E Kerem, N Rave-Harel, A Augarten, I Madgar, M Nissim-Rafinia, Y Yahav, R Goshen, L Bentur, J Rivlin, M Aviram, A Genem, O Chiba-Falek, MR Kraemer, A Simon, D Branski and B Kerem
Department of Pediatrics, Cystic Fibrosis Clinic, Shaare Zedek Medical Center, Jerusalem, Israel.

Some patients express various features of cystic fibrosis (CF) even though essential characteristics of the disease might be absent. Such patients may suffer from respiratory disease without pancreatic insufficiency and normal sweat chloride levels. Others may present as male infertility because of congenital bilateral aplasia of the vas deferens (CBAVD) with no other signs of CF. The 5T allele, a DNA variant in a noncoding region of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that reduces the level of the normal CFTR transcripts, was found in increased frequency among male patients with CBAVD. The purpose of this study was to investigate the possibility that the 5T allele is associated with dysfunction of organs other than the male reproductive system, leading to CF or atypical CF. Analysis of the 5T allele was performed on 148 subjects (29 with CF, 61 with atypical CF, and 58 with CBAVD) carrying 232 chromosomes with unidentified CFTR mutations, and on 142 non-CF chromosomes from healthy subjects of Ashkenazi origin. The frequency of the 5T allele among chromosomes from patients of Jewish Ashkenazi origin with CF and atypical CF (six of 33; 18%) was significantly higher than the frequency in the normal Ashkenazi population (eight of 142; 6%; p = 0.03). Analysis of the clinical presentation of the five patients with CF and the 12 patients with atypical CF carrying the 5T allele indicated that most patients suffered from respiratory disease presenting as asthma like symptoms, nasal polyposis, chronic sinusitis, chronic bronchitis, or bronchiectasis. Six patients had pancreatic insufficiency, two with meconium ileus. Sweat Cl- levels ranged from normal to elevated. Of the six male patients with respiratory disease who were old enough to be evaluated for fertility status, five were fertile and one had pancreatic insufficiency. Among male patients with CBAVD, 41% suffered from respiratory symptoms. Thus, the 5T allele is a variant with partial penetrance causing disease with an extreme variability of clinical presentation: from normal healthy fertile subjects or male patients with CBAVD to those with atypical or typical clinical phenotype of CF.

This article has been cited by other articles:

				Y. Yaakov, E. Kerem, Y. Yahav, J. Rivlin, H. Blau, L. Bentur, M. Aviram, E. Picard, T. Bdolah-Abram, and M. Wilschanski Reproducibility of Nasal Potential Difference Measurements in Cystic Fibrosis Chest, October 1, 2007; 132(4): 1219 - 1226. [Abstract] [Full Text] [PDF]

				F. Pagani, C. Stuani, M. Tzetis, E. Kanavakis, A. Efthymiadou, S. Doudounakis, T. Casals, and F. E. Baralle New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12 Hum. Mol. Genet., May 15, 2003; 12(10): 1111 - 1120. [Abstract] [Full Text] [PDF]

				J. B. Lyczak, C. L. Cannon, and G. B. Pier Lung Infections Associated with Cystic Fibrosis Clin. Microbiol. Rev., April 1, 2002; 15(2): 194 - 222. [Abstract] [Full Text] [PDF]

				M. Wilschanski, H. Famini, N. Strauss-Liviatan, J. Rivlin, H. Blau, H. Bibi, L. Bentur, Y. Yahav, H. Springer, M.R. Kramer, et al. Nasal potential difference measurements in patients with atypical cystic fibrosis Eur. Respir. J., June 1, 2001; 17(6): 1208 - 1215. [Abstract] [Full Text] [PDF]

				E. Marchand, C. Verellen-Dumoulin, M. Mairesse, L. Delaunois, P. Brancaleone, J.-F. Rahier, and O. Vandenplas Frequency of Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutations and 5T Allele in Patients With Allergic Bronchopulmonary Aspergillosis Chest, March 1, 2001; 119(3): 762 - 767. [Abstract] [Full Text] [PDF]

