, and the relative CF incidence for each
country or region included in the final analysis.
When plotting the resultant data (Fig. 2), a sta-
tistically significant relationship was found be-
tween ∆F508 and CF incidence (p = 0.01, R2 =
0.25). Thus, the variability in CF incidence
among countries correlates with the variability
of the ∆F508 mutation. Other studies have il-
lustrated this correlation as well [Lucotte et al.,
1995]. Although the strength of the relation-
ship may seem less than expected, it should be
recognized that the limited precision of CF inci-
dence data and the incompleteness of CFTR
allelic profiles may account for the predictive
powers of ∆F508 alone. In addition, the inci-
dence of CF across countries is influenced by
numerous non-genetic factors, which themselves
vary markedly on a worldwide basis (e.g., envi-
ronmental and clinical determinants such as
under diagnosis). There have been many specu-
lations as to the reason for the high prevalence
of ∆F508 and CF in Europe. One of the leading
hypotheses is that of heterozygote advantage,
stating that the carrier state of CF in some way
gave a selective advantage to those who carried
a single flawed CFTR allele. Possible mechanisms
include some resistance to diarrheal illnesses like
cholera, which directly stimulate the CFTR
channel [Romeo et al., 1989].
The apparent correlation between ∆F508 and
CF incidence was tested using two well-charac-
terized CF populations that have been studied
over more than 15 years by newborn screening
and genotyping in Brittany, France, and Wiscon-
sin. These two regions were not used in gener-
ating the linear regression model, and thus were
examined to assess the validity of the new model.
Using the regression model, Wisconsin was pro-
 WORLDWIDE ANALYSIS OF CFTR MUTATIONS 595

TABLE 3. Filtered Data for CF Incidence Across the Globe*

Incidence
Country or (1 case per Mutations ∆F508
population X births)a >0.5%b percentb Reference
These regions passed both Filter 1 and Filter 2:
Finland 25000 4 46.2 Lucotte et al. [1995]; Kere et al. [1994]
Mexico 8500 15 41.6 Grebe et al. [1994]
Sweden 7300 10 66.6 Lucotte et al. [1995]; Schaedel et al. [1999];
Romeo et al. [1989]
Poland 6000 11 57.1 Lucotte et al. [1995]
North Ireland 5350 7 56.6 Romeo et al. [1989]
Russia 4900 12 54.5 Lucotte et al. [1995]
Denmark 4700 6 87.5 Lucotte et al. [1995]
Norway 4500 6 60.2 Lucotte et al. [1995]
Netherlands 3650 9 74.2 Lucotte et al. [1995]; Collee et al. [1998]
Spain 3500 21 52.7 Lucotte et al. [1995]
Greece 3500 22 52.9 Lucotte et al. [1995]
Germany 3300 17 71.8 Lucotte et al. [1995]; Romeo et al. [1989]
United States 2835 10 68.6 Kosorok et al. [1996]; Romeo et al. [1989]
Czech Republic 2833 10 70.0 Lucotte et al. [1995]; Romeo et al. [1989]
United Kingdom 2600 5 75.3 Lucotte et al. [1995]; Romeo et al. [1989]
Australia 2500 8 76.9 Romeo et al. [1989]
Italy 2438 9 50.9 Lucotte et al. [1995]; Gasparini et al. [1999];
Romeo et al. [1989]
France 2350 12 67.7 Lucotte et al. [1995]
Switzerland 2000 9 57.2 Hergersberg et al. [1997]
Ireland 1800 7 70.4 Lucotte et al. [1995]
The following five regions did not pass Filter 2 Criterion:
United Arab Emirates 15876 n/a 26.9 Frossard et al. [1998]; Frossard et al. [1999]
Brazil 6902 n/a 47.7 Cabello et al. [1999]; Raskin et al. [1999];
Bernardino et al. [2000]
Estonia 4500 n/a 51.7 Klaassen et al. [1998]
Chile 4000 n/a 29.2 Rios et al. [1994]
Scotland 1984 n/a 71.3 Shrimpton et al. [1991]; Gilfillan et al. [1998]
*This table shows the final data set for CF incidences after filtering for incomplete data sets (filter 1) and mutation detection
methodology (filter 2). The results are ranked by incidence from lowest to highest. Incidence is represented as 1 Case per X
births (Column 2). Column 3 presents the data that was generated during phase one of this study. This column presents the total
number of mutations, including ∆F508, present in the listed population that exceed the 0.5% threshold. Those regions in the
lower section of the table did not have methods strong enough to pass Filter 2, and therefore were only used in the ∆F508 versus
Incidence regression analysis.
