Case Report: Three novel pathogenic ABCC2 mutations identified in two patients with Dubin-Johnson syndrome

Abstract

Background: Dubin-Johnson syndrome (DJS) is a rare autosomal recessive genetic disease which is caused by mutations in the ABCC2 gene; it is characterized by chronic hyperbilirubinemia. Here, we report two pedigrees affected with DJS which were caused by three novel pathogenic ABCC2 mutations. Case summary: The two patients exhibited intermittent low-grade, predominantly conjugated hyperbilirubinemia and showed no other abnormalities. They were diagnosed clinically with DJS. Three novel pathogenic ABCC2 mutations-c.2980delA, c.1834C>T, and c.4465_4473delinsGGCCCACAG-were identified by whole-exome sequencing. These mutations could be responsible for DJS in the two pedigrees. The genetic test confirmed the diagnosis of DJS. Conclusion: These results contributed to the genetic diagnosis of the two patients with DJS and expanded the variant database for the ABCC2 gene.

Keywords: ABCC2; Dubin–Johnson syndrome; hyperbilirubinemia; multidrug resistance-associated protein 2; mutation.

FIGURE 1

Family tree and genetic analysis of Family 1. (A) Proband III-3 was diagnosed with DJS. (B) Sanger sequencing revealed a compound heterozygous (c.2980delA and c.1834 C>T) ABCC2 mutation in III-3. IV-1 shared the heterozygous c.1834 C>T variant.

FIGURE 2

The family tree and genetic analysis of Family 2. (A) Proband II-2 suffered from DJS. (B) Direct sequencing showed a compound heterozygous (c.2980delA and c.4465_4473 delinsGGCCCACAG) ABCC2 mutation in II-2. I-1 was affected with the heterozygous c.4465_4473delinsGGCCCACAG mutation. II-2 harbored the heterozygous c.2980delA variant. (C) Locations of the mutations in MRP2. The schematic diagram of MRP2 was generated using Protter software (http://wlab.ethz.ch/protter/start/). MSD: membrane spanning domains, NBD: nucleotide binding domains.