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

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.