Genotypes and Phenotypes in Cystic Fibrosis and Cystic Fibrosis Transmembrane Regulator–Related Disorders

Abstract

Cystic fibrosis (CF) is characterized by remarkable variability in severity, rate of disease progression, and organ involvement. In spite of the considerable amount of data collected on the relationship between genotype and phenotype in CF, this is still a challenging matter of debate. Barriers to the interpretation of this connection are the large number of mutations in the CF transmembrane regulator (CFTR) gene, the difficulties in attributing several of them to a specific mode of dysfunction, and a limited number of the almost 2,000 mutations so far detected, which have been clinically annotated. In addition to that, the heterogeneity of clinical manifestations in individuals with the same CFTR genotypes indicates that disease severity is modulated by other genes and by environmental factors, of which the most relevant is possibly treatment in its aspects of appropriateness, early start in life, and adherence. The phenotype variability extends to conditions, named CFTR-related disorders, which are connected with CFTR dysfunction, but do not satisfy diagnostic criteria for CF. The current level of knowledge does not allow use of the CFTR genotype to predict individual outcome and cannot be used as an indicator of CF prognosis. This might change with the development of treatments targeting specific mutations and possibly capable of changing the natural history of the disease.

Keywords

cystic fibrosis - CFTR-related disorders - CFTR mutations - genotype–phenotype correlations - CBAVD - pancreatitis - bronchiectasis - modifier genes

• References

• 1 Rowntree RK, Harris A. The phenotypic consequences of CFTR mutations. Ann Hum Genet 2003; 67 (Pt 5) 471-485
• 2 Castellani C, Cuppens H, Macek Jr M , et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros 2008; 7 (3) 179-196
• 3 Knowles MR, Durie PR. What is cystic fibrosis?. N Engl J Med 2002; 347 (6) 439-442
• 4 Bombieri C, Claustres M, De Boeck K , et al. Recommendations for the classification of diseases as CFTR-related disorders. J Cyst Fibros 2011; 10 (Suppl. 02) S86-S102
• 5 Borowitz D, Parad RB, Sharp JK , et al; Cystic Fibrosis Foundation. Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond. J Pediatr 2009; 155 (6, Suppl): S106-S116
• 6 Ellsworth RE, Jamison DC, Touchman JW , et al. Comparative genomic sequence analysis of the human and mouse cystic fibrosis transmembrane conductance regulator genes. Proc Natl Acad Sci U S A 2000; 97 (3) 1172-1177
• 7 Riordan JR, Rommens JM, Kerem B , et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245 (4922) 1066-1073
• 8 Zielenski J, Rozmahel R, Bozon D , et al. Genomic DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics 1991; 10 (1) 214-228
• 9 Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration 2000; 67 (2) 117-133
• 10 Cystic Fibrosis Mutation Database Available at: http://www.genet.sickkids.on.ca/cftr
• 11 The Molecular Genetic Epidemiology of Cystic Fibrosis. Report of a Joint Meeting of WHO/ECFTN/ICF(M)A/ECFS. Available at: http://www.who.int/genomics/publicstions/en and WHO Geneva, Human Genetics Programme WHO/HGN/CF/WG/04.02
• 12 Morral N, Bertranpetit J, Estivill X , et al. The origin of the major cystic fibrosis mutation (delta F508) in European populations. Nat Genet 1994; 7 (2) 169-175
• 13 Macek Jr M, Mackova A, Hamosh A , et al. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%. Am J Hum Genet 1997; 60 (5) 1122-1127
• 14 Onay T, Zielenski J, Topaloglu O , et al. Cystic fibrosis mutations and associated haplotypes in Turkish cystic fibrosis patients. Hum Biol 2001; 73 (2) 191-203
• 15 Popa I, Pop L, Popa Z , et al. Cystic fibrosis mutations in Romania. Eur J Pediatr 1997; 156 (3) 212-213
