To investigate the clinical characteristics, mutation spectrum of the ABCC2 gene, and genotype-phenotype correlations in Chinese pediatric patients with Dubin-Johnson syndrome (DJS).

Six children diagnosed with DJS at Kunming Children’s Hospital from April 2018 to August 2021 were enrolled. Clinical, biochemical, and imaging data were collected. Peripheral blood samples were obtained from the probands and their families. Targeted high-throughput sequencing of ABCC2 was performed, with identified variants validated by Sanger sequencing and segregation analysis. Pathogenicity was assessed following established guidelines.

All patients presented primarily with jaundice; the proportion of serum direct bilirubin to total bilirubin ((DBIl/TBIl)) exceeded 20%. We identified 12 ABCC2 pathogenic mutant alleles, including 4 missense, 2 nonsense, 2 frameshift, 1 synonymous, 1 in-frame deletion, and 2 splice-site mutations. Among these, three were novel and previously unreported: c.4210_4212del, c.4237_4238insCT, and c.4532dupA. Exons 20, 28, and 30 emerged as mutational hotspots. Genotype-phenotype relationships were complex: carriers of in-frame deletions exhibited milder manifestations, while truncating mutations did not consistently lead to the most severe phenotypes. Comorbidities and allelic interactions together constituted a “composite pathogenicity burden” that determined phenotypic severity.

This study expands the ABCC2 mutation spectrum in Chinese DJS patients, reports three novel mutations, and introduces a “composite pathogenicity burden” model that highlights the multifactorial nature of clinical presentation. These findings provide a basis for improved genetic counseling and precision management of DJS.