Clinical UGT1A1 Genetic Analysis in Pediatric Patients: Experience of a Reference Laboratory

Background Neonatal hyperbilirubinemia can be severe or prolonged and warrant exploration into the underlying etiology, which may include genetic assessment of UGT1A1 for inherited disorders (i.e. Crigler–Najjar syndrome or Gilbert syndrome). Methods In our reference laboratory, we performed UGT1A1 gene sequencing analysis on 346 pediatric patients referred for a clinical indication of hyperbilirubinemia. Results Males ( n = 241) had significantly higher mean total bilirubin concentration compared to females ( n = 105) (9.7 and 7.3 mg/dL, respectively, p = 0.042); however, no sex-based difference was observed in frequency of known or suspected reduced function UGT1A1 variants. The presence of two UGT1A1 variants (consistent with Gilbert or Crigler–Najjar syndrome) occurred less frequently in neonates (aged ≤28 days) than older children (aged 1–18 years) (31.3% in neonates vs. 85.1%, p < 0.0001), and among neonates there was no significant difference in mean total bilirubin between those with two UGT1A1 variants and those without ( p = 0.47). Three novel variants, including c.337T>G (p.Y113D), c.1037C>A (p.A346E), and c.1469A>C (p.D490A) were identified. Among older children, the most common reason for referral was Gilbert syndrome (83.8%) and UGT1A1 genetic analysis confirmed a diagnosis of Gilbert syndrome in 79.0% of those children. Conclusions Among neonates, a population in which hyperbilirubinemia is common and often of multifactorial etiology, UGT1A1 genetic testing served as a useful clinical tool in ruling in or ruling out inherited hyperbilirubinemia. Here we describe our experience as a reference laboratory in clinical UGT1A1 full gene sequencing. Our results highlight the challenges in predicting the contribution of genetic variation in UGT1A1 to hyperbilirubinemia based on clinical parameters alone, particularly in neonates, and the utility of UGT1A1 full gene sequencing in the evaluation of neonatal and pediatric hyperbilirubinemia.