• 16 Bobadilla JL, Macek Jr M, Fine JP, Farrell PM. Cystic fibrosis: a worldwide analysis of CFTR mutations—correlation with incidence data and application to screening. Hum Mutat 2002; 19 (6) 575-606
• 17 Lao O, Andrés AM, Mateu E, Bertranpetit J, Calafell F. Spatial patterns of cystic fibrosis mutation spectra in European populations. Eur J Hum Genet 2003; 11 (5) 385-394
• 18 Mateu E, Calafell F, Ramos MD, Casals T, Bertranpetit J. Can a place of origin of the main cystic fibrosis mutations be identified?. Am J Hum Genet 2002; 70 (1) 257-264
• 19 Tsui LC. The spectrum of cystic fibrosis mutations. Trends Genet 1992; 8 (11) 392-398
• 20 Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993; 73 (7) 1251-1254
• 21 Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 1995; 29: 777-807
• 22 Frischmeyer PA, Dietz HC. Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet 1999; 8 (10) 1893-1900
• 23 Hentze MW, Kulozik AE. A perfect message: RNA surveillance and nonsense-mediated decay. Cell 1999; 96 (3) 307-310
• 24 Mickle JE, Macek Jr M, Fulmer-Smentek SB , et al. A mutation in the cystic fibrosis transmembrane conductance regulator gene associated with elevated sweat chloride concentrations in the absence of cystic fibrosis. Hum Mol Genet 1998; 7 (4) 729-735
• 25 Claustres M, Guittard C, Bozon D , et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat 2000; 16 (2) 143-156
• 26 Boyle MP, De Boeck K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med 2013; 1 (2) 158-163 [Erratum in: Lancet Respir Med 2013;1(2):101]
• 27 Anderson MP, Welsh MJ. Regulation by ATP and ADP of CFTR chloride channels that contain mutant nucleotide-binding domains. Science 1992; 257 (5077) 1701-1704
• 28 Schwiebert EM, Egan ME, Hwang TH , et al. CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP. Cell 1995; 81 (7) 1063-1073
• 29 Accurso FJ, Rowe SM, Clancy JP , et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 2010; 363 (21) 1991-2003
• 30 Ramsey BW, Davies J, McElvaney NG , et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365 (18) 1663-1672
• 31 Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature 1993; 362 (6416) 160-164
• 32 Akabas MH, Kaufmann C, Cook TA, Archdeacon P. Amino acid residues lining the chloride channel of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 1994; 269 (21) 14865-14868
• 33 Seibert FS, Linsdell P, Loo TW, Hanrahan JW, Riordan JR, Clarke DM. Cytoplasmic loop three of cystic fibrosis transmembrane conductance regulator contributes to regulation of chloride channel activity. J Biol Chem 1996; 271 (44) 27493-27499
• 34 Highsmith WE, Burch LH, Zhou Z , et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med 1994; 331 (15) 974-980
• 35 De Braekeleer M, Allard C, Leblanc JP, Simard F, Aubin G. Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Hum Genet 1997; 101 (2) 208-211
• 36 Sheppard DN, Ostedgaard LS, Winter MC, Welsh MJ. Mechanism of dysfunction of two nucleotide binding domain mutations in cystic fibrosis transmembrane conductance regulator that are associated with pancreatic sufficiency. EMBO J 1995; 14 (5) 876-883
• 37 Haardt M, Benharouga M, Lechardeur D, Kartner N, Lukacs GL. C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. A novel class of mutation. J Biol Chem 1999; 274 (31) 21873-21877
• 38 McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet 2003; 361 (9370) 1671-1676
• 39 McKone EF, Goss CH, Aitken ML. CFTR genotype as a predictor of prognosis in cystic fibrosis. Chest 2006; 130 (5) 1441-1447
• 40 Ferec C, Cutting GR. Assessing the Disease-Liability of Mutations in CFTR. Cold Spring Harb Perspect Med 2012; 2 (12) a009480
• 41 Kerem E, Kerem B. Genotype-phenotype correlations in cystic fibrosis. Pediatr Pulmonol 1996; 22 (6) 387-395
• 42 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 (5) 387-391
