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. 1994 Jun 4;308(6942):1469–1472. doi: 10.1136/bmj.308.6942.1469

Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis: four years' experience.

E Ranieri 1, B D Lewis 1, R L Gerace 1, R G Ryall 1, C P Morris 1, P V Nelson 1, W F Carey 1, E F Robertson 1
PMCID: PMC2540319  PMID: 8019280

Abstract

OBJECTIVE--To assess the performance and impact of a two tier neonatal screening programme for cystic fibrosis based on an initial estimation of immunoreactive trypsinogen followed by direct gene analysis. DESIGN--Four year prospective study of two tier screening strategy. First tier: immunoreactive trypsinogen measured in dried blood spot samples from neonates aged 3-5 days. Second tier: direct gene analysis of cystic fibrosis mutations (delta F508, delta I506, G551D, G542X, and R553X) in samples with immunoreactive trypsinogen concentrations in highest 1% and in all neonates with meconium ileus or family history of cystic fibrosis. SETTING--South Australian Neonatal Screening Programme, Adelaide. SUBJECTS--All 88,752 neonates born in South Australia between December 1989 and December 1993. INTERVENTIONS--Neonates with two identifiable mutations were referred directly for clinical assessment and confirmatory sweat test; infants with only one identifiable mutation were recalled for sweat test at age 3-4 weeks. Parents of neonates identified as carriers of cystic fibrosis mutation were counselled and offered genetic testing. MAIN OUTCOME MEASURES--Identification of all children with cystic fibrosis in the screened population. RESULTS--Of 1004 (1.13%) neonates with immunoreactive trypsinogen > or = 99th centile, 912 (90.8%) had no identifiable mutation. 23 neonates were homozygotes or compound heterozygotes; 69 carried one identifiable mutation, of whom six had positive sweat tests. Median age at clinical assessment for the 29 neonates with cystic fibrosis was 3 weeks; six had meconium ileus and two had affected siblings. 63 neonates were identified as carriers of a cystic fibrosis mutation. Extra laboratory costs for measuring immunoreactive trypsinogen and direct gene analysis were $A1.50 per neonate screened. CONCLUSION--This strategy results in early and accurate diagnosis of cystic fibrosis and performs better than screening strategies based on immunoreactive trypsinogen measurement alone.