a
CF incidence values were derived from those references listed in column 5.
b
Data derived from this investigation, see Table 1 for applicable references.

jected to have a CF incidence of 1:2,976 [95%
CI = 1:2,500–1:3,676], given a ∆F508 preva-
lence of 71.25% [Gregg et al., 1997]. The actual
Caucasian CF incidence in Wisconsin is 1:3,419
[Kosorok et al., 1996]. Brittany was projected
to have a CF incidence of 1:2,309 (95% CI =
1:2,309–1:3,508) based on a ∆F508 prevalence
of 75.8%. The actual incidence is 1:2,913 [Scotet
et al., 2000].
There also appeared to be an inverse correla-
tion when examining the total number of muta-
tions greater than 0.5% with regard to ∆F508
prevalence; however, this relationship was not
statistically significant (p = 0.15, R2 = 0.11).
There was no relationship observed between the
number of mutations greater than 0.5% and the
population CF incidence values (p = 0.61, R2 =
0.01), i.e., a greater variety of CFTR mutations
does not appear to influence disease incidence.
Using the data presented in Table 3 and Fig-
ure 2, we illustrate that ∆F508 plays a significant
role in determining at least one of these variables,
CF incidence. By performing regression analysis,
we were able to estimate that ∆F508 is contribut-
ing at least 1/4 of the total influence, on average,
to CF incidence. Regression analysis allowed for
the approximation of CF incidence based on
∆F508 prevalence in two well-characterized popu-
lations. Clearly, this linear regression line will not
apply to all populations. Factors such as founder
effects, consanguineous unions, and random hu-
man migration all tend to shift any gene or muta-
tion pool away from Hardy-Weinberg equilibrium.
A prime example is the unexpectedly low
∆F508%, high S549R%, and 88.4% detection rate
in the United Arab Emirates, a region that has
experienced all of these confounding factors to
some extent.
596 BOBADILLA ET AL.

FIGURE 2. ∆F508 vs. incidence with linear regression analysis. This graph illustrates the relationship of ∆F508 to the CF
incidence. Dashed lines represent the 95% CI for incidence when the regression is modeled and analyzed to predict
incidence based on ∆F508 values. Analysis shows a significant positive correlation between the ∆F508% and the total
population CF incidence. Statistical analysis indicates that ∆F508 contributes roughly 1/4 of the total population CF
incidence on average. Those countries that are bolded were not included in the second tear of regression analysis due to
failure to meet inclusion criterion for filter 2.

SPECULATION AND FUTURE ISSUES
When examining the mutational arrays of
populations within the United States, two mu-
tations are of special interest, namely R1162X
and 3849+10KbC→T. Recent studies [Mercier
et al., 1992, 1994] show that R1162X has been
found in certain Native American populations,
as well as the U.S. Hispanic CF patient pool.
3849+10KbC→T has been found in both the
Mexican [Villalobos-Torres et al., 1997; Liang et
al., 1998; Orozco et al., 2000] and the Southwest
U.S. Hispanic [Grebe et al., 1994], as well as cer-
tain Native American CF patients [Mercier et al.,
1994], but is not a common mutation in Europe
(Table 1). Those regions of Europe that have also
been shown to exhibit this mutation (i.e., Poland
and Ashkenazi Jewish populations) do so most
likely as a result of mutational recurrence [Morral
et al., 1994], and not a direct founder effect. Fu-
ture further haplotype analysis of these mutation-
sharing chromosomes will help to strengthen this
concept of non-related recurrent mutations. The
need to probe for the 3849+10KbC→T muta-
tion in screening programs is even more impor-
tant than including other minor CFTR alleles.
