Download PDF
J Pediatr Genet 2020; 09(01): 040-043
DOI: 10.1055/s-0039-1694964
Case Report
Georg Thieme Verlag KG Stuttgart · New York

A Novel Pathogenic Variant of the CFTR Gene in a Patient with Cystic Fibrosis Phenotype—c.4096A > T

Ahmet Burak Arslan
1   Department of Medical Genetics, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
,
Ayşe Gül Zamani
1   Department of Medical Genetics, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
,
Sevgi Pekcan
2   Pediatric Pulmonology Division, Department of Pediatrics, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
,
Mahmut Selman Yıldırım
1   Department of Medical Genetics, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
› Author Affiliations
Further Information

Publication History

18 December 2018

11 July 2019

Publication Date:
28 August 2019 (online)

    Permissions and Reprints

Abstract

Cystic fibrosis is a chronic multisystemic disease originating from functional alterations in CFTR (cystic fibrosis transmembrane conductance regulator) protein. To date, more than 300 pathogenic variants have been described in the literature. However, the diagnosis of CF, which was thought to become easier after the CFTR gene was identified, became more complicated due to the enormous amount of variations. In this study, we present a patient whose clinical findings were consistent with cystic fibrosis (CF) and showed a homozygous missense change that is not previously reported in the CFTR gene as pathogenic. In the next-generation sequencing analysis, homozygous c.4096A > T single-nucleotide exchange (I1366F [p.Ile1366Phe], missense) was shown in both alleles of the patient' CFTR gene. According to our database analysis, this variant has not yet been previously reported (VarSome, ClinVar, MutationTaster, Ensembl, dbSNP, PubMed). We do consider the change as pathogenic since the patient's findings were compatible with CF and the data analysis was in favor of pathogenicity. The most recent consensus report published in 2017 emphasized the importance of CFTR gene analysis, and this study emphasizes the difficulties of associating CFTR gene variations with a clinical picture and constitutes a new data on the genotype–phenotype correlation of CFTR variants. Also, considering the frequency of CF (according to World Health Organization data, every 1 out of 2,000–3,000 infants is born with CF in European Union countries and every 1 out of 3,500 in the United States) as well as the increasing rate of molecular studies performed on CF patients worldwide, reporting novel variation has an additional value.

Keywords

CFTR (cystic fibrosis transmembrane conductance regulator) - novel - pathogenic variant - cystic fibrosis - next-generation sequencing
 