				P. Desmarquest, D. Feldmann, A. Tamalat, M. Boule, B. Fauroux, G. Tournier, and A. Clement Genotype Analysis and Phenotypic Manifestations of Children With Intermediate Sweat Chloride Test Results Chest, December 1, 2000; 118(6): 1591 - 1597. [Abstract] [Full Text] [PDF]

				P. G. NOONE, C. A. PUE, Z. ZHOU, K. J. FRIEDMAN, E. L. WAKELING, M. GANESHANANTHAN, R. H. SIMON, L. M. SILVERMAN, and M. R. KNOWLES Lung Disease Associated with the IVS8 5T Allele of the CFTR Gene Am. J. Respir. Crit. Care Med., November 1, 2000; 162(5): 1919 - 1924. [Abstract] [Full Text]

				J. MASSIE, D. DU SART, K. FORSHAW, J. CARLIN, and S M FORREST The relationship between neonatal immunoreactive trypsinogen, Delta F508, and IVS8-5T J. Med. Genet., August 1, 2000; 37(8): 629 - 632. [Full Text]

				M. Nissim-Rafinia, O. Chiba-Falek, G. Sharon, A. Boss, and B. Kerem Cellular and viral splicing factors can modify the splicing pattern of CFTR transcripts carrying splicing mutations Hum. Mol. Genet., July 22, 2000; 9(12): 1771 - 1778. [Abstract] [Full Text] [PDF]

				M. WILSCHANSKI, C. FAMINI, H. BLAU, J. RIVLIN, A. AUGARTEN, A. AVITAL, B. KEREM, and E. KEREM A Pilot Study of the Effect of Gentamicin on Nasal Potential Difference Measurements in Cystic Fibrosis Patients Carrying Stop Mutations Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): 860 - 865. [Abstract] [Full Text] [PDF]

				K. J. Friedman and L. M. Silverman Cystic Fibrosis Syndrome: A New Paradigm for Inherited Disorders and Implications for Molecular Diagnostics Clin. Chem., July 1, 1999; 45(7): 929 - 931. [Full Text] [PDF]

				J. F. Chmiel, M. L. Drumm, M. W. Konstan, T. W. Ferkol, and C. M. Kercsmar Pitfall in the Use of Genotype Analysis as the Sole Diagnostic Criterion for Cystic Fibrosis Pediatrics, April 1, 1999; 103(4): 823 - 826. [Abstract] [Full Text]

				I. Bronsveld, J. Bijman, F. Mekus, M. Ballmann, H. J Veeze, and B. Tümmler Clinical presentation of exclusive cystic fibrosis lung disease Thorax, March 1, 1999; 54(3): 278 - 281. [Abstract] [Full Text]

				W. Lissens, K. Z. Mahmoud, E. El-Gindi, A. Abdel-Sattar, S. Seneca, A. Van Steirteghem, and I. Liebaers Molecular analysis of the cystic fibrosis gene reveals a high frequency of the intron 8 splice variant 5T in Egyptian males with congenital bilateral absence of the vas deferens Mol. Hum. Reprod., January 1, 1999; 5(1): 10 - 13. [Abstract] [Full Text] [PDF]

				J. M. PILEWSKI and R. A. FRIZZELL Role of CFTR in Airway Disease Physiol Rev, January 1, 1999; 79(1): 215 - 255. [Abstract] [Full Text] [PDF]

				M. Wilschanski, J. Rivlin, S. Cohen, A. Augarten, H. Blau, M. Aviram, L. Bentur, C. Springer, Y. Vila, D. Branski, et al. Clinical and Genetic Risk Factors for Cystic Fibrosis-related Liver Disease Pediatrics, January 1, 1999; 103(1): 52 - 57. [Abstract] [Full Text] [PDF]

				J. A. Cohn, K. J. Friedman, P. G. Noone, M. R. Knowles, L. M. Silverman, and P. S. Jowell Relation between Mutations of the Cystic Fibrosis Gene and Idiopathic Pancreatitis N. Engl. J. Med., September 3, 1998; 339(10): 653 - 658. [Abstract] [Full Text] [PDF]