Patients with this mutation can present with no
elevation of sweat chloride levels, but sino-
pulmonary disease is still moderate to severe. A
delay in such a diagnosis on the genetic level could
result in significant lung involvement by the time
the diagnosis is made clinically.
One of the major European genetic contribu-
tors to the New World Latin population was
Spain. Since the 3849+10KbC→T mutation is
not high in the Spanish population, it seems
plausible that the indigenous people of the
Americas are the source of introduction of this
mutation into the Hispanic mutation pool of the
 WORLDWIDE ANALYSIS OF
Americas. This theory is further strengthened
by the observation that this mutation is the sec-
ond most prevalent mutation in the Zuni Pueblo
population [Mercier et al., 1994]. By extrapo-
lating this hypothesis to other populations, it is
reasonable to assume that 3849+10KbC→T will
likely be present at higher percentages in other
Native American populations, as well as in those
countries in Central and South America that
have close ties to Amerindian ancestry (Ecua-
dor and Chile in this study). Currently, the un-
derstanding of CF-causing mutations is very
limited with regard to the Native American,
Central, and South American populations; how-
ever, by examining the Mexican and U.S. His-
panic mutational arrays, it may be possible to
predict which mutations were originally indig-
enous to the Americas.
RECOMMENDATIONS AND APPLICATIONS
Aside from the major mutations above, there
are many other CFTR alleles that are present
only in specific populations or at variable per-
centages in different populations, i.e., M1101K
in the Hutterite Brethren [Zielenski et al., 1993].
These are the “minor” mutations that take on
special significance when one is selecting CFTR
alleles to test for in screening programs. Achiev-
ing high sensitivity in prenatal and neonatal
screening, as well as avoiding inadvertent dis-
crimination, requires knowledge of regional an-
cestry and/or CFTR arrays. Some countries have
only a few mutations that account for the vast
majority of CF patients, but other countries have
many CFTR alleles.
Based on our comprehensive assessment, we
offer recommendations (Table 2) for CF neona-
tal screening programs of North America where
trypsinogen/DNA testing is being implemented
to achieve early diagnosis. The list contains: 1)
all mutations present at 0.1% prevalence or
greater, based on analysis of 25,048 U.S. CF chro-
mosomes from the CFF registry [Cystic Fibrosis
Foundation, 1998]; 2) CFTR alleles that have
been commonly identified in many minority
populations of the United States (African Ameri-
can (12.3% population), Hispanic (12.5% popu-
lation), Native American (0.9% population),
and Asian American (3.6% population)) [US
Census Bureau, 2000b]; and 3) common Euro-
pean founder mutations that are anticipated to
be common throughout the United States. The
CFTR MUTATIONS 597
cutoff of 0.1% for the CFF data was used be-
cause of the exceedingly large sample size, over
25,000 chromosomes. Because of this, we are
confident of the prevalence of these mutations,
and offer them as options in multi-mutation
screening programs for the United States.
CFTR panels employing these 50 alleles can
also be applied to screening newborn populations
of Western Europe, but genotype profiles of spe-
cific regions should be examined carefully be-
fore implementation [Farrell, 2000]. When
relative weighting is done for each mutation,
based on ethnic prevalence in the United States,
the results indicate that the panel recommended
in Table 2 is expected to detect 86.3% of the CF
chromosomes of U.S. patients. This is nearly a
4% increase in detection based on the CFF Reg-
istry data (82.5%), and a 2.5% increase when
compared to the ACMG/ACOG panel (83.8%).
These detection rates are based on the total CF
population in the United States. Clearly, this
expanded panel will have more of an impact on
the regional and state levels than the national
level. Geographical variation of persons of dif-
fering ethnic backgrounds will largely alter the
application and contribution of the extended
panel in many regions.
