Genetic Variants Associated with Suspected Neonatal Hypoxic Ischaemic Encephalopathy: A Study in a South African Context

被引:0
|
作者
Foden, Caroline J. [1 ]
Durant, Kevin [2 ]
Mellet, Juanita [1 ]
Joubert, Fourie [3 ]
van Rensburg, Jeanne [1 ]
Masemola, Khomotso [4 ,5 ]
Velaphi, Sithembiso C. [6 ]
Nakwa, Firdose L. [6 ]
Horn, Alan R. [7 ]
Pillay, Shakti [7 ]
Kali, Gugu [8 ]
Coetzee, Melantha [9 ]
Ballot, Daynia E. [10 ]
Kalua, Thumbiko [1 ]
Babbo, Carina [1 ]
Pepper, Michael S. [1 ]
NESHIE Working Grp
机构
[1] Univ Pretoria, Inst Cellular & Mol Med, Fac Hlth Sci, ZA-0084 Pretoria, South Africa
[2] BixBio Ltd, ZA-8001 Cape Town, South Africa
[3] Univ Pretoria, Genom Res Inst, Ctr Bioinformat & Computat Biol, Dept Biochem Genet & Microbiol, ZA-0002 Pretoria, South Africa
[4] Univ Pretoria, Kalafong Hosp, Dept Paediat & Child Hlth, ZA-0084 Pretoria, South Africa
[5] Univ Pretoria, Fac Hlth Sci, ZA-0084 Pretoria, South Africa
[6] Univ Witwatersrand, Chris Hani Baragwanath Acad Hosp, Dept Paediat & Child Hlth, Sch Clin Med,Fac Hlth Sci, ZA-2193 Johannesburg, South Africa
[7] Univ Cape Town, Groote Schuur Hosp, Dept Paediat & Child Hlth, Div Neonatal Med, ZA-7701 Cape Town, South Africa
[8] Stellenbosch Univ, Tygerberg Hosp Neonatal Unit, Dept Paediat & Child Hlth, ZA-7600 Cape Town, South Africa
[9] Univ Pretoria, Steve Biko Acad Hosp, Fac Hlth Sci, Div Neonatol,Dept Paediat & Child Hlth, ZA-0084 Pretoria, South Africa
[10] Univ Witwatersrand, Charlotte Maxeke Johannesburg Acad Hosp, Fac Hlth Sci, Dept Paediat & Child Hlth, ZA-2193 Johannesburg, South Africa
基金
英国医学研究理事会;
关键词
hypoxic ischaemic encephalopathy; genetic variants; whole genome; SEQUENCE VARIANTS; COMPLEX TRAITS; GUIDELINES; MECHANISMS; EXPRESSION; DISCOVERY; MIGRATION; GENOMICS; DATABASE; REGIONS;
D O I
10.3390/ijms26052075
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 x 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.
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页数:21
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