Correlation of UGT1A1 genotypes with newborn hyperbilirubinemia using newborn genetic screening

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.

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).

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.

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.