• 43 American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 486: Update on carrier screening for cystic fibrosis. Obstet Gynecol 2011; 117 (4) 1028-1031
• 44 Ramalho AS, Beck S, Penque D , et al. Transcript analysis of the cystic fibrosis splicing mutation 1525-1G>A shows use of multiple alternative splicing sites and suggests a putative role of exonic splicing enhancers. J Med Genet 2003; 40 (7) e88
• 45 Zielenski J, Bozon D, Markiewicz D , et al. Analysis of CFTR transcripts in nasal epithelial cells and lymphoblasts of a cystic fibrosis patient with 621 + 1G—>T and 711 + 1G—>T mutations. Hum Mol Genet 1993; 2 (6) 683-687
• 46 Chu CS, Trapnell BC, Curristin S, Cutting GR, Crystal RG. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet 1993; 3 (2) 151-156
• 47 Amaral MD, Pacheco P, Beck S , et al. Cystic fibrosis patients with the 3272-26A>G splicing mutation have milder disease than F508del homozygotes: a large European study. J Med Genet 2001; 38 (11) 777-783
• 48 Kerem E, Rave-Harel N, Augarten A , et al. A cystic fibrosis transmembrane conductance regulator splice variant with partial penetrance associated with variable cystic fibrosis presentations. Am J Respir Crit Care Med 1997; 155 (6) 1914-1920
• 49 Ramalho AS, Beck S, Meyer M, Penque D, Cutting GR, Amaral MD. Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis. Am J Respir Cell Mol Biol 2002; 27 (5) 619-627
• 50 Rave-Harel N, Kerem E, Nissim-Rafinia M , et al. The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. Am J Hum Genet 1997; 60 (1) 87-94
• 51 Chiba-Falek O, Kerem E, Shoshani T , et al. The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C—>T mutation. Genomics 1998; 53 (3) 276-283
• 52 Highsmith Jr WE, Burch LH, Zhou Z , et al. Identification of a splice site mutation (2789 +5 G > A) associated with small amounts of normal CFTR mRNA and mild cystic fibrosis. Hum Mutat 1997; 9 (4) 332-338
• 53 Chillón M, Dörk T, Casals T , et al. A novel donor splice site in intron 11 of the CFTR gene, created by mutation 1811+1.6kbA—>G, produces a new exon: high frequency in Spanish cystic fibrosis chromosomes and association with severe phenotype. Am J Hum Genet 1995; 56 (3) 623-629
• 54 Pagani F, Stuani C, Tzetis M , et al. New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12. Hum Mol Genet 2003; 12 (10) 1111-1120
• 55 Nissim-Rafinia M, Kerem B. The splicing machinery is a genetic modifier of disease severity. Trends Genet 2005; 21 (9) 480-483
• 56 Teng H, Jorissen M, Van Poppel H, Legius E, Cassiman JJ, Cuppens H. Increased proportion of exon 9 alternatively spliced CFTR transcripts in vas deferens compared with nasal epithelial cells. Hum Mol Genet 1997; 6 (1) 85-90
• 57 Mak V, Jarvi KA, Zielenski J, Durie P, Tsui LC. Higher proportion of intact exon 9 CFTR mRNA in nasal epithelium compared with vas deferens. Hum Mol Genet 1997; 6 (12) 2099-2107
• 58 Chiba-Falek O, Parad RB, Kerem E, Kerem B. Variable levels of normal RNA in different fetal organs carrying a cystic fibrosis transmembrane conductance regulator splicing mutation. Am J Respir Crit Care Med 1999; 159 (6) 1998-2002
• 59 Castellani C ; CFTR2 team. CFTR2: How will it help care?. Paediatr Respir Rev 2013; 14 (Suppl. 01) 2-5
• 60 Sosnay PR, Siklosi KR, Van Goor F , et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet 2013; 45 (10) 1160-1167
• 61 Clinical and Functional Translation of CFTR (CFTR2) Project Available at: http://www.cftr2.org
• 62 Borgo G, Gasparini P, Bonizzato A, Cabrini G, Mastella G, Pignatti PF. Cystic fibrosis: the delta F508 mutation does not lead to an exceptionally severe phenotype. A cohort study. Eur J Pediatr 1993; 152 (12) 1006-1011
• 63 Lai HJ, Cheng Y, Cho H, Kosorok MR, Farrell PM. Association between initial disease presentation, lung disease outcomes, and survival in patients with cystic fibrosis. Am J Epidemiol 2004; 159 (6) 537-546
