{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:49:37Z","timestamp":1793148577547,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The National University of Malaysia","award":["UKM PPI\/111\/8\/JEP-2024-1000"],"award-info":[{"award-number":["UKM PPI\/111\/8\/JEP-2024-1000"]}]},{"award":["UKM PPI\/111\/8\/JEP-2024-1000"],"award-info":[{"award-number":["UKM PPI\/111\/8\/JEP-2024-1000"]}],"id":[{"id":"https:\/\/ror.org\/00bw8d226","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJNS"],"abstract":"<jats:p>Severe Combined Immunodeficiency (SCID), Spinal Muscular Atrophy (SMA), and X-Linked Agammaglobulinemia (XLA) are rare but life-threatening genetic disorders in infants that can lead to severe infections, progressive neuromuscular degeneration, or severe immune dysfunction associated with significant morbidity and mortality if not diagnosed early. Advances in newborn screening (NBS) technologies have enabled pre-symptomatic detection of these conditions, allowing early initiation of life-saving interventions such as hematopoietic stem cell transplantation, gene therapy, and immunoglobulin replacement therapy. However, the absence of a standardized national clinical pathway linking screening, confirmatory testing, and specialist referral in Malaysia continues to contribute to delayed diagnosis and suboptimal patient outcomes. This review examines and synthesizes current evidence on the clinical pathways for early diagnosis and management of SCID, SMA, and XLA, with particular emphasis on diagnostic workflows, screening technologies, and healthcare system challenges within the Malaysian context. The review examines disease epidemiology, consequences of delayed diagnosis, and the role of expanded NBS under the Screening for Health, Intervention, Nurturing of Every Child (SHINE) program in improving early diagnosis and management. In addition, the paper outlines the current NBS landscape, the use of multiplex real-time polymerase chain reaction (PCR) assays for simultaneous detection of T-cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and survival motor neuron 1 (SMN1) gene deletion of exon 7 from dried blood spot (DBS) samples. A structured diagnostic framework incorporating screening interpretation, confirmatory testing, and urgency-based referral pathways is also proposed. By addressing current operational barriers and coordinating laboratory referral systems, expanding NBS programs could significantly improve early diagnosis and long-term outcomes for infants affected by SCID, SMA, and XLA in Malaysia.<\/jats:p>","DOI":"10.3390\/ijns12030045","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T01:03:23Z","timestamp":1782263003000},"page":"45","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Development of Clinical Pathways for Early Diagnosis and Management of SCID, SMA, and XLA Through Newborn Screening in Malaysia"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4901-858X","authenticated-orcid":false,"given":"Alia","family":"Zainudin","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia"},{"name":"Research Center, Tunku Ampuan Besar Tuanku Aishah Rohani Hospital, Universiti Kebangsaan Malaysia (UKM) Specialist Children\u2019s Hospital, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thin Thin","family":"Aye","sequence":"additional","affiliation":[{"name":"Arcadia Life Sciences, L3-E-10A, Level 3, HIVE 5, Taman Teknologi MRANTI, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe Chen Sze","family":"Yun","sequence":"additional","affiliation":[{"name":"Arcadia Life Sciences, L3-E-10A, Level 3, HIVE 5, Taman Teknologi MRANTI, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6630-1218","authenticated-orcid":false,"given":"Gaayathri","family":"Kumarasamy","sequence":"additional","affiliation":[{"name":"Arcadia Life Sciences, L3-E-10A, Level 3, HIVE 5, Taman Teknologi MRANTI, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5615-5966","authenticated-orcid":false,"given":"Adli","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia"},{"name":"Research Center, Tunku Ampuan Besar Tuanku Aishah Rohani Hospital, Universiti Kebangsaan Malaysia (UKM) Specialist Children\u2019s Hospital, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia"},{"name":"Institute of IR4.0, Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia"},{"name":"Infection and Immunology Health and Advanced Medicine Cluster, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kumarasamy, G., Khairiz, K., Chang, W.L., Aye, T.T., and Ali, A. 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