Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 1997 Apr;34(4):297–301. doi: 10.1136/jmg.34.4.297

CFTR mutations and IVS8-5T variant in newborns with hypertrypsinaemia and normal sweat test.

C Castellani 1, A Bonizzato 1, G Mastella 1
PMCID: PMC1050915  PMID: 9138152

Abstract

Neonates positive for immunoreactive trypsinogen assay (IRT) and negative for sweat test have formerly been found to carry the major cystic fibrosis (CF) mutation, delta F508, much more frequently than the general population. Among the 716 IRT positive newborns detected by a three tier (IRT, mutation analysis plus meconium lactase assay, sweat test) CF screening programme in north eastern Italy during the period January 1993 to March 1996, we found 45 carriers, a number significantly higher than the expected 17 (p < 0.001). We speculated that some of these heterozygotes could actually be affected by a very mild form of CF, and carry on the other chromosome an undetected CFTR mutation or a DNA variant, such as the 5-thymidine allele in intron 8 of the CFTR gene (IVS8-5T). This hypothesis was tested in four samples; group A (the 45 carriers mentioned above), group B (51 non-carrier, IRT positive neonates), group C (50 IRT negative neonates), and group D (90 CF adult female carriers). Chromosomes with IVS8-5T were seven (7.78%) in group A, seven (6.86%) in group B, five (5%) in group C, and four in group D (2.22%). The 5T prevalence in group A was significantly higher (p < 0.05) compared to group D; similarly, a higher (p < 0.05) 5T frequency in group A compared to group C was detected by considering the chromosomes free from CFTR mutations. This study is consistent with previous papers in finding among neonates with high trypsin levels a CF carrier frequency significantly higher than that expected. It is also suggested that in at least some babies raised trypsin levels at birth could be a phenotypic expression of compound heterozygosity for a major CF mutation plus IVS8-5T.