• 64 Santis G, Osborne L, Knight RA, Hodson ME. Independent genetic determinants of pancreatic and pulmonary status in cystic fibrosis. Lancet 1990; 336 (8723) 1081-1084
• 65 Lester LA, Kraut J, Lloyd-Still J , et al. Delta F508 genotype does not predict disease severity in an ethnically diverse cystic fibrosis population. Pediatrics 1994; 93 (1) 114-118
• 66 Vanscoy LL, Blackman SM, Collaco JM , et al. Heritability of lung disease severity in cystic fibrosis. Am J Respir Crit Care Med 2007; 175 (10) 1036-1043
• 67 Mekus F, Ballmann M, Bronsveld I, Bijman J, Veeze H, Tümmler B. Categories of deltaF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics. Twin Res 2000; 3 (4) 277-293
• 68 Corey M, Edwards L, Levison H, Knowles M. Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis. J Pediatr 1997; 131 (6) 809-814
• 69 Geborek A, Hjelte L. Association between genotype and pulmonary phenotype in cystic fibrosis patients with severe mutations. J Cyst Fibros 2011; 10 (3) 187-192
• 70 de Gracia J, Mata F, Alvarez A , et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax 2005; 60 (7) 558-563
• 71 Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cystic fibrosis. In: Scriver C, Vogelstein B, Beaudet AL, , et al., eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill Professional; 2001: 5121-5188
• 72 Knowles MR, Drumm M. The influence of genetics on cystic fibrosis phenotypes. Cold Spring Harb Perspect Med 2012; 2 (12) a009548
• 73 Gaskin KJ, Durie P, Lee L, Hill R, Forstner GG. Colipase and lipase secretion in childhood-onset pancreatic insufficiency. Delineation of patients with steatorrhea secondary to relative colipase deficiency. Gastroenterology 1984; 86 (1) 1-7
• 74 Durno C, Corey M, Zielenski J, Tullis E, Tsui L-C, Durie P. Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology 2002; 123 (6) 1857-1864
• 75 Augarten A, Ben Tov A, Madgar I , et al. The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype. Eur J Gastroenterol Hepatol 2008; 20 (3) 164-168
• 76 Ooi CY, Dorfman R, Cipolli M , et al. Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology 2011; 140 (1) 153-161
• 77 Taussig LM, Lobeck CC, di Sant'Agnese PA, Ackerman DR, Kattwinkel J. Fertility in males with cystic fibrosis. N Engl J Med 1972; 287 (12) 586-589
• 78 Wilschanski M, Corey M, Durie P , et al. Diversity of reproductive tract abnormalities in men with cystic fibrosis. JAMA 1996; 276 (8) 607-608
• 79 Koch C, Cuppens H, Rainisio M , et al; Investigators of the ERCF. European Epidemiologic Registry of Cystic Fibrosis (ERCF): comparison of major disease manifestations between patients with different classes of mutations. Pediatr Pulmonol 2001; 31 (1) 1-12
• 80 Wilschanski M, Rivlin J, Cohen S , et al. Clinical and genetic risk factors for cystic fibrosis-related liver disease. Pediatrics 1999; 103 (1) 52-57
• 81 Blackman SM, Deering-Brose R, McWilliams R , et al. Relative contribution of genetic and nongenetic modifiers to intestinal obstruction in cystic fibrosis. Gastroenterology 2006; 131 (4) 1030-1039
• 82 Allan JL, Robbie M, Phelan PD, Danks DM. Familial occurrence of meconium ileus. Eur J Pediatr 1981; 135 (3) 291-292
• 83 Kerem E, Corey M, Kerem B, Durie P, Tsui LC, Levison H. Clinical and genetic comparisons of patients with cystic fibrosis, with or without meconium ileus. J Pediatr 1989; 114 (5) 767-773
• 84 Drumm ML, Konstan MW, Schluchter MD , et al; Gene Modifier Study Group. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 2005; 353 (14) 1443-1453
• 85 Bartlett JR, Friedman KJ, Ling SC , et al; Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA 2009; 302 (10) 1076-1083
• 86 Blackman SM, Commander CW, Watson C , et al. Genetic modifiers of cystic fibrosis-related diabetes. Diabetes 2013; 62 (10) 3627-3635
