{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T15:00:54Z","timestamp":1784905254088,"version":"3.55.0"},"reference-count":60,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Neonatal encephalopathy (NE) is a major cause of neonatal mortality and long-term neurological disability. Although hypoxic\u2013ischaemic encephalopathy (HIE) is the most common cause, several genetic disorders may mimic or coexist with hypoxic\u2013ischaemic injury. Next-generation sequencing has emerged as a promising diagnostic tool in this setting. This systematic review evaluated the current evidence on genomic sequencing in NE. Material and methods: A systematic review was conducted according to PRISMA 2020 guidelines and prospectively registered in PROSPERO. PubMed\/MEDLINE, Embase, and Scopus were searched from inception to June 2026. Eligible studies included neonates (\u226428 days) with NE, suspected or confirmed HIE, HIE mimics, or unexplained NE who underwent genomic sequencing. Whole-exome sequencing (WES), whole-genome sequencing (WGS), clinical exome sequencing (CES), rapid genomic sequencing, and targeted next-generation sequencing panels were considered. Study quality was assessed using the Newcastle\u2013Ottawa Scale. Results: Seven studies met the inclusion criteria. Considerable heterogeneity was observed regarding patient selection, sequencing strategies, and reported outcomes. Among diagnostic sequencing studies, diagnostic yield ranged from 23.5% to 53.1%. Pathogenic and likely pathogenic variants were identified in genes associated with developmental and epileptic encephalopathies, metabolic disorders, mitochondrial diseases, and neurodevelopmental syndromes, including SCN2A, KCNQ2, CACNA1A, STXBP1, PTPN11, BCOR, MMUT, COQ2, and GBE1. Genomic sequencing frequently refined or changed the initial diagnosis, improved prognostic assessment and genetic counselling, and, in selected cases, guided disease-specific treatment. One study investigated genetic susceptibility to hypoxic\u2013ischaemic injury rather than diagnostic sequencing. Conclusions: Genomic sequencing provides clinically meaningful diagnoses in a substantial proportion of neonates with unexplained NE or atypical HIE presentations. Current evidence supports integrating genomic sequencing into the diagnostic evaluation of selected infants, although larger prospective studies are needed to define its optimal timing, clinical utility, and cost-effectiveness.<\/jats:p>","DOI":"10.3390\/genes17080862","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T13:53:26Z","timestamp":1784901206000},"page":"862","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genomic Sequencing in Neonatal Encephalopathy and Suspected Hypoxic\u2013Ischaemic Encephalopathy: A Systematic Review"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8935-5710","authenticated-orcid":false,"given":"Dario","family":"Colacurci","sequence":"first","affiliation":[{"name":"Department of Public Health, University of Naples Federico II, via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0454-7946","authenticated-orcid":false,"given":"Laura","family":"Sarno","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reproductive Science and Dentistry, University of Naples Federico II, via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Fiore","sequence":"additional","affiliation":[{"name":"Mother and Child Department, University Hospital Federico II, via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Raimondi","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Translational Medical Sciences, Federico II University, via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Department of Public Health, University of Naples Federico II, via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0593-9063","authenticated-orcid":false,"given":"Angelo","family":"Sirico","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialized Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, via Armanni 14, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costantino","family":"Di Carlo","sequence":"additional","affiliation":[{"name":"Department of Public Health, University of Naples Federico II, via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Bifulco","sequence":"additional","affiliation":[{"name":"Department of Public Health, University of Naples Federico II, via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Guida","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reproductive Science and Dentistry, University of Naples Federico II, via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe Maria","family":"Maruotti","sequence":"additional","affiliation":[{"name":"Department of Public Health, University of Naples Federico II, via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1038\/s41390-025-03986-2","article-title":"Neonatal encephalopathy and hypoxic-ischemic encephalopathy: The state of the art","volume":"98","author":"Chakkarapani","year":"2025","journal-title":"Pediatr. 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