Full text

PDF
297

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bonizzato A., Bisceglia L., Marigo C., Nicolis E., Bombieri C., Castellani C., Borgo G., Zelante L., Mastella G., Cabrini G. Analysis of the complete coding region of the CFTR gene in a cohort of CF patients from north-eastern Italy: identification of 90% of the mutations. Hum Genet. 1995 Apr;95(4):397–402. doi: 10.1007/BF00208963. [DOI] [PubMed] [Google Scholar]
  2. Cabrini G., Pederzini F., Perobelli L., Mastella G. An evaluation of an enzyme immunoassay method for immunoreactive trypsin in dried blood spots. Clin Biochem. 1990 Jun;23(3):213–219. doi: 10.1016/0009-9120(90)90614-z. [DOI] [PubMed] [Google Scholar]
  3. Chehab F. F., Wall J. Detection of multiple cystic fibrosis mutations by reverse dot blot hybridization: a technology for carrier screening. Hum Genet. 1992 May;89(2):163–168. doi: 10.1007/BF00217117. [DOI] [PubMed] [Google Scholar]
  4. Chillón M., Casals T., Mercier B., Bassas L., Lissens W., Silber S., Romey M. C., Ruiz-Romero J., Verlingue C., Claustres M. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995 Jun 1;332(22):1475–1480. doi: 10.1056/NEJM199506013322204. [DOI] [PubMed] [Google Scholar]
  5. Chu C. S., Trapnell B. C., Curristin S., Cutting G. R., Crystal R. G. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet. 1993 Feb;3(2):151–156. doi: 10.1038/ng0293-151. [DOI] [PubMed] [Google Scholar]
  6. Crossley J. R., Elliott R. B., Smith P. A. Dried-blood spot screening for cystic fibrosis in the newborn. Lancet. 1979 Mar 3;1(8114):472–474. doi: 10.1016/s0140-6736(79)90825-0. [DOI] [PubMed] [Google Scholar]
  7. Cuppens H., Teng H., Raeymaekers P., De Boeck C., Cassiman J. J. CFTR haplotype backgrounds on normal and mutant CFTR genes. Hum Mol Genet. 1994 Apr;3(4):607–614. doi: 10.1093/hmg/3.4.607. [DOI] [PubMed] [Google Scholar]
  8. Dörk T., Fislage R., Neumann T., Wulf B., Tümmler B. Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations. Hum Genet. 1994 Jan;93(1):67–73. doi: 10.1007/BF00218916. [DOI] [PubMed] [Google Scholar]
  9. Estivill X. Complexity in a monogenic disease. Nat Genet. 1996 Apr;12(4):348–350. doi: 10.1038/ng0496-348. [DOI] [PubMed] [Google Scholar]
  10. Gasparini P., Bonizzato A., Dognini M., Pignatti P. F. Restriction site generating-polymerase chain reaction (RG-PCR) for the probeless detection of hidden genetic variation: application to the study of some common cystic fibrosis mutations. Mol Cell Probes. 1992 Feb;6(1):1–7. doi: 10.1016/0890-8508(92)90064-5. [DOI] [PubMed] [Google Scholar]
  11. Kiesewetter S., Macek M., Jr, Davis C., Curristin S. M., Chu C. S., Graham C., Shrimpton A. E., Cashman S. M., Tsui L. C., Mickle J. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet. 1993 Nov;5(3):274–278. doi: 10.1038/ng1193-274. [DOI] [PubMed] [Google Scholar]
  12. Laroche D., Travert G. Abnormal frequency of delta F508 mutation in neonatal transitory hypertrypsinaemia. Lancet. 1991 Jan 5;337(8732):55–55. doi: 10.1016/0140-6736(91)93377-l. [DOI] [PubMed] [Google Scholar]
  13. Lucotte G., Perignon J. L., Lenoir G. Transient neonatal hypertrypsinaemia as test for delta F508 heterozygosity. Lancet. 1991 Apr 20;337(8747):988–988. doi: 10.1016/0140-6736(91)91634-7. [DOI] [PubMed] [Google Scholar]
  14. Patrizio P., Zielenski J. Congenital absence of the vas deferens: a mild form of cystic fibrosis. Mol Med Today. 1996 Jan;2(1):24–31. doi: 10.1016/1357-4310(96)88755-7. [DOI] [PubMed] [Google Scholar]
  15. Pederzini F., Faraguna D., Giglio L., Pedrotti D., Perobelli L., Mastella G. Development of a screening system for cystic fibrosis: meconium or blood spot trypsin assay or both? Acta Paediatr Scand. 1990 Oct;79(10):935–942. doi: 10.1111/j.1651-2227.1990.tb11355.x. [DOI] [PubMed] [Google Scholar]
  16. Pignatti P. F., Bombieri C., Benetazzo M., Casartelli A., Trabetti E., Gilè L. S., Martinati L. C., Boner A. L., Luisetti M. CFTR gene variant IVS8-5T in disseminated bronchiectasis. Am J Hum Genet. 1996 Apr;58(4):889–892. [PMC free article] [PubMed] [Google Scholar]
  17. Rock M. J., Mischler E. H., Farrell P. M., Wei L. J., Bruns W. T., Hassemer D. J., Laessig R. H. Newborn screening for cystic fibrosis is complicated by age-related decline in immunoreactive trypsinogen levels. Pediatrics. 1990 Jun;85(6):1001–1007. [PubMed] [Google Scholar]
  18. Rommens J., Kerem B. S., Greer W., Chang P., Tsui L. C., Ray P. Rapid nonradioactive detection of the major cystic fibrosis mutation. Am J Hum Genet. 1990 Feb;46(2):395–396. [PMC free article] [PubMed] [Google Scholar]
  19. Walsh P. S., Metzger D. A., Higuchi R. Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. Biotechniques. 1991 Apr;10(4):506–513. [PubMed] [Google Scholar]
  20. Waters D. L., Dorney S. F., Gaskin K. J., Gruca M. A., O'Halloran M., Wilcken B. Pancreatic function in infants identified as having cystic fibrosis in a neonatal screening program. N Engl J Med. 1990 Feb 1;322(5):303–308. doi: 10.1056/NEJM199002013220505. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES