{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T10:07:48Z","timestamp":1784801268184,"version":"3.55.0"},"reference-count":42,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Genepath"},{"name":"Pathology Queensland"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Neonatal Screen.","IJNS"],"abstract":"<jats:p>Newborn screening benefits children with rare diseases by enabling early detection and intervention, which improves health outcomes. False-positive results are one harm of screening, with infants subject to further testing to resolve a positive screen and parents susceptible to psychosocial distress while awaiting the results. Newborn bloodspot screening (NBS) for severe combined immunodeficiency (SCID) using quantitative polymerase chain reaction (qPCR) and cystic fibrosis (CF) screening using immunoreactive trypsinogen (IRT) have high false-positive rates, with more than five infants screening positive and unaffected, for each child diagnosed. We used first-tier targeted gene sequencing (TGS) to prospectively screen 3025 newborns for CF, SCID and spinal muscular atrophy (SMA) and compared the results to current screening protocols using multiplex qPCR and IRT. TGS identified one infant with CF, missed by the IRT assay, and detected an infant with SMA, who screened positive with multiplex qPCR. TGS had zero false-positive results for SCID, CF and SMA. By contrast, multiplex qPCR and IRT screening protocols had approximately nine false positives for each child diagnosed with CF (positive predictive value, PPV 10.00%) and SCID (PPV 10.13%). Replacing current SCID and CF screening protocols with TGS would reduce NBS false positives and may result in a higher sensitivity for CF. TGS sensitivity and specificity would be comparable to qPCR for SMA. A larger trial is required to determine TGS sensitivity and cost-effectiveness.<\/jats:p>","DOI":"10.3390\/ijns12030056","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T09:11:26Z","timestamp":1784797886000},"page":"56","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Improving Severe Combined Immunodeficiency and Cystic Fibrosis Newborn Screening by Replacing Current Tests with First-Tier Targeted Gene Sequencing"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6150-7233","authenticated-orcid":false,"given":"Bennett O. V.","family":"Shum","sequence":"first","affiliation":[{"name":"Preventive Health Division, Genepath, Sydney, NSW 2067, Australia"},{"name":"EMBL Australia Node in Single Molecule Science, School of Biomedical Sciences, University of NSW, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7608-3995","authenticated-orcid":false,"given":"Carel","family":"Pretorius","sequence":"additional","affiliation":[{"name":"Department of Chemical Pathology, Pathology Queensland, Queensland Health, Brisbane, QLD 4029, Australia"},{"name":"Faculty of Health and Behavioural Sciences, University of QLD, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya","family":"Henner","sequence":"additional","affiliation":[{"name":"Preventive Health Division, Genepath, Sydney, NSW 2067, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emre","family":"Basar","sequence":"additional","affiliation":[{"name":"Preventive Health Division, Genepath, Sydney, NSW 2067, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1364-4783","authenticated-orcid":false,"given":"Urs","family":"Wilgen","sequence":"additional","affiliation":[{"name":"Department of Chemical Pathology, Pathology Queensland, Queensland Health, Brisbane, QLD 4029, Australia"},{"name":"Faculty of Health and Behavioural Sciences, University of QLD, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4593-1581","authenticated-orcid":false,"given":"Glenn","family":"Bennett","sequence":"additional","affiliation":[{"name":"Preventive Health Division, Genepath, Sydney, NSW 2067, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4929-0929","authenticated-orcid":false,"given":"Jacobus P. J.","family":"Ungerer","sequence":"additional","affiliation":[{"name":"Department of Chemical Pathology, Pathology Queensland, Queensland Health, Brisbane, QLD 4029, Australia"},{"name":"Faculty of Health and Behavioural Sciences, University of QLD, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","unstructured":"Commonwealth of Australia, Department of Health, Disability and Ageing (2017). Newborn Bloodspot Screening National Policy Framework."},{"key":"ref_2","unstructured":"Wilson, J.M.G., and Jungner, G. (1968). Principles and Practice of Screening for Disease, World Health Organisation. Contract No. 34."},{"key":"ref_3","unstructured":"Commonwealth of Australia, Department of Health, Disability and Ageing (2026, March 30). 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