• 87 Cutting GR. Modifier genes in Mendelian disorders: the example of cystic fibrosis. Ann N Y Acad Sci 2010; 1214: 57-69
• 88 Weiler CA, Drumm ML. Genetic influences on cystic fibrosis lung disease severity. Front Pharmacol 2013; 4: 40
• 89 Gallati S. Disease-modifying genes and monogenic disorders: experience in cystic fibrosis. Appl Clin Genet 2014; 7: 133-146
• 90 Guillot L, Beucher J, Tabary O, Le Rouzic P, Clement A, Corvol H. Lung disease modifier genes in cystic fibrosis. Int J Biochem Cell Biol 2014; 52: 83-93
• 91 Garred P, Pressler T, Madsen HO , et al. Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest 1999; 104 (4) 431-437
• 92 Griese M, Birrer P, Demirsoy A. Pulmonary surfactant in cystic fibrosis. Eur Respir J 1997; 10 (9) 1983-1988
• 93 Postle AD, Mander A, Reid KB , et al. Deficient hydrophilic lung surfactant proteins A and D with normal surfactant phospholipid molecular species in cystic fibrosis. Am J Respir Cell Mol Biol 1999; 20 (1) 90-98
• 94 Singh PK, Jia HP, Wiles K , et al. Production of beta-defensins by human airway epithelia. Proc Natl Acad Sci U S A 1998; 95 (25) 14961-14966 [Erratum in: Proc Natl Acad Sci U S A 1999;96(5):2569]
• 95 Crovella S, Segat L, Amato A , et al. A polymorphism in the 5′ UTR of the DEFB1 gene is associated with the lung phenotype in F508del homozygous Italian cystic fibrosis patients. Clin Chem Lab Med 2011; 49 (1) 49-54
• 96 Tesse R, Cardinale F, Santostasi T , et al. Association of beta-defensin-1 gene polymorphisms with Pseudomonas aeruginosa airway colonization in cystic fibrosis. Genes Immun 2008; 9 (1) 57-60
• 97 Hull J, Thomson AH. Contribution of genetic factors other than CFTR to disease severity in cystic fibrosis. Thorax 1998; 53 (12) 1018-1021
• 98 Bremer LA, Blackman SM, Vanscoy LL , et al. Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis. Hum Mol Genet 2008; 17 (14) 2228-2237
• 99 Corvol H, Boelle PY, Brouard J , et al. Genetic variations in inflammatory mediators influence lung disease progression in cystic fibrosis. Pediatr Pulmonol 2008; 43 (12) 1224-1232
• 100 Arkwright PD, Pravica V, Geraghty PJ , et al. End-organ dysfunction in cystic fibrosis: association with angiotensin I converting enzyme and cytokine gene polymorphisms. Am J Respir Crit Care Med 2003; 167 (3) 384-389
• 101 Wright FA, Strug LJ, Doshi VK , et al. Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nat Genet 2011; 43 (6) 539-546
• 102 Hillian AD, Londono D, Dunn JM , et al; CF Gene Modifier Study Group. Modulation of cystic fibrosis lung disease by variants in interleukin-8. Genes Immun 2008; 9 (6) 501-508
• 103 Brouard J, Knauer N, Boelle PY , et al. Influence of interleukin-10 on Aspergillus fumigatus infection in patients with cystic fibrosis. J Infect Dis 2005; 191 (11) 1988-1991
• 104 Dorfman R, Sandford A, Taylor C , et al. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J Clin Invest 2008; 118 (3) 1040-1049
• 105 McDougal KE, Green DM, Vanscoy LL , et al. Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis. Eur J Hum Genet 2010; 18 (6) 680-684
• 106 Chalmers JD, Fleming GB, Hill AT, Kilpatrick DC. Impact of mannose-binding lectin insufficiency on the course of cystic fibrosis: A review and meta-analysis. Glycobiology 2011; 21 (3) 271-282
• 107 Vankeerberghen A, Scudiero O, De Boeck K , et al. Distribution of human beta-defensin polymorphisms in various control and cystic fibrosis populations. Genomics 2005; 85 (5) 574-581
• 108 Laki J, Laki I, Németh K , et al. The 8.1 ancestral MHC haplotype is associated with delayed onset of colonization in cystic fibrosis. Int Immunol 2006; 18 (11) 1585-1590
• 109 Beucher J, Boëlle PY, Busson PF, Muselet-Charlier C, Clement A, Corvol H ; French C F Modifier Gene Study Investigators. AGER -429T/C is associated with an increased lung disease severity in cystic fibrosis. PLoS ONE 2012; 7 (7) e41913
