Can Incorporating Molecular Testing Improve the Accuracy of Newborn Screening for Congenital Adrenal Hyperplasia?

Details

• Alternative Title:
  J Clin Endocrinol Metab
• Personal Author:
  Sarafoglou, Kyriakie ; Gaviglio, Amy ; Wolf, Carrie ; Lorentz, Cindy P. ; Lteif, Aida ; Kyllo, Jennifer ; Radloff, Gretchen ; Detwiler, Zachary ; Cuthbert, Carla D. ; Hodges, James S. ; Grosse, Scott D. ; Greene, Christopher N. ; Cordovado, Suzanne
• Description:
  Context:
  
  Single-tier newborn screening (NBS) for congenital adrenal hyperplasia (CAH) using 17-hydroxyprogesterone (17OHP) measured by fluoroimmunoassay (FIA) in samples collected at 24 to 48 hours produces a high false-positive rate (FPR). Second-tier steroid testing can reduce the FPR and has been widely implemented.
  
  Objective:
  
  We investigated the accuracy of an alternative multitier CAH NBS protocol that incorporates molecular testing of the CYP21A2 gene and reduces the first-tier 17OHP cutoff to minimize missed cases.
  
  Methods:
  
  We create a Minnesota-specific CYP21A2 pathogenic variants panel; developed a rapid, high-throughput multiplex, allele-specific-primer-extension assay; and performed a 1-year retrospective analysis of Minnesota NBS results comparing metrics between a conventional steroid-based 2-tier protocol and a molecular-based multitier NBS protocol, applied post hoc.
  
  Results:
  
  CYP21A2 gene sequencing of 103 Minnesota families resulted in a Minnesota-specific panel of 21 pathogenic variants. The Centers for Disease Control and Prevention created a molecular assay with 100% accuracy and reproducibility. Two-tier steroid-based screening of 68 659 live births during 2015 resulted in 2 false negatives (FNs), 91 FPs, and 1 true positive (TP). A 3-tier protocol with a lower first-tier steroid cutoff, second-tier 21-variant CYP21A2 panel, and third-tier CYP21A2 sequencing would have resulted in 0 FNs, 52 FPs, and 3 TPs.
  
  Conclusion:
  
  Incorporation of molecular testing could improve the accuracy of CAH NBS, although some distinct challenges of molecular testing may need to be considered before implementation by NBS programs.
  
  
• Keywords:
  Congenital Adrenal Hyperplasia CYP21A2 Gene Newborn Screening Premature Infants
• Source:
  J Clin Endocrinol Metab.
• Pubmed ID:
  38701341
• Pubmed Central ID:
  PMC11531606
• Document Type:
  Journal Article
• Funding:
  CC999999/ImCDC/Intramural CDC HHSUnited States/
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:5698f8439adc5707745e7ddc224abfe333b847965d4934e884415a2d24418e4d61b048728badd1150cdfc9048835a65282cc0f911d90e71b9b46f71034c85577
• Download URL:
  https://stacks.cdc.gov/view/cdc/168901/cdc_168901_DS1.pdf
• File Type:
  [PDF - 539.02 KB ]