{"doi":"10.1210/clinem/dgae297","title":"Can Incorporating Molecular Testing Improve the Accuracy of Newborn Screening for Congenital Adrenal Hyperplasia?","abstract":"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.","journal":"The Journal of Clinical Endocrinology & Metabolism","year":2024,"id":455780,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9635,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":955834,"name":"Amy Gaviglio","orcid":"0000-0001-7598-3820","position":1,"is_corresponding":false},{"id":1280275,"name":"Carrie Wolf","orcid":null,"position":2,"is_corresponding":false},{"id":1280276,"name":"Cindy Pham Lorentz","orcid":null,"position":3,"is_corresponding":false},{"id":429384,"name":"Aida Lteif","orcid":null,"position":4,"is_corresponding":false},{"id":1128256,"name":"Jennifer Kyllo","orcid":null,"position":5,"is_corresponding":false},{"id":535689,"name":"Gretchen A. Radloff","orcid":null,"position":6,"is_corresponding":false},{"id":1280277,"name":"Zachary Detwiler","orcid":null,"position":7,"is_corresponding":false},{"id":363021,"name":"Carla Cuthbert","orcid":null,"position":8,"is_corresponding":false},{"id":1790,"name":"James S. Hodges","orcid":"0000-0001-7467-6941","position":9,"is_corresponding":false},{"id":332593,"name":"Scott D. Grosse","orcid":"0000-0003-1078-6855","position":10,"is_corresponding":false},{"id":1279866,"name":"Christopher N. Greene","orcid":"0000-0002-4313-7870","position":11,"is_corresponding":false},{"id":363022,"name":"Suzanne K. Cordovado","orcid":null,"position":12,"is_corresponding":false},{"id":436044,"name":"Kyriakie Sarafoglou","orcid":"0000-0002-5741-3629","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-19T02:03:22.974789Z","pmid":"38701341","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}