• 110 Corvol H, Beucher J, Boëlle PY , et al. Ancestral haplotype 8.1 and lung disease severity in European cystic fibrosis patients. J Cyst Fibros 2012; 11 (1) 63-67
• 111 Gu Y, Harley IT, Henderson LB , et al. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature 2009; 458 (7241) 1039-1042
• 112 Frangolias DD, Ruan J, Wilcox PJ , et al. Alpha 1-antitrypsin deficiency alleles in cystic fibrosis lung disease. Am J Respir Cell Mol Biol 2003; 29 (3, Pt 1) 390-396
• 113 Mahadeva R, Stewart S, Bilton D, Lomas DA. Alpha-1 antitrypsin deficiency alleles and severe cystic fibrosis lung disease. Thorax 1998; 53 (12) 1022-1024
• 114 Dorfman R, Li W, Sun L , et al. Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results. Hum Genet 2009; 126 (6) 763-778
• 115 Sun L, Rommens JM, Corvol H , et al. Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nat Genet 2012; 44 (5) 562-569
• 116 Li W, Soave D, Miller MR , et al. Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities. Hum Genet 2014; 133 (2) 151-161
• 117 Dorfman R, Taylor C, Lin F , et al; Members of Canadian Consortium for CF Genetic Studies. Modulatory effect of the SLC9A3 gene on susceptibility to infections and pulmonary function in children with cystic fibrosis. Pediatr Pulmonol 2011; 46 (4) 385-392
• 118 Viel M, Leroy C, Hubert D, Fajac I, Bienvenu T. ENaCbeta and gamma genes as modifier genes in cystic fibrosis. J Cyst Fibros 2008; 7 (1) 23-29
• 119 Marson FA, Bertuzzo CS, Hortencio TD, Ribeiro JD, Bonadia LC, Ribeiro AF. The ACE gene D/I polymorphism as a modulator of severity of cystic fibrosis. BMC Pulm Med 2012; 12: 41
• 120 Flamant C, Henrion-Caude A, Boëlle PY , et al. Glutathione-S-transferase M1, M3, P1 and T1 polymorphisms and severity of lung disease in children with cystic fibrosis. Pharmacogenetics 2004; 14 (5) 295-301
• 121 Feuillet-Fieux MN, Nguyen-Khoa T, Loriot MA , et al. Glutathione S-transferases related to P. aeruginosa lung infection in cystic fibrosis children: preliminary study. Clin Biochem 2009; 42 (1-2) 57-63
• 122 Henrion-Caude A, Flamant C, Roussey M , et al. Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism. Hepatology 2002; 36 (4, Pt 1) 913-917
• 123 Grasemann H, Knauer N, Büscher R, Hübner K, Drazen JM, Ratjen F. Airway nitric oxide levels in cystic fibrosis patients are related to a polymorphism in the neuronal nitric oxide synthase gene. Am J Respir Crit Care Med 2000; 162 (6) 2172-2176
• 124 Grasemann H, Storm van's Gravesande K, Buscher R , et al. Endothelial nitric oxide synthase variants in cystic fibrosis lung disease. Am J Respir Crit Care Med 2003; 167 (3) 390-394
• 125 Grasemann H, Storm van's Gravesande K, Gärtig S , et al. Nasal nitric oxide levels in cystic fibrosis patients are associated with a neuronal NO synthase (NOS1) gene polymorphism. Nitric Oxide 2002; 6 (2) 236-241
• 126 Texereau J, Marullo S, Hubert D , et al. Nitric oxide synthase 1 as a potential modifier gene of decline in lung function in patients with cystic fibrosis. Thorax 2004; 59 (2) 156-158
• 127 Sharer N, Schwarz M, Malone G , et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998; 339 (10) 645-652
• 128 Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998; 339 (10) 653-658
• 129 Castellani C, Bonizzato A, Rolfini R, Frulloni L, Cavallini GC, Mastella G. Increased prevalence of mutations of the cystic fibrosis gene in idiopathic chronic and recurrent pancreatitis. Am J Gastroenterol 1999; 94 (7) 1993-1995
• 130 Castellani C, Gomez Lira M, Frulloni L , et al. Analysis of the entire coding region of the cystic fibrosis transmembrane regulator gene in idiopathic pancreatitis. Hum Mutat 2001; 18 (2) 166
