Background and aims: The ABCC2 gene is implicated in Dubin-Johnson syndrome (DJS), a rare autosomal recessive liver disorder. The primary aim of this study was to determine the diagnostic value of ABCC2 genetic testing in the largest cohort of DJS reported to date. The high number of patients with cholestatic manifestations in this series prompted us to evaluate the genetic contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.
Methods: The cohort study included 32 patients with clinical DJS diagnosis, and 372 patients referred for the following disorders: including low phospholipid-associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP), and benign recurrent intrahepatic cholestasis (BRIC). ABCC2 was screened by next-generation sequencing.
Results: Most patients with clinical DJS had positive genetic diagnosis (n=30; 94%), with a great diversity of point mutations and copy number variations in ABCC2. Strikingly, 8 (27%) of these patients showed transient cholestatic features at presentation: 4 neonatal cholestasis, 2 ICP, 1 contraceptive-induced cholestasis, and 1 sporadic cholestasis. Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP, or BRIC did not differ significantly from that of the general population.
Conclusions: This large series reveals that DJS is a highly homogeneous Mendelian disorder involving a large spectrum of ABCC2 variants. Genetic testing is crucial to establish early DJS diagnosis in patients with atypical presentations, such as neonatal cholestasis. This study also provides no evidence for the contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.
Localization in the ABCC2 canalicular transporter of pathogenic variants identified in patients with Dubin-Johnson syndrome