Investigating CFTR gene variations in patient groups with positive newborn screening test results and preliminary clinical diagnosis of cystic fibrosis in the eastern anatolia region of Turkey

Cystic fibrosis (CF, OMIM: #219700), caused by biallelic pathogenic variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is the most common monogenic disease. The present study aimed to investigate CFTR gene variations in patients with a positive screening test result for CF and those with a clinical suspicion of CF. Overall, 443 patients (190 females/253 males) were retrospectively included. Of these, a positive neonatal screening test result for CF was reported in 124 patients (58 females/66 males) and a preliminary clinical diagnosis of CF based on recurrent lung infection and/or delayed weight gain was reported in 327 patients (134 females/193 males). All patients were evaluated based on clinical findings, sweat test (ST) results, and CFTR gene sequence analysis results. In the group of 116 patients having a positive neonatal screening test result for CF, heterozygous variations were observed in 21 (18%) patients, compound heterozygous variations in 9 (8%) patients, and homozygous variations in 5 (4%) patients. In the group of 327 patients with a clinical suspicion of CF, heterozygous variations were observed in 52 (16%) patients, compound heterozygous variations in 26 (8%) patients, and homozygous variations in 11 (3%) patients. When the two groups were cumulatively evaluated, the most common mutant alleles were Pro1013Leu (10.4%), Tyr515* (9.6%), and Phe508del (4.8%). In the total study sample of 443 patients, 51 different variants were detected. To the best of our knowledge, this is the first comprehensive study that demonstrated CFTR gene variation distribution in the Eastern Anatolia Region of Turkey. In this study, mutation distribution was highly heterogeneous, and we believe that investigation of the entire CFTR gene is necessary and would improve the diagnostic rates for CF in the Turkish population.

PDF

___

Therrell BL Jr, Hannon WH, Hoffman G, Ojodu J, Farrell PM. Immunoreactive trypsinogen (IRT) as a biomarker for cystic fibrosis: challenges in newborn dried blood spot screening. Mol Genet Metab. 2012;106:1-6.

World Health Organization. The molecular genetic epidemiology of cystic fibrosis, http://www.who.int/genomics/publications/en.3. Ratjen F, Bell SC, Rowe SM, et al. Cystic fibrosis. Nat Rev Dis Primers. 2015;1:15010.

Gentzsch M, Mall MA. Ion channel modulators in cystic fibrosis. Chest. 2018;154:383-93.

Grossman S, Grossman LC. Pathophysiology of cystic fibrosis: implications for critical care nurses. Crit Care Nurse. 2005;25:46-51.

Castellani C, Assael BM. Cystic fibrosis: a clinical view. Cell Mol Life Sci. 2017;74:129-40.

Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989;245:1073-80.

Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245:1066-73.

Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989;245:1059- 65.

Cystic fibrosis mutation database [Internet]. Available: http://www.genet. sickk ids.on.ca

Simmonds NJ. Is it cystic fibrosis? The challenges of diagnosing cystic fibrosis. Paediatr Respir Rev. 2019;31:6-8.

Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992-2001.

Crossley JR, Elliott RB, Smith PA. Dried-blood spot screening for cystic fibrosis in the newborn. Lancet 1979;1:472-474.

Gonska T, Ratjen F. Newborn screening for cystic fibrosis. Expert Rev Respir Med. 2015;9:619-31.

Schmidt M, Werbrouck A, Verhaeghe N, et al. Strategies for newborn screening for cystic fibrosis: A systematic review of health economic evaluations. J Cyst Fibros. 2018;17:306-15.

Ren CL, Borowitz DS, Gonska T, et al. Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis. J Pediatr. 2017;181S:S45-S51.e1.

. Kopanos C, Tsiolkas V, Kouris A, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:1978-80.

Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-424.

De Boeck K. Cystic fibrosis in the year 2020: A disease with a new face. Acta Paediatr. 2020;109:893-9.

Groves T, Robinson P, Wiley V, Fitzgerald DA. Long-term outcomes of children with intermediate sweat chloride values in infancy. J Pediatr. 2015;166:1469-74.e743.

Başaran AE, Başaran A, Kocacik DF, et al. Initial regional evaluation of the Cystic Fibrosis Newborn Screening Program: data from the Mediterranean coast of Turkey. Turk J Med Sci. 2019;49:1655-61.22. Şaşihüseyinoğlu AŞ, Altıntaş DU, Bişgin A, et al. Two years of newborn screening for cystic fibrosis in Turkey: Çukurova experience. Turk J Pediatr. 2019;61:505-12.

Course CW, Hanks R. Newborn screening for cystic fibrosis: Is there benefit for everyone? Paediatr Respir Rev. 2019;31:3-5.

Alibakhshi R, Kianishirazi R, Cassiman JJ, et al. Analysis of the CFTR gene in Iranian cystic fibrosis patients: identification of eight novel mutations. J Cyst Fibros. 2008;7:102-9.

Siryani I, Jama M, Rumman N, et al. Distribution of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in a cohort of patients residing in Palestine. PLoS One. 2015;10:e0133890.

Lao O, Andrés AM, Mateu E, et al. Spatial patterns of cystic fibrosis mutation spectra in European populations. Eur J Hum Genet. 2003;11:385- 94.

Kilinç MO, Ninis VN, Dağli E, et al. Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. Am J Med Genet. 2002;113:250-7.

Onay T, Zielenski J, Topaloglu O, et al. Cystic fibrosis mutations and associated haplotypes in Turkish cystic fibrosis patients. Hum Biol. 2001;73:191-203.

Ülgenalp A. Strip Assay Metodu Kullanılarak "Cystic fibrosis transmembrane conductance regulator (CFTR)" Geni mutasyonlarının analizi, Dokuz Eylül Üniversitesi Tıp Fakültesi Derg. 2009;23:47-51.

Öztürk ÖG, Kibar F, Karaçor EDZ, et al. Adana İlinde CFTR Gen Mutasyonlarının Değerlendirilmesi. Cukurova Med J. 2014;38:202-8.

Gümüş E. Examination of CFTR gene mutations in patient groups with borderline sweat test and clinical preliminary diagnosis of cystic fibrosis by next-generation sequencing method in Şanlıurfa province. JAREM 2019;9:86-90.

Onay T, Topaloglu O, Zielenski J, et al. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998;102:224-30.

Hämmerle MM, Aleksandrov AA, Riordan JR. Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability. J Biol Chem. 2001;276:14848-54.

Atag E, Bas Ikizoglu N, Ergenekon AP, et al. Novel mutations and deletions in cystic fibrosis in a tertiary cystic fibrosis center in Istanbul. Pediatr Pulmonol. 2019;54:743-50.

Bonyadi M, Omrani O, Rafeey M, et al. Spectrum of CFTR gene mutations in Iranian Azeri Turkish patients with cystic fibrosis. Genet Test Mol Biomarkers. 2011;15:89-92.

Loukas YL, Thodi G, Molou E, et al. Clinical diagnostic Next-Generation sequencing: the case of CFTR carrier screening. Scand J Clin Lab Invest. 2015;75:374-81.

Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med. 2004;6:387-91.