Targeted extended cystic fibrosis mutation testing on known and at-risk patients and relatives

This paper reports mathematically derived residual risks of being a carrier or being affected with cystic fibrosis following various screening scenarios to assist in interpreting test results and advising patients. While parental screening with 23 American College of Medical Genetics (ACMG) cystic fibrosis mutations defines the 64% of affected U.S. Caucasian fetuses with two detectable mutations, newborn screening for elevated immunoreactive trypsinogen (IRT) and sweat chloride identifies an additional 36% of affected newborns with zero or one detected mutation. The relatives of these affected newborns with less than two detectable mutations have higher posterior (after) 23 mutation-negative test risks of carrying undetected mutations. These calculations emphasize how knowledge of the mutations in the related affected patient substantially improves upon the quality of after-test advice to patients. Furthermore, negative tests of the partner without a family history and/or more extensive cystic fibrosis transmembrane conductance regulator (CFTR) gene testing also increases the likelihood that a negative report is truly negative. When a newborn patient with zero or one detected CFTR mutation has an inconclusive sweat test result, the sweat test should be repeated before ordering additional often unnecessary CFTR gene sequencing. Given the same composite mutation panel test accuracy, a higher proportion of reported test results would be correct during parental screening than when testing at-risk fetuses or symptomatic newborns. Prenatal and newborn screening would be enhanced substantially by medical professionals offering copies of all positive parental and newborn test reports to the parents to share with their relatives. These principles are likely to be applicable to other genetic diseases as the most common mutation frequencies are reported.