Correlation of UGT1A1 genotypes with newborn hyperbilirubinemia using newborn genetic screening

Background This study evaluated whether uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1 ) variants identified through newborn genetic screening are associated with the development of clinically significant neonatal hyperbilirubinemia. Methods Next-generation sequencing (NGS) was performed in 1,019 newborns, and pathogenic (P)/likely pathogenic (LP) UGT1A1 findings were confirmed by Sanger sequencing. This single-center cohort study was based on routine NBGS and bilirubin assessments, whereas genotype–phenotype correlations were analyzed retrospectively using routinely collected clinical data. Newborns with confirmed biallelic or multi-allelic UGT1A1 variants were grouped as homozygous (Hom), compound heterozygous (CH, confirmed in trans), or three-loci (3 loci, confirmed in trans), and were compared with a randomly selected control group without UGT1A1 variants. TcB levels were measured at prespecified timepoints (postnatal days 1, 4, and 42). Results Seventy-five newborns had confirmed biallelic or multi-allelic UGT1A1 variants (Hom, n  = 45; CH, n  = 26; 3 loci, n  = 4), and 40 newborns served as controls. The most frequent variants were c.211G>A and c.-41_-40dup; c.1091C>T and c.686C>A were less common. TcB values did not differ across groups on days 1 and 4, but were higher in all mutation groups than in controls on day 42 ( P  < 0.001), with the highest values observed in the 3-loci group. Clinically significant neonatal hyperbilirubinemia, defined as clinician-documented hyperbilirubinemia requiring phototherapy during the neonatal period, was rare (four cases in total; 3/75 in the mutation group and 1/40 in controls; P  = 0.367), although the small number of events precludes firm between-group inference. Conclusions In this single-center cohort, common UGT1A1 variants were associated with mildly elevated TcB levels at 6 weeks, suggesting slower postnatal bilirubin clearance, but showed little association with clinically significant neonatal hyperbilirubinemia. These findings support a variant-level reporting strategy for newborn genetic screening (NBGS). Routinely classifying common UGT1A1 variants (c.211G>A, c.-41_-40dup, c.1091C>T, and c.686C>A) as moderate-/high-risk and performing routine segregation analysis for multi-locus variants would likely increase genetic counseling burden and parental anxiety while providing minimal additional clinical benefit.