Genomic sequencing as a key primary recommendation for neonatal hyperbilirubinemia: a population-based multicenter study

Dabin Huang; Xia Gu; Weizhong Li; Hongying Mi; Haiquan Zeng; Guiying Zhuang; Sitao Li; Congcong Shi; Tao Wei; Wei Zhou; Xin Xiao; Wenhao Zhou; Hu Hao

doi:10.1016/j.jgg.2025.09.002

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Genomic sequencing as a key primary recommendation for neonatal hyperbilirubinemia: a population-based multicenter study

doi: 10.1016/j.jgg.2025.09.002

a. Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China;
b. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University Guangzhou, Guangdong 510655, China;
c. Department of Neonatology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China;
d. Inborn Errors of Metabolism Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China;
e. Department of Neonatology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China;
f. Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, China;
g. Department of Neonatology, Maternal and Child Health Hospital of Qingyuan City, Qingyuan, Guangdong 511500, China;
h. Department of Neonatology, The Maternal and Child Health Care Hospital of Huadu, Guangzhou, Guangdong 510800, China;
i. Department of Bioengineering, College of Food Science, South China Agricultural University, Guangzhou, Guangdong 510642, China;
j. Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China

Funds:

This work was supported by the Guangzhou Science and Technology Plan Project (2024B03J0191) to Hu Hao, and the Research Projects of the Sixth Affiliated Hospital, Sun Yat-sen University (No.2023-053 and No.2023-063) to Hu Hao.

Received Date: 2025-06-03
Accepted Date: 2025-09-04
Rev Recd Date: 2025-08-30

Available Online: 2025-09-11

Abstract

Abstract

Genetic variations are risk factors for neonatal hyperbilirubinemia (NHB), a common cause of infant hospitalization in the first postnatal week, but their contribution and long-term impacts remain unclear. This population-based multicenter study enrolls 1,780 hospitalized NHB newborns and 38,158 genetically screened newborns across 20 hospitals (2019–2022). Excluding cases with clear clinical causes, 977 NHB cases are categorized into genetic variation-positive and -negative groups. Results show significantly higher NHB-related gene variants (81.63% vs. 65.62%) and positive variation rates (36.29% vs. 9.4%) in NHB cases than in the general newborn population (all P < 0.001). Among the 977 NHB cases, 325 (33.3%) have positive variants, with higher rates of severe hyperbilirubinemia (16.9% vs. 9.7%, P = 0.001), prolonged jaundice (36.3% vs. 27.6%, P = 0.005), and cholestasis/hypercholanaemia (23.7% vs. 14.7%, P < 0.001) in the positive group. Cumulative genetic variants in bilirubin metabolism pathways exhibit dose-dependent associations with increased risks of complications. Long-term follow-up reveals that UGT1A1 variants prolong jaundice up to 1 month, while severe SLC10A1 variants cause persistent cholestasis/hypercholanaemia beyond 9 months. This large-scale evidence highlights genetic factors as key NHB determinants, with implications for neonatal care protocols to integrate genetic testing and establish long-term surveillance for variant carriers.
- Neonatal hyperbilirubinemia,
- Jaundice polygene metabolic disorder,
- Genetic variations,
- Prolonged jaundice,
- Multicenter observational

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