When the panels are re-examined with an
ethnic frame in mind, the detection rates differ
significantly. Based on the data compiled in this
paper, for African American CF patients, the
ACMG/ACOG panel will detect an estimated
three CFTR mutations accounting for a 62.2%
chromosomal identification rate. Our extended
panel will encompass nine mutations in this group
and extend the detection rate to 72.4% (a 10.2%
increase in chromosome detection). Similarly, for
Hispanic/Mexican CF patients, the ACGM/
ACOG panel will detect an estimated 11 muta-
tions accounting for a 62.8% chromosomal iden-
tification rate. Our extended panel will encompass
19 mutations in this group and extend the detec-
tion rate to 72.7% (a 9.9% increase in detection).
Currently, it is premature to predict the implica-
tions of this panel on detection in the Native
American, Arab, and Asian populations that re-
side in the United States, as their population
specific mutations are poorly defined and char-
acterized at this time.
The practical advantages of a “pan-ethnic
mutation panel” have recently been described
in detail for U.S. populations [Heim et al., 2001].
598 BOBADILLA ET AL.
Using two CFTR panels detecting either 70 or
86 mutations in an assessment of 5,840 CF chro-
mosomes, this study demonstrated better detec-
tion of CF mutations (81.4%) than that achieved
with the ACMG/ACOG panel (75.3%). Perhaps
even more significant is their observation of
markedly improved sensitivity in non-Caucasian
populations compared to the 25 mutation panel.
Their “rationale for a pan-ethnic mutation
panel” includes comments that we heartily en-
dorse: “It is impractical to expect comprehen-
sive assessment of the ethnic background of
every individual referred for testing . . . in many
cases, individuals are themselves not fully aware
of their ethnic backgrounds. As the constitution
of the U.S. populations continues to change, a
pan-ethnic approach will be essential.”
In Figure 3, we present the 1990 U.S. census
data organized by major ethnic groups to help
provide a guide for the application of the entire
or partial sections of the panel of mutations pre-
sented in Table 2. This census information will
help serve as a guide in determining the relative
influence of ethnic sub-populations on the total
mutation array in a given region. Native Ameri-
can populations tend to be isolated into distinct
regions throughout the United States. In most
non-concentrated regions of the United States
they make up less than one percent of the total
population, while in the concentrated regions
they account for 60% and greater. This pattern
allows for easier identification and targeting of
specific regions using a customized array of Na-
tive American CFTR mutations that can be se-
lected from Tables 1 and 2. Pacific Islander and
Asian populations tend to be spread across the
states. In most regions they account for less than
1% of the total population; however, scattered
pockets of 1%–3% and 3%–10% do exist. Un-
fortunately, these regions have no distinct pat-
tern, and therefore the mutations specific to
these populations should be considered in all
screening regions. Currently, these mutations are
poorly defined and we present only those which
are well known to exist in certain Asian popula-
tions. Further characterization is needed to con-
fidently predict useful screening protocols in
most Asian populations. Because African Ameri-
cans account for greater than 50% of the total
population throughout much of the southeast-
ern United States, it is essential to include these
mutations into any prenatal or neonatal CF
screening implemented in these states. This is
particularly true in view of a CF incidence that
is higher [Kosorok et al., 1996] than originally
predicted [Kulczycki and Schauf, 1974] in this
population. When examining the remainder of
the country, however, it appears that in most
regions these African American mutations would
be common enough to warrant inclusion. There-
fore, we include them in the list of Table 2. His-
panic populations are traditionally concentrated
in the southwestern United States and Califor-
nia where they can account for greater than 60%
of the total population in these regions. In addi-
tion, Hispanic individuals account for a signifi-
cant proportion (1%–9%) of the total population
in large number of the remaining states. There-
fore, Hispanic-specific mutations should also be
considered in all screening regions, as listed in
Table 2.
