Foden, Caroline J.Durant, KevinMellet, JuanitaJoubert, FourieVan Rensburg, JeanneMasemola, Mogomane Yvonne KhomotsoVelaphi, Sithembiso C.Nakwa, Firdose L.Horn, Alan R.Pillay, ShaktiKali, GuguCoetzee, MelanthaBallot, Daynia E.Kalua, ThumbikoBabbo, CarinaPepper, Michael SeanNESHIE Working Group2025-10-092025-10-092025-03Foden, C.J.; Durant, K.; Mellet, J.; Joubert, F.; van Rensburg, J.; Masemola, K.; Velaphi, S.C.; Nakwa, F.L.; Horn, A.R.; Pillay, S.; et al. Genetic Variants Associated with Suspected Neonatal Hypoxic Ischaemic Encephalopathy: A Study in a South African Context. International Journal of Molecular Sciences 2025, 26, 2075. https://doi.org/10.3390/ ijms26052075.1661-6596 (print)1442-0067 (online)10.3390/ ijms26052075http://hdl.handle.net/2263/104682DATA AVAILABILITY STATEMENT : Genetic variant calls in .csv format, per individual for both neonates and BixBio controls, are available for the allele frequency-filtered data set, i.e., the data set used to perform association testing and produce the results in this study. These data are available on reasonable request from the corresponding author and provided the proposed use of the data is approved by the Research Ethics Committee of the University of Pretoria Medical School. The sharing of full whole-genome data sequences has not been approved by the Research Ethics Committee, due to the personal nature of genomic data and the vulnerable nature of the study population, i.e., neonates with a severe health condition for whom consent was provided by their parent(s). The data offered to be shared are sufficient to reproduce the results of this study or conduct further NESHIE-related analysis.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–severe NESHIE through whole-genome, unbiased analysis. Variant filtering and prioritization were performed, followed by association testing both on a case–control 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 < 6.2 × 10−4), 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.en© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Hypoxic ischaemic encephalopathyGenetic variantsWhole genomeArticle