• 131 Dumur V, Gervais R, Rigot JM , et al. Abnormal distribution of CF delta F508 allele in azoospermic men with congenital aplasia of epididymis and vas deferens. Lancet 1990; 336 (8713) 512
• 132 Anguiano A, Oates RD, Amos JA , et al. Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis. JAMA 1992; 267 (13) 1794-1797
• 133 Bombieri C, Benetazzo M, Saccomani A , et al. Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease. Hum Genet 1998; 103 (6) 718-722
• 134 Girodon E, Sternberg D, Chazouillères O , et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene defects in patients with primary sclerosing cholangitis. J Hepatol 2002; 37 (2) 192-197
• 135 Miller PW, Hamosh A, Macek Jr M , et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis. Am J Hum Genet 1996; 59 (1) 45-51
• 136 Raman V, Clary R, Siegrist KL, Zehnbauer B, Chatila TA. Increased prevalence of mutations in the cystic fibrosis transmembrane conductance regulator in children with chronic rhinosinusitis. Pediatrics 2002; 109 (1) E13
• 137 Wang X, Moylan B, Leopold DA , et al. Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population. JAMA 2000; 284 (14) 1814-1819
• 138 Mak V, Jarvi KA. The genetics of male infertility. J Urol 1996; 156 (4) 1245-1256 , discussion 1256–1257
• 139 Cuppens H, Cassiman J-J. CFTR mutations and polymorphisms in male infertility. Int J Androl 2004; 27 (5) 251-256
• 140 Claustres M. Molecular pathology of the CFTR locus in male infertility. Reprod Biomed Online 2005; 10 (1) 14-41
• 141 Jarvi K, McCallum S, Zielenski J , et al. Heterogeneity of reproductive tract abnormalities in men with absence of the vas deferens: role of cystic fibrosis transmembrane conductance regulator gene mutations. Fertil Steril 1998; 70 (4) 724-728
• 142 Stuhrmann M, Dörk T. CFTR gene mutations and male infertility. Andrologia 2000; 32 (2) 71-83
• 143 Casals T, Bassas L, Egozcue S , et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod 2000; 15 (7) 1476-1483
• 144 Groman JD, Hefferon TW, Casals T , et al. Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign. Am J Hum Genet 2004; 74 (1) 176-179
• 145 Thauvin-Robinet C, Munck A, Huet F , et al; collaborating working group on p.Arg117His. CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders. J Med Genet 2013; 50 (4) 220-227
• 146 Ratbi I, Legendre M, Niel F , et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod 2007; 22 (5) 1285-1291
• 147 Taulan M, Girardet A, Guittard C , et al. Large genomic rearrangements in the CFTR gene contribute to CBAVD. BMC Med Genet 2007; 8: 22
• 148 Bareil C, Guittard C, Altieri J-P, Templin C, Claustres M, des Georges M. Comprehensive and rapid genotyping of mutations and haplotypes in congenital bilateral absence of the vas deferens and other cystic fibrosis transmembrane conductance regulator-related disorders. J Mol Diagn 2007; 9 (5) 582-588
• 149 Dörk T, Dworniczak B, Aulehla-Scholz C , et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet 1997; 100 (3-4) 365-377
• 150 Mercier B, Verlingue C, Lissens W , et al. Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients. Am J Hum Genet 1995; 56 (1) 272-277
• 151 Rave-Harel N, Madgar I, Goshen R , et al. CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens. Am J Hum Genet 1995; 56 (6) 1359-1366
• 152 Weiske WH, Sälzler N, Schroeder-Printzen I, Weidner W. Clinical findings in congenital absence of the vasa deferentia. Andrologia 2000; 32 (1) 13-18
• 153 Sakamoto H, Yajima T, Suzuki K, Ogawa Y. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation associated with a congenital bilateral absence of vas deferens. Int J Urol 2008; 15 (3) 270-271
• 154 Josserand RN, Bey-Omar F, Rollet J , et al. Cystic fibrosis phenotype evaluation and paternity outcome in 50 males with congenital bilateral absence of vas deferens. Hum Reprod 2001; 16 (10) 2093-2097
