Misclassification of VLCAD carriers due to variable confirmatory testing after a positive NBS result

摘要

The Iowa Newborn Screening (NBS) Program began screening for very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) in 2003. Untreated VLCAD can lead to liver failure, heart failure, and death. Current confirmatory testing recommendations by the American College of Medical Genetics (ACMG) for VLCAD list molecular and functional analysis (i.e., fibroblast fatty acid oxidation probe) as optional. This can lead to misclassification of VLCAD carriers as false positives. Iowa implemented a comprehensive VLCAD confirmatory testing algorithm at the beginning of 2016 that included both molecular and fibroblast analysis. Here, we compare the historic multi-algorithmic confirmatory testing protocol (2005–2016) to this comprehensive protocol (2016–2017). A metabolic specialist reviewed all medical records and NBS data for each out-of-range VLCAD that fell in each testing period. During the comprehensive testing period, 48,651 specimens were screened. Thirteen individuals with out-of-range C14:1 results were classified as follows after review: ten carriers, zero true positives, zero false positives, zero lost to follow-up, and four unable to assess carrier status. During the variable testing period, a total of 486,566 specimens were screened. Eighty-five individuals with out-of-range C14:1 were classified as follows: 45 carriers, two true positives, four false positives, four lost to follow-up, and 30 unable to assess carrier status. Our findings suggest that many out-of-range VLCAD cases that do not receive molecular confirmatory testing could be carriers mistakenly classified as false positives. We recommend comprehensive molecular and functional testing for all children with out-of-range VLCAD NBS results.Electronic supplementary materialThe online version of this article (10.1007/s12687-019-00409-8) contains supplementary material, which is available to authorized users.