{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T01:17:43Z","timestamp":1793409463918,"version":"4.5.0"},"reference-count":78,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T00:00:00Z","timestamp":1740614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","award":["GIPD 96783"],"award-info":[{"award-number":["GIPD 96783"]}],"id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","award":["INV-022216"],"award-info":[{"award-number":["INV-022216"]}],"id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","award":["INV-041062"],"award-info":[{"award-number":["INV-041062"]}],"id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bill and Melinda Gates Foundation","award":["GIPD 96783"],"award-info":[{"award-number":["GIPD 96783"]}]},{"name":"Bill and Melinda Gates Foundation","award":["INV-022216"],"award-info":[{"award-number":["INV-022216"]}]},{"name":"Bill and Melinda Gates Foundation","award":["INV-041062"],"award-info":[{"award-number":["INV-041062"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neonatal encephalopathy suspected to be due to hypoxic ischaemic encephalopathy (NESHIE) carries the risk of death or severe disability (cognitive defects and cerebral palsy). Previous genetic studies on NESHIE have predominantly focused on exomes or targeted genes. The objective of this study was to identify genetic variants associated with moderate\u2013severe NESHIE through whole-genome, unbiased analysis. Variant filtering and prioritization were performed, followed by association testing both on a case\u2013control basis and to compare the grades of severity and\/or progression. Association testing on neonates with NESHIE (N = 172) and ancestry-matched controls (N = 288) produced 71 significant genetic variants (false discovery rate corrected p-value &lt; 6.2 \u00d7 10\u22124), all located in non-coding regions and not previously implicated in NESHIE. Disease-associated variants in non-coding regions are considered to affect regulatory functions, possibly by modifying gene expression, promoters, enhancers, or DNA structure. The most significant variant was at position 6:162010973 in the Parkin RBR E3 ubiquitin protein ligase (PRKN) intron. Intronic variants were also identified in genes involved in inflammatory processes (SLCO3A1), DNA repair (ZGRF1), synaptogenesis (CNTN5), haematopoiesis (ASXL2), and the transcriptional response to hypoxia (PADI4). Ten variants were associated with a higher severity or lack of improvement in NESHIE, including one in ADAMTS3, which encodes a procollagen amino protease with a role in angiogenesis and lymphangiogenesis. This analysis represents one of the first efforts to analyze whole-genome data to investigate the genetic complexity of NESHIE in diverse ethnolinguistic groups of African origin and provides direction for further study.<\/jats:p>","DOI":"10.3390\/ijms26052075","type":"journal-article","created":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T03:37:57Z","timestamp":1740627477000},"page":"2075","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Genetic Variants Associated with Suspected Neonatal Hypoxic Ischaemic Encephalopathy: A Study in a South African Context"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4542-1750","authenticated-orcid":false,"given":"Caroline J.","family":"Foden","sequence":"first","affiliation":[{"name":"Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0084, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Durant","sequence":"additional","affiliation":[{"name":"BixBio Limited, Cape Town 8001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0109-9853","authenticated-orcid":false,"given":"Juanita","family":"Mellet","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0084, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4998-7531","authenticated-orcid":false,"given":"Fourie","family":"Joubert","sequence":"additional","affiliation":[{"name":"Centre for Bioinformatics and Computational Biology, Genomics Research Institute, Department of Biochemistry, Genetics, and Microbiology, University of Pretoria, Pretoria 0002, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3224-0071","authenticated-orcid":false,"given":"Jeanne","family":"van Rensburg","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0084, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khomotso","family":"Masemola","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, Kalafong Hospital and Faculty of Health Sciences, University of Pretoria, Pretoria 0084, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sithembiso C.","family":"Velaphi","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, Chris Hani Baragwanath Academic Hospital, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firdose L.","family":"Nakwa","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, Chris Hani Baragwanath Academic Hospital, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7795-4900","authenticated-orcid":false,"given":"Alan R.","family":"Horn","sequence":"additional","affiliation":[{"name":"Division of Neonatal Medicine, Department of Paediatrics and Child Health, Groote Schuur Hospital, University of Cape Town, Cape Town 7701, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakti","family":"Pillay","sequence":"additional","affiliation":[{"name":"Division of Neonatal Medicine, Department of Paediatrics and Child Health, Groote Schuur Hospital, University of Cape Town, Cape Town 7701, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1426-1207","authenticated-orcid":false,"given":"Gugu","family":"Kali","sequence":"additional","affiliation":[{"name":"Tygerberg Hospital Neonatal Unit, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town 7600, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melantha","family":"Coetzee","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Paediatrics and Child Health, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria 0084, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daynia E.","family":"Ballot","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, Charlotte Maxeke Johannesburg Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thumbiko","family":"Kalua","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0084, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Babbo","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0084, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6406-2380","authenticated-orcid":false,"given":"Michael S.","family":"Pepper","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0084, South 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