• 155 Gilljam M, Moltyaner Y, Downey GP , et al. Airway inflammation and infection in congenital bilateral absence of the vas deferens. Am J Respir Crit Care Med 2004; 169 (2) 174-179
• 156 Whitcomb DC. Genetic aspects of pancreatitis. Annu Rev Med 2010; 61: 413-424
• 157 Chen JM, Férec C. Genetics and pathogenesis of chronic pancreatitis: the 2012 update. Clin Res Hepatol Gastroenterol 2012; 36 (4) 334-340
• 158 Whitcomb DC. Genetic risk factors for pancreatic disorders. Gastroenterology 2013; 144 (6) 1292-1302
• 159 Noone PG, Zhou Z, Silverman LM, Jowell PS, Knowles MR, Cohn JA. Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastroenterology 2001; 121 (6) 1310-1319
• 160 Weiss FU, Simon P, Bogdanova N , et al. Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut 2005; 54 (10) 1456-1460
• 161 Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas 2006; 33 (3) 221-227
• 162 Tzetis M, Kaliakatsos M, Fotoulaki M , et al. Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis. Clin Genet 2007; 71 (5) 451-457
• 163 de Cid R, Ramos MD, Aparisi L , et al. Independent contribution of common CFTR variants to chronic pancreatitis. Pancreas 2010; 39 (2) 209-215
• 164 Audrézet MP, Chen JM, Le Maréchal C , et al. Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis. Eur J Hum Genet 2002; 10 (2) 100-106
• 165 Cohn JA. Reduced CFTR function and the pathobiology of idiopathic pancreatitis. J Clin Gastroenterol 2005; 39 (4) (Suppl. 02) S70-S77
• 166 McShane PJ, Naureckas ET, Tino G, Strek ME. Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2013; 188 (6) 647-656
• 167 King P. Pathogenesis of bronchiectasis. Paediatr Respir Rev 2011; 12 (2) 104-110
• 168 Pasteur MC, Helliwell SM, Houghton SJ , et al. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med 2000; 162 (4, Pt 1) 1277-1284
• 169 Casals T, De-Gracia J, Gallego M , et al. Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations?. Clin Genet 2004; 65 (6) 490-495
• 170 Pignatti PF, Bombieri C, Benetazzo M , et al. CFTR gene variant IVS8-5T in disseminated bronchiectasis. Am J Hum Genet 1996; 58 (4) 889-892
• 171 Girodon E, Cazeneuve C, Lebargy F , et al. CFTR gene mutations in adults with disseminated bronchiectasis. Eur J Hum Genet 1997; 5 (3) 149-155
• 172 Tzetis M, Efthymiadou A, Strofalis S , et al. CFTR gene mutations—including three novel nucleotide substitutions—and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Genet 2001; 108 (3) 216-221
• 173 King PT, Freezer NJ, Holmes PW, Holdsworth SR, Forshaw K, Sart DD. Role of CFTR mutations in adult bronchiectasis. Thorax 2004; 59 (4) 357-358
• 174 Ziedalski TM, Kao PN, Henig NR, Jacobs SS, Ruoss SJ. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest 2006; 130 (4) 995-1002
• 175 Milosevic K, Nikolic A, Divac Rankov A, Ljujic M, Nestorovic B, Radojkovic D. Analysis of CFTR Gene Variants in Idiopathic Bronchiectasis in Serbian Children. Pediatr Allergy Immunol Pulmonol 2013; 26 (2) 93-98
• 176 Puéchal X, Bienvenu T, Génin E , et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis 2011; 70 (4) 653-659
• 177 Bienvenu T, Sermet-Gaudelus I, Burgel PR , et al. Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2010; 181 (10) 1078-1084
• 178 Carter K, Currie GP, Devereux G. Patients with bronchiectasis: look for specific causes. QJM 2006; 99 (3) 196-197
• 179 Hubert D, Fajac I, Bienvenu T , et al. Diagnosis of cystic fibrosis in adults with diffuse bronchiectasis. J Cyst Fibros 2004; 3 (1) 15-22
• 180 Mott LS, Gangell CL, Murray CP, Stick SM, Sly PD ; AREST CF. Bronchiectasis in an asymptomatic infant with cystic fibrosis diagnosed following newborn screening. J Cyst Fibros 2009; 8 (4) 285-287
• 181 Noone PG, Knowles MR. ‘CFTR-opathies’: disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations. Respir Res 2001; 2 (6) 328-332