[Analysis of familial intrahepatic cholestasis caused by ubiquitin-specific peptidase 53 gene mutation].

Objective

To investigate the clinical characteristics and gene mutation status of progressive familial intrahepatic cholestasis caused by a ubiquitin-specific peptidase 53 (USP53) gene mutation (USP53-FIC) in a family.

Methods

A female infant patient with USP53-FIC and her family who presented to the Department of Gastroenterology, Children's Hospital Affiliated with Zhengzhou University, in May 2025 with a one-month history of jaundice and yellow urine, which worsened over a one-week period of ecchymosis, were selected as the study subjects. Peripheral blood samples were collected from the patient, her parents, and her elder brother for whole-exome sequencing of the family, followed by Sanger sequencing for validation.

Results

The patient was a 5-month-23-day-old female presenting primarily with jaundice of the skin and sclera, dark urine, and skin ecchymosis. Liver function tests indicated cholestasis, normal gamma-glutamyl transferase, and abnormal coagulation function. Whole-exome sequencing of the family revealed a compound heterozygous variant of c.1558C>T and c.829dup in the USP53 gene, inherited from her mother and father, respectively. Sanger sequencing confirmed that the patient's older brother carried the same variants. The c.1558C>T was previously reported as a pathogenic variant, while c.829dup was previously unreported. PVS1 + PM2_Supporting + PM3 was reported as a pathogenic variant according to the American Society for Medical Genetics and Genomics variant rating guidelines.

Conclusion

The compound heterozygous variant c.1558C>T and c.829dup in the USP53 gene are the genetic cause of this USP53-FIC in a family. USP53-FIC should be suspected for infants who suddenly develop cholestasis accompanied by coagulation disorders but normal gamma-glutamyl transferase levels. Genetic testing is helpful in clarifying the diagnosis and guiding treatment. The c.829dup variant enriches the variant spectrum of the USP53 gene.