American Journal Of Biomedical Science & Pharmaceutical Innovation
11
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VOLUME
Vol.05 Issue03 2025
PAGE NO.
11-14
10.37547/ajbspi/Volume05Issue03-03
The Genetic Spectrum of Cystic Fibrosis in Different
Populations
Кhamidova
Farida Muinova
Samarkand State Medical University, Uzbekistan
Hamraev Bekzod Zhuramurodovich
Samarkand State Medical University, Uzbekistan
Received:
13 January 2025;
Accepted:
26 February 2025;
Published:
13 March 2025
Abstract:
Cystic fibrosis (CF) is a hereditary disease caused by mutations in the CFTR gene, which regulates chloride
ion transport in epithelial cells. To date, more than 1,500 CFTR mutations have been identified, with their
prevalence varying among different ethnic groups. This article reviews data on the frequency and spectrum of
CFTR mutations in various populations, including Iran, Turkey, Russia, the USA, Australia, and Europe. Special
attention is given to neonatal CF screening programs, their effectiveness, challenges related to false-negative
results, and the need to adapt mutation panels based on ethnic characteristics. Studies confirm that expanding
genetic panels, lowering IRT threshold values, and implementing a differentiated screening approach can
significantly improve diagnostic accuracy and patient outcomes.
Keywords:
Cystic fibrosis, children, lungs, CFTR gene.
Introduction:
To date, more than 1,500 mutations in
the CFTR gene have been identified, with their
prevalence varying among different ethnic groups.
Several studies have been conducted in Iran to examine
the distribution of CFTR mutations among cystic
fibrosis (CF) patients. In northeastern Iran, an analysis
of 56 patients identified 24 mutant alleles (21.42%),
with the most common being ΔF508 (10.71%) (1).
Another study in Mazandaran Province found only one
mutation, ΔF508, among 30 CF patients, accounting for
21.7% (2). Similarly, an analysis of CFTR mutations in 70
Iranian patients showed that ΔF508 was present in
17.8% of alleles, N1303K in 4.3%, and G542X in 3.6%
(3).
The CFTR gene is located on chromosome 7 (locus
7q31) and encodes the cystic fibrosis transmembrane
conductance regulator, which controls chloride ion
transport. Mutations in this gene lead to thickened
secretions from exocrine glands, causing dysfunction in
the respiratory, digestive, and reproductive systems
(4).
According to WHO data, the incidence of cystic fibrosis
(CF) among newborns ranges from 1:600 to 1:1200,
with approximately 300 children diagnosed with CF
annually in Russia. In recent years, due to early
neonatal screening and improved therapy, the average
life expectancy of CF patients has increased from 5 to
40 years in developed countries and up to 23 years in
Moscow and St. Petersburg (4).
In Russia, the most common mutation is F508del, found
in over 60% of patients. However, more than 1,200
CFTR gene mutations have been identified, including
rare regional variants such as L138ins in the Middle
Urals (5) and c.1545_1546del in Chechnya (6).
A study conducted in Turkey revealed that the
prevalence of CF in Central Anatolia is similar to that in
Northern Europe, with an incidence rate of 2.9 per
10,000 live births in Konya and 2.8 per 10,000 in
Kayseri. Among 30 CF patients, the F508del mutation
was the most frequent (17/30), with half of the patients
being homozygous and the other half compound
heterozygous (7).
A comparative study in Australia evaluated three
neonatal screening strategies between 1989 and 2008.
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American Journal of Applied Science and Technology (ISSN: 2771-2745)
It was found that incorporating a CFTR 12-mutation
panel increased diagnostic sensitivity from 86.6%
(using only IRT) to 95.8% (8).
In the United States, the newborn screening program
for cystic fibrosis (CF NBS) has evolved over two
decades. An analysis of false-negative cases in New
Jersey revealed that some patients with severe
respiratory diseases were not detected during initial
testing. This led to an update of the CF NBS algorithm,
which now includes a lower IRT threshold and an
expanded panel covering 139 CFTR variants (9).
In the U.S., expanded CFTR panels include up to 402
mutations; however, high false-negative rates persist
among Asian and African American populations (10).
In Australia, a study by Lee & Orton (2025) found that
the sensitivity of CFTR panels among South Asians was
64%, the lowest among all ethnic groups. In Europe, the
prevalence of the F508del mutation is higher among
Northern Europeans (95.6%) compared to Southern
European populations (12).
In Turkey, a national CF NBS program has been in place
since 2015, based on a two-step measurement of
immunoreactive trypsinogen levels (IRT-1/IRT-2). A
study by Çoksüer et al. (2025) showed that this method
has low sensitivity (80.3%) and a positive predictive
value (PPV) of 23.3%, along with high rates of false-
negative (FNP) and false-positive results. Among 66
infants diagnosed with CF, 19.7% were identified solely
based on clinical suspicion, highlighting the need to
revise IRT threshold values and explore alternative
strategies to improve screening accuracy.
