Calculating posterior cystic fibrosis risk with echogenic bowel and one characterized cystic fibrosis mutation: Avoiding pitfalls in the risk calculations

We describe a general approach to derive fetal risk following two separate test results that each raise the likelihood of the same fetal abnormality w ithout clearly determining whether the abnormality exists. Echogenic bowel observed on fetal ultrasonography may have multiple causes, including an a priori risk of approximately 1% of cystic fibrosis (CF). On numerous occasi ons our laboratory tests have detected only normal cystic fibrosis transmem brane regulator (CFTR) alleles in fetuses with echogenic bowel. This result indicates that another cause most likely explains the abnormal ultrasound finding. One of our tested fetuses was heterozygous for the Delta F508 CFTR mutation and had a normal karyotype. Over 770 CFTR mutations have been des cribed, and a significant proportion of parental mutant alleles could not b e detected by our 25-mutation test. Further mutation analysis demonstrated that the fetus' mother carried the Delta F508 mutation but the father (of d ifferent ethnic background than the mother) did not carry a detectable muta tion. Thus, this test result substantially increased the risk of the fetus having CF, while still not giving a definitive answer to whether the fetus was affected. A rigorous mathematical analysis determined that the 1% risk of CF following ultrasound study was increased to slightly under 12% follow ing DNA analysis. The case is described, and the mathematical formulas are explained and illustrated with examples, along with a review of conditional probability (Appendix 2). Am. J. Med. Genet. 82:329-335, 1999. (C) 1999 Wi ley-Liss, Inc.