Figure 4 presents the 2000 census data. Un-
fortunately, national scale graphical illustrations
at the county level were not yet available at the
time of publication. When comparing the 1990
and 2000 data sets, we see that there is very little
change in the relative geographical distribution
of most of the ethnic groups across the United
States; however, the relative percentage of per-
sons belonging to these various ethnic groups
has significantly risen in many regions. As the
2000 census data is further tabulated and inte-
grated into databases, more detailed ethnic dis-
tribution maps will be available at http://
factfinder.census.gov/. This information is essen-
tial in designing a high-yield low-cost screening
panel that is to be applied at the state or county
level.
Not depicted in these graphic illustrations
are strong European influences upon the mu-
tation pool, specifically, those population that
have their own distinct mutation spectrum. As
an example, we will discuss the Slavic influ-
ence throughout the United States. The ma-
FIGURE 3. Distribution of different ethnic groups across
the United States in 1990. This figure represents US Cen-
sus Bureau data from the 1990 US census. Data is plot-
ted at a countywide resolution with included legends. A:
Distribution of African American persons in the United
States in 1990. B: Distribution of Hispanic persons in
the United States in 1990. C: Distribution of American
Indian, Eskimo, and Aleut persons in the United States
in 1990. D: Distribution of Asian and Pacific Islander
persons in the United States in 1990. [US Census Bu-
reau, 1990].
WORLDWIDE ANALYSIS OF CFTR MUTATIONS 599
600 BOBADILLA ET AL.

FIGURE 4. Distribution of different ethnic groups and total population across the United States in 2000. This figure
represents US Census Bureau data from the 2000 US census. Data is plotted at a statewide resolution with included
legends. A: Distribution of African-American persons. B: Distribution of Hispanic persons. C: Distribution of American
Indian and Alaskan natives. D: Distribution of Asian persons. E: Distribution of Native Hawaiians and other Pacific
Islanders. F: Distribution of total U.S. population in 2000 by state [US Census Bureau, 2000a].

jority of Slavic immigrants came to the United
States between 1880 and 1920, and settled in
roughly one-third of the states, focused mainly
in the Northeast, Midwest, and California
(www1.umn.edu/ihrc/sites.htm, www.feefhs.org).
Although most immigrants have assimilated
with the U.S. majority population, strong en-
dogamous central and eastern European popu-
lations remain in New York, Toronto, and
Chicago, and are continuously increased by
 WORLDWIDE ANALYSIS OF
influx from Poland, Russia, and Romania. Thus,
inclusion of CFTR dele2,3 (21 kb) into the U.S.
screening panels will substantially improve ge-
netic diagnosis of CF in European Americans
of central and eastern European origin.
We have also recommended the inclusion of
other prototypical European mutations, includ-
ing prevalent mutations from Irish, French, Ger-
man, Scandinavian, Swiss, Welsh, and other
strong influences to the American gene pool
(Table 2).
CONCLUSIONS
Currently, CF neonatal screening programs
are emerging with a variety of methods being
used to facilitate early diagnosis [Hammond et
al., 1991; Wilcken et al., 1995; Gasparini et al.,
1999]. The evolution of tests is described in de-
tail elsewhere [Farrell, 2000] and has featured a
progression from immunoreactive trypsinogen
testing [Hammond et al., 1991] to a two-tier
combination of trypsinogen and DNA analysis
for either the ∆F508 allele or multiple CFTR
mutations. With the opportunity for DNA-
based, multi-mutational diagnostics becoming
available, now is the time to initiate planning
for uniform and comprehensive newborn screen-
ing programs that avoid disparities in detection.
Many common genetic diseases have been
shown to have significant diversity in causative
mutations when examined on a large population
or international levels. Cystic fibrosis is perhaps
the epitome of mutational diversity since more
than 1,000 CFTR alleles have been identified
to date [Cystic Fibrosis Genetic Analysis Con-
sortium (CFGAC), 2000]. With such a great het-
erogeneity, those screening programs that rely
on the detection of a small sub-population of
mutations are almost destined to have an inter-
nal bias. Incorporation of such a methodological
bias into screening programs could significantly
reduce the number of newborns identified as CF
positive during the genetic tier of screening.
