American Journal Of Biomedical Science & Pharmaceutical Innovation 11 https://theusajournals.com/index.php/ajbspi VOLUME Vol.05 Issue03 2025 PAGE NO. 11-14 DOI 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. https://doi.org/10.37547/ajbspi/Volume05Issue03-03 https://doi.org/10.37547/ajbspi/Volume05Issue03-03 American Journal of Applied Science and Technology 12 https://theusajournals.com/index.php/ajast 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 American Journal of Applied Science and Technology 13 https://theusajournals.com/index.php/ajast American Journal of Applied Science and Technology (ISSN: 2771-2745) 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. REFERENCES Mehdizadeh Hakkak A, Keramatipour M, Talebi S, Brook A, Tavakol Afshari J, Raazi A, Kianifar HR. Analysis of CFTR Gene Mutations in Children with Cystic Fibrosis, First Report from North-East of Iran. Iran J Basic Med Sci. 2013 Aug;16(8):917-21. Dooki MR, Akhavan-Niaki H, Juibary AG. Detecting Common CFTR Mutations by Reverse Dot Blot Hybridization Method in Cystic Fibrosis First Report from Northern Iran. Iran J Pediatr. 2011 Mar;21(1):51- 7. Alibakhshi R, Zamani M. Mutation analysis of CFTR gene in 70 Iranian cystic fibrosis patients. Iran J Allergy Asthma Immunol. 2006 Mar;5(1):3-8. Эседов Э. М. и др. Муковисцидоз-актуальная проблема медицины //Вестник оториноларингологии. – 2016. – Т. 81. – №. 5. – С. 15- 18. Шадрина В. В., Красовский С. А., Кондратьева Е. И., Фурман Е. Г. ЭПИДЕМИОЛОГИЧЕСКИЕ И КЛИНИЧЕСКИЕ ОСОБЕННОСТИ «СРЕДНЕ- УРАЛЬСКОГО» ПАТОГЕННОГО ВАРИАНТА НУКЛЕОТИДНОЙ ПОСЛЕДОВАТЕЛЬНОСТИ L138ins В ГЕНЕ CFTR ПРИ МУКОВИСЦИДОЗЕ. Медицинский вестник Северного Кавказа. 2020;15(2):283-288. Горинова Ю. В., Савостьянов К. В., Пушков А. А., Никитин А. Г., Пеньков Е. Л., Красовский С. А.,Симонова О. И., Намазова-Баранова Л. С. Генотип-фенотипические корреляции течения кистозного фиброза у российских детей. Первое описание одиннадцати новых мутаций. Вопросы современной педиатрии. 2018; 17 (1): 61–69. Hangül M, Pekcan S, Köse M, Acıcan D, Şahlar TE, Erdoğan M, Kendirci M, Güney D, Öznavruz H, Demir O, Ercan Ö, Göçlü F. The Incidence of Cystic Fibrosis in the Central Region of Anatolia in Turkey Between 2015 and 2016. Balkan Med J. 2019 May 10;36(3):179-183. Massie RJ, Curnow L, Glazner J, Armstrong DS, Francis I. Lessons learned from 20 years of newborn screening for cystic fibrosis. Med J Aust. 2012 Jan 16;196(1):67- 70. Baldwin K, Barker EM, Carayannopoulos M, Farrell PM, Zanni R, Scanlin TF. Severe lung disease in children with cystic fibrosis missed in newborn screening. Pediatr Pulmonol. 2024 Jan;59(1):163-168. McGarry M. E. et al. Detection of disease‐causing CFTR variants in state newborn screening programs //Pediatric pulmonology. – 2023. – Т. 58. – №. 2. – С. 465-474 Ли Э., Ортон К. Скрининг носительства муковисцидоза в Австралии: сравнение секвенирования и целевых панелей у представителей разных национальностей // Журнал медицинской генетики. – 2025. – Т. 62. – №. 3. – С. 219-226. Антипов В. В., Антипова С. И. Этнические аспекты и междисциплинарные проблемы медицины часть 1. Этнические проблемы здоровья // Медицинские новости. 