Case Report: Mild BRIC-like cholestasis despite a gross USP53 deletion—novel findings and literature review

We report a pediatric case of cholestatic liver disease associated with two novel compound heterozygous variants in the <i>USP53</i> gene: a truncating c.1219A>T (p.Lys407*) variant inherited from the father and a maternally inherited gross deletion involving exons 13-19. Despite the disruptive nature of these variants, the patient presented with a benign recurrent intrahepatic cholestasis (BRIC) characterized by episodic pruritus, jaundice and elevated bile acids with preserved liver function between episodes. Liver histology revealed fibrosis with a cholestatic component, consistent with mild progressive familial intrahepatic cholestasis (PFIC) features. Molecular diagnosis was confirmed by whole-exome sequencing (WES), chromosomal microarray, and Sanger sequencing. A systematic review of 39 published cases was conducted, revealing that <i>USP53</i>-related disease exhibits broad clinical variability, ranging from BRIC to PFIC7. Our findings expand the spectrum of <i>USP53</i> variants, underscore the relevance of large deletions and emphasize the inclusion of <i>USP53</i> in genetic panels for idiopathic low-gamma-glutamyl transferase (GGT) cholestasis.