Molecular biology of glucose-6-phosphate dehydrogenase and UDP-glucuronosyltransferase 1A1 in the development of neonatal unconjugated hyperbilirubinemia

Yi-Li Hung; Pi-Feng Chang; Ching-Shan Huang

doi:10.1016/j.pedneo.2024.02.003

Molecular biology of glucose-6-phosphate dehydrogenase and UDP-glucuronosyltransferase 1A1 in the development of neonatal unconjugated hyperbilirubinemia

Pediatr Neonatol. 2024 Mar 3:S1875-9572(24)00020-2. doi: 10.1016/j.pedneo.2024.02.003. Online ahead of print.

Authors

Yi-Li Hung¹, Pi-Feng Chang², Ching-Shan Huang³

Affiliations

¹ Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan; School of Medicine, National Tsing-Hua University, Hsinchu City, Taiwan.
² Department of Pediatrics, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei City, Taiwan; Department of Electronic Engineering, Oriental Institute of Technology, Pan-Chiao, New Taipei City, Taiwan.
³ Department of Clinical Pathology, Cathay General Hospital, Taipei, Taiwan. Electronic address: ching.shan.h@gmail.com.

PMID: 38480019
DOI: 10.1016/j.pedneo.2024.02.003

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and variants of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene are the most common genetic causes of neonatal unconjugated hyperbilirubinemia (NUH). In this review, we searched PubMed for articles on the genetic causes of NUH published before December 31, 2022, and analyzed the data. On the basis of the results, we reached eight conclusions: (1) 37 mutations of the G6PD gene are associated with NUH; (2) the clinical manifestation of G6PD deficiency depends not only on ethnicity but also on the molecular mechanisms underlying the deficiency (and thus its severity); (3) of mutations in the UGT1A1 gene, homozygous c.-53A(TA)₆TAA > A(TA)₇TAA is the main cause of NUH in Caucasians and Africans, whereas homozygous c.211G > A is the main genetic cause of NUH in East Asians; (4) in Indonesian neonates, homozygous c.-3279T > G is the most common cause of NUH development, and neither c.-53 A(TA)₆TAA > A(TA)₇TAA nor c.211G > A causes it; (5) in breast-fed East Asian neonates, the TA7 repeat variant of the UGT1A1 gene protects against the development of NUH; (6) G6PD deficiency combined with homozygous c.211G > A variation of the UGT1A1 gene increases the risk of severe NUH; (7) in Pakistani and Caucasian patients with Crigler-Najjar syndrome type 2 (CN-2), point mutations of the UGT1A1 gene are widely distributed and frequently occur with variation at nucleotide -53, whereas in Asian patients with CN-2, compound homozygous variations in the coding region are frequently observed; and (8) records of G6PD deficiency and UGT1A1 variation status for a neonate offer useful pharmacogenomic information that can aid long-term care. These results indicate that timely diagnosis of NUH through molecular tests is crucial and that early initiation of treatment for the neonates and educational programs for their parents improves outcomes.

Keywords: Glucose-6-phosphate dehydrogenase; Neonatal unconjugated hyperbilirubinemia; UDP-Glucuronosyltransferase 1A1.

Publication types

Review