2016. №7 (262). Çoksüer F, Kartal Öztürk G, Duman Şenol H, Barlık M, American Journal of Applied Science and Technology 14 https://theusajournals.com/index.php/ajast American Journal of Applied Science and Technology (ISSN: 2771-2745) Özaslan MM, Girgin Dindar B, Ocak E, Halis E, Atacan Öğütcü Ş, Gülen F, Demir E. Newborn Screening Program for Cystic Fibrosis in Türkiye: Experiences from False-Negative Tests and Requirement for Optimization. Balkan Med J. 2025 Jan 2;42(1):45-53. Thimmesch M, Berardis S, Hanssens L, Quentin C, Boemer F, Luis G, Dewulf JP, Marie S, Marcelis L, Lefèvre N, Libioulle C, Dideberg V, Philippeau M, Revencu N, Boboli H. Four-year evaluation of neonatal cystic fibrosis screening in Southern Belgium. Eur J Pediatr. 2024 Nov 21;184(1):38. Dell’Edera D. et al. Analysis of cystic fibrosis gene mutations in children with cystic fibrosis and in 964 infertile couples within the region of Basilicata, Italy: a research study //Journal of Medical Case Reports. – 2014. – Т. 8. – С. 1-7. McGarry ME, Sciortino S, Graham S, Bishop T, Gibb ER. Improved detection of cystic fibrosis by the California Newborn Screening Program for all races and ethnicities. Pediatr Pulmonol. 2024 Nov;59(11):2901- 2909. Majid H. et al. Spectrum of cystic Fibrosis conductance regulator gene mutations reported in Pakistani descent cystic Fibrosis patients //J Coll Physicians Surg Pak. – 2022. – Т. 32. – №. 8. – С. 1042-1046. Terlizzi V, Claut L, Tosco A, Colombo C, Raia V, Fabrizzi B, Lucarelli M, Angeloni A, Cimino G, Castaldo A, Marsiglio L, Timpano S, Cirilli N, Moroni L, Festini F, Piccinini P, Zavataro L, Bonomi P, Taccetti G, Southern KW, Padoan R. A survey of the prevalence, management and outcome of infants with an inconclusive diagnosis following newborn bloodspot screening for cystic fibrosis (CRMS/CFSPID) in six Italian centres. J Cyst Fibros. 2021 Sep;20(5):828-834. Terlizzi V, Fevola C, Presti S, et al. Critical Issues in the Management of CRMS/CFSPID Children: A National Real-World Survey. Pediatr Pulmonol. 2025 Jan;60(1):e27483. doi: 10.1002/ppul.27483. Munck A, Bourmaud A, Bellon G, Picq P, Farrell PM; DPAM Study Group. Phenotype of children with inconclusive cystic fibrosis diagnosis after newborn screening. Pediatr Pulmonol. 2020 Apr;55(4):918-928. Barben J, Castellani C, Munck A, Davies JC, de Winter- de Groot KM, Gartner S, Kashirskaya N, Linnane B, Mayell SJ, McColley S, Ooi CY, Proesmans M, Ren CL, Salinas D, Sands D, Sermet-Gaudelus I, Sommerburg O, Southern KW; European CF Society Neonatal Screening Working Group (ECFS NSWG). Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). J Cyst Fibros. 2021 Sep;20(5):810-819. Баратаева Л., Рахмонова Ш. Янги тугилган болаларда учрайдиган муковисцидознинг ичакшаклини учраш даражаси ва иммуногистологик хусусиятлари //Актуальные вопросы фундаментальной медицины: сегодня и в будущем. – 2024. – Т. 1. – №. 1. – С. 38-38. Pathak A. et al. Human microbiome and respiratory diseases //Human Microbiome Drug Targets. – Elsevier, 2025. – С. 123-131. Хамидова Фарида Муиновна, ., и Рузикулов Собир Йовлиевич, . (2024). ГЕНЕТИЧЕСКИЙ РИСК РЕСПИРАТОРНОГО ДИСТРЕССА У МЛАДЕНЦЕВ. Американский журнал биомедицинской науки и фармацевтических инноваций , 4 (07), 16–27. Akhmedov Y. A. et al. MORPHORANGENOLOGICAL CHARACTERISTICS IN EARLY DIAGNOSIS OF CHILDREN WITH INFLAMMATORY PULMONARY DISEASES //American Journal Of Biomedical Science & Pharmaceutical Innovation. – 2024. – Т. 4. – №. 06. – С. 31-40. Anatolyevna B. S., Muinovna K. F. Morphofunctional relationships of cells in the bronch in chronic inflammation //The American Journal of Medical Sciences and Pharmaceutical Research. – 2023. – Т. 5. – №. 06. – С. 100-104.