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

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

doi:10.1210/clinem/dgae297

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

5 03 2024
By Sarafoglou, Kyriakie ; Gaviglio, Amy ; Wolf, Carrie ; ...
Source: J Clin Endocrinol Metab.

Public Access Version Available on: November 03, 2025, 12:00 AM

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English

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Details:

Alternative Title:

J Clin Endocrinol Metab
Personal Author:

Sarafoglou, Kyriakie ; Gaviglio, Amy ; Wolf, Carrie ; Lorentz, Cindy P. ; Lteif, Aida ; ... More +

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 Less -
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:

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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:

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urn:sha-512:5698f8439adc5707745e7ddc224abfe333b847965d4934e884415a2d24418e4d61b048728badd1150cdfc9048835a65282cc0f911d90e71b9b46f71034c85577
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Supporting Files:

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