In the French-speaking community of Belgium, an
improved IRT-DNA screening algorithm has been
implemented since 2020, incorporating a 12-variant
CFTR panel and a fail-safe IRT/IRT method. A four-year
evaluation (14) demonstrated a sensitivity of 95% and
a median diagnosis age of 23 days, indicating a high
level of early detection and timely treatment.
In Italy, the incidence of cystic fibrosis (CF) among
Caucasian newborns is estimated at 1/2500
–
1/3000. A
study by Dell’Edera et al. (2014) analyzed the
prevalence of CFTR mutations among CF patients and
infertile couples in the Basilicata region. CFTR
mutations were detected in 6.85% of individuals
screened, exceeding the hypothetical carrier frequency
(4%). While F508del was the most common cause of CF,
rare regional mutations were also identified. The study
highlighted the need for expanded screening panels to
improve diagnostic accuracy and disease prevention.
In the United States, neonatal screening is mandatory
and includes IRT level measurement, a CFTR variant
panel, and CFTR sequencing if a single variant is
detected. However, a study by McGarry et al. (2024)
revealed significant racial and ethnic disparities in NBS
sensitivity. Asian (OR 6.3) and Black infants (OR 2.5)
were more likely to receive false-negative results,
attributed to low IRT levels or incomplete mutation
panels. The introduction of an expanded CFTR panel
covering 402 variants improved CF detection across all
racial and ethnic groups.
The spectrum of CFTR mutations in cystic fibrosis (CF)
patients of Pakistani origin differs significantly from
Western populations. A study by Majid et al. (2025)
reported a high frequency of rare mutations,
emphasizing the need to adapt screening programs for
this ethnic group.
The prevalence of CRMS/CFSPID varies by geographic
region and the neonatal screening (NBS) algorithms
used. A study conducted in six Italian centers found that
the ratio of CF patients to infants with CRMS/CFSPID
was 1:1.30, higher than in countries with a greater
prevalence of the F508del mutation (18). In the United
States, the frequency of CRMS is estimated to be higher
than expected due to the inclusion of expanded gene
sequencing in NBS protocols (21).
Children with CRMS/CFSPID generally have a milder
clinical course compared to those with a confirmed CF
diagnosis. The Italian study (18, 19) found that infants
with CRMS/CFSPID had significantly lower levels of
immunoreactive trypsinogen (IRT) and sweat chloride
concentrations, with the F508del mutation present in
only 20% of alleles.
Another study (20) demonstrated that by the age of
seven, children with CRMS/CFSPID showed less severe
lung involvement compared to CF patients. They
experienced fewer hospitalizations, had better lung
function, and had lower rates of complications such as
Pseudomonas aeruginosa and Staphylococcus aureus
infections. However, in 44% of these children, the
diagnosis was later revised to CF, highlighting the need
for careful long-term monitoring.
Additionally, according to Barben et al. (2021), despite
the generally favorable prognosis for most patients
with CRMS/CFSPID, some may develop CF or CFTR-
related disorders (CFTR-RD) during adolescence or
adulthood. Therefore, educating families about
potential risks and disease symptoms is crucial.
The lack of a standardized approach to managing
children with CRMS/CFSPID has led to significant
variations in clinical practice across different centers
(18). For example, the frequency of sweat testing
ranged from 8% to 100%, while recommendations for
salt supplementation varied from 11% to 90%.
The updated international guidelines (21) introduced a
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key recommendation for a detailed assessment of
children with CRMS/CFSPID at the age of six. This
evaluation includes lung function tests and chest
imaging, allowing for informed decisions regarding
further monitoring. Families are also advised to receive
clear instructions on symptoms that require medical
attention.
In Uzbekistan, studies by Barataeva L. and Rakhmonova
Sh. (2024) confirm that the intestinal form of CF is
predominant among newborns. However, data on
specific CFTR mutations in this region remain limited.
Thus, the study of CFTR gene mutations across different
populations demonstrates significant ethnic and
geographic variations in their prevalence. Data on
mutation frequencies are essential for optimizing
newborn screening programs, prenatal testing, and
genetic counseling. Advancements in diagnostic
methods, including expanded mutation panels and
lower IRT threshold values, contribute to earlier
disease detection, which is crucial for improving patient
outcomes.
CONCLUSIONS
1.The genetic variability of CFTR differs significantly by
ethnicity, necessitating the adaptation of screening
programs for various populations.
2.The F508del mutation is the most common in Europe
and Russia but is less frequent in Asia and among
African Americans. Some regions have specific rare
mutations.
3.Neonatal CF screening programs have demonstrated
varying effectiveness, with expanded mutation panels
and lower IRT thresholds improving diagnostic
sensitivity.
4.The false-negative rate remains high among Asian
and African American infants, highlighting the need to
refine NBS algorithms.
5.Patients with CRMS/CFSPID require long-term
monitoring, as some may develop classical CF over
time.
6.Genetic studies and CFTR mutation analysis play a key
role in optimizing screening, prenatal testing, and
genetic counseling.
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