Cystic fibrosis in South Africa: A changing diagnostic paradigm

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.

Background. A 2011 South African (SA) survey noted substantial variability in provision of therapeutic hypothermia (TH) for moderate- severe neonatal encephalopathy due to suspected hypoxic-ischaemic encephalopathy (NESHIE). Objectives. To describe facilities, including TH, for babies with NESHIE in SA tertiary/specialised public hospitals. Methods. A survey was emailed to representatives of all public tertiary/specialised hospitals with tertiary neonatal beds in SA. The survey contained questions regarding bed numbers, equipment, staffing, follow-up and barriers to the implementation of TH. Results. Responses were received from all 25 hospitals across the nine provinces. Most hospitals (n/N=22/25; 88%) provided TH (median (range) per province: 2 (1 - 8)). The hospitals providing TH had more total neonatal beds (p=0.011) and more admissions with moderate- severe NESHIE (p=0.008) compared with those not providing TH. Most cooling centres (n/N=20/22; 91%) provided TH in their NICUs; six of these also cooled at lower levels of care. There was access to amplitude integrated electroencephalography (aEEG) and automated cooling in 91% of cooling centres. Manual cooling was used by 50% if automated TH was not available, 82% of which were validated methods. Late arrival was the most frequent barrier to provision of TH (80%). Conclusion. All provinces and most tertiary/specialised hospitals with tertiary neonatal beds in SA provided TH in 2023. The use of acceptable monitoring and cooling methods was widespread but insufficient, and some cooling methods in use were not validated. National registers and standardised protocols for patient selection and management are needed.