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Selected References

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  1. Boland C., Thompson N. L. Effects of newborn screening of cystic fibrosis on reported maternal behaviour. Arch Dis Child. 1990 Nov;65(11):1240–1244. doi: 10.1136/adc.65.11.1240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chatfield S., Owen G., Ryley H. C., Williams J., Alfaham M., Goodchild M. C., Weller P. Neonatal screening for cystic fibrosis in Wales and the West Midlands: clinical assessment after five years of screening. Arch Dis Child. 1991 Jan;66(1 Spec No):29–33. doi: 10.1136/adc.66.1_spec_no.29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dankert-Roelse J. E., Knol K., ten Kate L. P. Effects of neonatal screening for cystic fibrosis on reproduction, attitudes toward reproductive behaviour and genetic knowledge. Acta Univ Carol Med (Praha) 1990;36(1-4):99–101. [PubMed] [Google Scholar]
  4. Dankert-Roelse J. E., te Meerman G. J., Martijn A., ten Kate L. P., Knol K. Survival and clinical outcome in patients with cystic fibrosis, with or without neonatal screening. J Pediatr. 1989 Mar;114(3):362–367. doi: 10.1016/s0022-3476(89)80552-9. [DOI] [PubMed] [Google Scholar]
  5. Farrell P. M., Mischler E. H. Newborn screening for cystic fibrosis. The Cystic Fibrosis Neonatal Screening Study Group. Adv Pediatr. 1992;39:35–70. [PubMed] [Google Scholar]
  6. GIBSON L. E., COOKE R. E. A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics. 1959 Mar;23(3):545–549. [PubMed] [Google Scholar]
  7. Green M. R., Weaver L. T., Heeley A. F., Nicholson K., Kuzemko J. A., Barton D. E., McMahon R., Payne S. J., Austin S., Yates J. R. Cystic fibrosis identified by neonatal screening: incidence, genotype, and early natural history. Arch Dis Child. 1993 Apr;68(4):464–467. doi: 10.1136/adc.68.4.464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gregg R. G., Wilfond B. S., Farrell P. M., Laxova A., Hassemer D., Mischler E. H. Application of DNA analysis in a population-screening program for neonatal diagnosis of cystic fibrosis (CF): comparison of screening protocols. Am J Hum Genet. 1993 Mar;52(3):616–626. [PMC free article] [PubMed] [Google Scholar]
  9. Heeley A. F., Bangert S. K. The neonatal detection of cystic fibrosis by measurement of immunoreactive trypsin in blood. Ann Clin Biochem. 1992 Jul;29(Pt 4):361–376. doi: 10.1177/000456329202900401. [DOI] [PubMed] [Google Scholar]
  10. Henry R. L., Boulton T. J., Roddick L. G. False negative results on newborn screening for cystic fibrosis. J Paediatr Child Health. 1990 Jun;26(3):150–151. doi: 10.1111/j.1440-1754.1990.tb02413.x. [DOI] [PubMed] [Google Scholar]
  11. Kerem B. S., Zielenski J., Markiewicz D., Bozon D., Gazit E., Yahav J., Kennedy D., Riordan J. R., Collins F. S., Rommens J. M. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8447–8451. doi: 10.1073/pnas.87.21.8447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kerem B., Rommens J. M., Buchanan J. A., Markiewicz D., Cox T. K., Chakravarti A., Buchwald M., Tsui L. C. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989 Sep 8;245(4922):1073–1080. doi: 10.1126/science.2570460. [DOI] [PubMed] [Google Scholar]
  13. Kerem E., Corey M., Kerem B. S., Rommens J., Markiewicz D., Levison H., Tsui L. C., Durie P. The relation between genotype and phenotype in cystic fibrosis--analysis of the most common mutation (delta F508). N Engl J Med. 1990 Nov 29;323(22):1517–1522. doi: 10.1056/NEJM199011293232203. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Kraemer R., Hadorn B., Rossi E. Classification at time of diagnosis and subsequent survival in children with cystic fibrosis. Helv Paediatr Acta. 1977 Jul;32(2):107–114. [PubMed] [Google Scholar]
  16. 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]
  17. Lin H. C., Kirby L. T., Ng W. G., Reichardt J. K. On the molecular nature of the Duarte variant of galactose-1-phosphate uridyl transferase (GALT). Hum Genet. 1994 Feb;93(2):167–169. doi: 10.1007/BF00210604. [DOI] [PubMed] [Google Scholar]
  18. Nelson P. V., Carey W. F., Morris C. P., Pollard A. C. The frequency of the common (delta F508) cystic fibrosis mutation in the Australian population. Med J Aust. 1990 Mar 19;152(6):328–328. [PubMed] [Google Scholar]
  19. Nissenblatt M. J., Bias W., Borgaonkar D., Dixon S., Cody R. P. Familial erythroleukemia: four cases of the Diguglielmo syndrome in close relatives. Johns Hopkins Med J. 1982 Jan;150(1):1–9. [PubMed] [Google Scholar]
  20. Ranieri E., Ryall R. G., Morris C. P., Nelson P. V., Carey W. F., Pollard A. C., Robertson E. F. Neonatal screening strategy for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis. BMJ. 1991 May 25;302(6787):1237–1240. doi: 10.1136/bmj.302.6787.1237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rock M. J., Mischler E. H., Farrell P. M., Bruns W. T., Hassemer D. J., Laessig R. H. Immunoreactive trypsinogen screening for cystic fibrosis: characterization of infants with a false-positive screening test. Pediatr Pulmonol. 1989;6(1):42–48. doi: 10.1002/ppul.1950060111. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Ryall R. G., Gjerde E. M., Gerace R. L., Ranieri E. Modifying an enzyme immunoassay of immunoreactive trypsinogen to use time-resolved fluorescence. Clin Chem. 1993 Feb;39(2):224–228. [PubMed] [Google Scholar]
  24. Ryley H. C., Goodchild M. C., Dodge J. A. Screening for cystic fibrosis. Br Med Bull. 1992 Oct;48(4):805–822. doi: 10.1093/oxfordjournals.bmb.a072579. [DOI] [PubMed] [Google Scholar]
  25. Spence W. C., Paulus-Thomas J., Orenstein D. M., Naylor E. W. Neonatal screening for cystic fibrosis: addition of molecular diagnostics to increase specificity. Biochem Med Metab Biol. 1993 Apr;49(2):200–211. doi: 10.1006/bmmb.1993.1022. [DOI] [PubMed] [Google Scholar]
  26. Wesley A. W., Smith P. A., Elliott R. B. Experience with neonatal screening for cystic fibrosis in New Zealand using measurement of immunoreactive trypsinogen. Aust Paediatr J. 1989 Jun;25(3):151–155. doi: 10.1111/j.1440-1754.1989.tb01440.x. [DOI] [PubMed] [Google Scholar]

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