Misclassification of VLCAD carriers due to variable confirmatory testing after a positive NBS result
- 15 Downloads
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.
KeywordsNewborn screening VLCAD Molecular testing Diagnostic testing Case definitions
The authors thank the Iowa Ladies Football Academy and the Stead Family Department of Pediatrics University of Iowa Hospital and Clinics for providing the support that made this study possible.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Human and animal rights and informed consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
- American College of Medical Genetics/American Society of Human Genetics T, Technology Transfer Committee Working G (2000) Tandem mass spectrometry in newborn screening. Am Coll Med Genet/Am Soc Hum Genet Test Technol Transf Comm Work Group Genet Med 2:267–269. https://doi.org/10.1097/00125817-200007000-00011 Google Scholar
- Genetics ACoM (2001) ACMG ACT Sheets and Confirmatory Algorithms. In: Bethesda (MD)Google Scholar
- Leslie ND, Valencia CA, Strauss AW, Zhang K (1993) Very long-chain acyl-coenzyme A dehydrogenase deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews((R)). Seattle (WA)Google Scholar
- Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, Elsea SH, Sutton VR, Sun Q, Graham BH, Craigen WJ, Zhang VW, Wong LJC (2015) Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab 116:139–145. https://doi.org/10.1016/j.ymgme.2015.08.011 CrossRefGoogle Scholar
- NewSTEPs (2018) NewSTEPs case definitions. Association of Public Health Laboratories. https://wwwnewstepsorg/case-definitions. Accessed 25 July 2018
- Scalais E, Bottu J, Wanders RJ, Ferdinandusse S, Waterham HR, De Meirleir L (2015) Familial very long chain acyl-CoA dehydrogenase deficiency as a cause of neonatal sudden infant death: improved survival by prompt diagnosis. Am J Med Genet A 167A:211–214. https://doi.org/10.1002/ajmg.a.36803 CrossRefGoogle Scholar
- Zytkovicz TH, Fitzgerald EF, Marsden D, Larson CA, Shih VE, Johnson DM, Strauss AW, Comeau AM, Eaton RB, Grady GF (2001) Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program. Clin Chem 47:1945–1955Google Scholar