  • References

  • 1 Clinical and Functional Translation of CFTR. https://cftr2.org/ . Accessed September 29, 2019
    PubMed
  • 2 Cystic fibrosis mutation database. Hospital for Sick Children, Toronto. www.genet.sickkids.on.ca . Accessed September 29, 2018
    PubMedGoogle Scholar
  • 3 Poulou M, Fylaktou I, Fotoulaki M, Kanavakis E, Tzetis M. Cystic fibrosis genetic counseling difficulties due to the identification of novel mutations in the CFTR gene. J Cyst Fibros 2012; 11 (04) 344-348
    CrossrefPubMedGoogle Scholar
  • 4 Kopanos C, Tsiolkas V, Kouris A. , et al. VarSome: the human genomic variant search engine. Oxford Bioinformatics 2019; 35 (11) 1978-1980
    PubMedGoogle Scholar
  • 5 Quang D, Chen Y, Xie X. DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics 2015; 31 (05) 761-763
    CrossrefPubMedGoogle Scholar
  • 6 Hughes EE, Stevens CF, Saavedra-Matiz CA. , et al; New York State Cystic Fibrosis Newborn Screening Consortium. Clinical sensitivity of cystic fibrosis mutation panels in a diverse population. Hum Mutat 2016; 37 (02) 201-208
    CrossrefPubMedGoogle Scholar
  • 7 Terlizzi V, Castaldo G, Salvatore D. , et al. Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. J Med Genet 2017; 54 (04) 224-235
    CrossrefPubMedGoogle Scholar
  • 8 Rosenstein BJ, Cutting GR. ; Cystic Fibrosis Foundation Consensus Panel. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr 1998; 132 (04) 589-595
    CrossrefPubMedGoogle Scholar
  • 9 De Boeck K, Wilschanski M, Castellani C. , et al; Diagnostic Working Group. Cystic fibrosis: terminology and diagnostic algorithms. Thorax 2006; 61 (07) 627-635
    CrossrefPubMedGoogle Scholar
  • 10 De Boeck K, Derichs N, Fajac I. , et al; ECFS Diagnostic Network Working Group; EuroCareCF WP3 Group on CF diagnosis. New clinical diagnostic procedures for cystic fibrosis in Europe. J Cyst Fibros 2011; 10 (Suppl. 02) S53-S66
    PubMedGoogle Scholar
  • 11 Smyth AR, Bell SC, Bojcin S. , et al; European Cystic Fibrosis Society. European cystic fibrosis society standards of care: best practice guidelines. J Cyst Fibros 2014; 13 (Suppl. 01) S23-S42
    PubMedGoogle Scholar
  • 12 Farrell PM, White TB, Ren CL. , et al. Diagnosis of cystic fibrosis: consensus guidelines from the cystic fibrosis foundation. J Pediatr 2017; 181S: S4-S15 , 15.e1
    PubMedGoogle Scholar
  • 13 Bahassi M, Stambrook PJ. Next-generation sequencing technologies: breaking the sound barrier of human genetics. Mutagenesis 2014; 29 (05) 303-310
    CrossrefPubMedGoogle Scholar
  • 14 Grosu DS, Hague L, Chelliserry M. , et al. Clinical investigational studies for validation of a next-generation sequencing in vitro diagnostic device for cystic fibrosis testing. Expert Rev Mol Diagn 2014; 14 (05) 605-622
    CrossrefPubMedGoogle Scholar
  • 15 Baker MW, Atkins AE, Cordovado SK, Hendrix M, Earley MC, Farrell PM. Improving newborn screening for cystic fibrosis using next-generation sequencing technology: a technical feasibility study. Genet Med 2016; 18 (03) 231-238
    PubMedGoogle Scholar
  • 16 Trujillano D, Ramos MD, González J. , et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet 2013; 50 (07) 455-462
    CrossrefPubMedGoogle Scholar
  • 17 Loukas YL, Thodi G, Molou E, Georgiou V, Dotsikas Y, Schulpis KH. Clinical diagnostic Next-Generation sequencing: the case of CFTR carrier screening. Scand J Clin Lab Invest 2015; 75 (05) 374-381
    CrossrefPubMedGoogle Scholar
  • 18 Essawi O, Farraj M, De Leeneer K. , et al. Next generation sequencing to determine the cystic fibrosis mutation spectrum in Palestinian population. Dis Markers 2015; 2015: 458653
    PubMedGoogle Scholar
  • 19 Sheth S, Shea JC, Bishop MD. , et al. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet 2003; 113 (03) 286-292
    CrossrefPubMedGoogle Scholar
  • 20 Gallegos-Orozco JF, , E Yurk C, Wang N. , et al. Lack of association of common cystic fibrosis transmembrane conductance regulator gene mutations with primary sclerosing cholangitis. Am J Gastroenterol 2005; 100 (04) 874-878
    CrossrefPubMedGoogle Scholar
  • 21 Sorensen RU, Stern RC, Chase P, Polmar SH. Defective cellular immunity to gram-negative bacteria in cystic fibrosis patients. Infect Immun 1979; 23 (02) 398-402
    CrossrefPubMedGoogle Scholar
  • 22 Ferrer Marcelles A, Bellver Moreira P, Cobos Barroso N, Liñán Cortés S, Codina Grau G, Fernández Pérez F. Cystic fibrosis: a microbiological study over an 8-year period [in Spanish]. Arch Bronconeumol 1995; 31 (10) 494-500
    CrossrefPubMedGoogle Scholar
  • 23 Blau H, Linnane B, Carzino R. , et al. Induced sputum compared to bronchoalveolar lavage in young, non-expectorating cystic fibrosis children. J Cyst Fibros 2014; 13 (01) 106-110
    CrossrefPubMedGoogle Scholar
  • 24 McCarthy MM, Rourk MH, Spock A. Bacteremia in patients with cystic fibrosis. Clin Pediatr (Phila) 1980; 19 (11) 746-748
    CrossrefPubMedGoogle Scholar
  • 25 World Health Organization. https://www.who.int/genomics/public/geneticdiseases/en/index2.html#CF . Accessed September 20, 2018
    PubMed