Therefore, the greatest current challenge in CF
neonatal screening, when it is employed as a di-
agnostic tool, is to ensure high sensitivity (ide-
ally 100%) while avoiding exclusion of any
minority populations. Meeting this challenge will
require carefully planned trypsinogen/CFTR
multi-mutation analysis [Farrell, 2000] includ-
ing the alleles that occur in the population en-
compassed by the screening program.
CFTR MUTATIONS 601
A good example of this hidden bias would be
in Hispanic CF newborns in the United States.
The 3849+10kbC→T mutation is rare when
compared to the most common CF mutations
worldwide; however, it represents nearly 2.5%
of the Southwest U.S. Hispanic CF chromo-
somes. If this mutation is missed in a screening
program, the affected CF newborn is at even
greater risk for long-term complications than
most CF newborns. This mutation often does
not cause changes in the sweat chloride level,
so the “gold standard” for clinical diagnosis may
be virtually useless. Furthermore, the mere label
of Hispanic or Mexican American tends to di-
minish consideration of CF as a possible diag-
nosis, since CF is typically thought of as a
Caucasian or western European disease. Clearly,
this scenario presents a problem to the diagno-
sis of CF in certain populations. With the com-
bined efforts of characterizing mutational
heterogeneity as a function of geography and
ethnicity, and the expansion of screening proto-
cols to account for these population-specific
mutations, many of these missed diagnoses can
be potentially avoided. Results of the Wiscon-
sin randomized controlled trial have demon-
strated nutritional benefits [Farrell, 2000] and
other studies suggest better pulmonary outcomes
with early diagnosis [Waters et al., 1999; Mérelle
et al., 2001].
In conclusion, the frequency of most CFTR
mutations is highly variable and is often a func-
tion of the ethnic or geographic origin of the
parents and grandparents of the affected child.
As new technology is introduced that will allow
for the implementation of large-scale, multi-
mutation screening programs, it is essential to
have a complete understanding of what popula-
tions are carriers for which mutations. This is
not only true for cystic fibrosis, but for other
common genetic disorders with a large number
of causative mutations. Without thorough de-
lineation of the identity and differential distri-
bution of mutations at the planning stage for
newborn screening programs, regions will be
unprepared to utilize future DNA interrogation
technologies as the powerful diagnostic tools that
they promise to be, i.e., realize their potential.
There is also a great risk of introducing an inter-
nal bias into any screening program that does
not properly select the correct mutational array
associated with the population or populations
602 BOBADILLA ET AL.
that it is servicing. An example of this problem
is provided by the current issue being addressed
by the American College of Medical Genetics
(ACMG) and the American College of Obste-
tricians and Gynecologists (ACOG) regarding
carrier screening [Grody et al., 2001]. The
ACMG focused its recommendations for the CF
carrier screening on “non-Jewish Caucasians and
Ashkenazi Jews.” Several minority populations
in North America are not well served when only
25 CFTR alleles are included, as Table 2 clearly
shows. In fact, the panel may not even serve Jew-
ish populations adequately based on a recent
study aimed at evaluation of screening policies
[Orgad et al., 2001]. In addition, another study
of a typical CF Center population of ethnically
diverse patients residing in California under-
scores the need for a “pan-ethnic mutation
panel” [Heim et al., 2001] in a neonatal screen-
ing program [Wine et al., 2001]. Consequently,
ultimate goals for any CF screening program
must first be identification of the population-
specific CF mutational arrays, secondly the ex-
pansion of counseling and support networks, and
thirdly, the implementation of a population-tai-
lored screening protocol. With the information
provided in this article and using recommended
procedures [Farrell, 2000], newborn screening
for CF can soon progress from the current IRT/
DNA (∆F508) methods to a superior IRT/DNA
(CFTR) strategy.
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