A novel pathogenic variant for dubin-johnson syndrome in a case of hyperbilirubinemia and metabolic associated fatty liver disease.

BACKGROUND

Dubin-Johnson Syndrome (DJS; OMIM 237500) is a rare autosomal recessive disorder caused by pathogenic variants in the ABCC2 gene, encoding for the multidrug resistance protein 2 (MRP2), resulting in impeded biliary excretion of bilirubin metabolites. It is typically characterized by chronic or intermittent jaundice and conjugated hyperbilirubinemia.

CASE PRESENTATION: We report the case of a 54-year-old male with hyperbilirubinemia (mostly conjugated) and hypertransaminasemia. Hypertransaminasemia was due to presence of Metabolic dysfunction-associated fatty liver disease (MASLD), while whole-genome sequencing revealed a homozygous missense variant affecting ABCC2 (c.3893G > A, p.Gly1298Asp), a previously undescribed variant likely linked to hyperbilirubinemia. It is an extremely rare genetic variant (allele frequency = 6.2 × 10-7). In silico analyses predicted the variant to be highly pathogenic (CADD score 29; AlphaMissense score 0.978; PhyloP 8.87; DynaMut ΔΔG = -0.765 kcal·mol-1 and ΔΔSVib = -0.234 kcal·mol-1·K-1). Structural modeling suggested no gross conformational changes but potential effects local conformation and overall function of the protein.

CONCLUSIONS

We describe a novel ABCC2 mutation associated with Dubin-Johnson Syndrome. This finding expands the spectrum of ABCC2 variants to evaluate in case of hyperbilirubinemia and highlights the importance of genetic testing in unexplained cases of conjugated hyperbilirubinemia.