Cholestasis Due to USP53 Deficiency

J Pediatr Gastroenterol Nutr. 2021 May 1;72(5):667-673. doi: 10.1097/MPG.0000000000002926.


Objectives: Although a number of genetic forms of cholestasis have been identified, the genetic etiology of disease remains unidentified in a subset of cholestasis patients.

Methods: Whole exome sequencing (WES) was performed in DNA from patients diagnosed with cholestasis, at different points on the continuum from progressive familial intrahepatic cholestasis to benign recurrent intrahepatic cholestasis, in whom no disease mutations in known cholestasis genes had been identified. Candidate genes were then assessed in a larger patient sample, by targeted next-generation sequencing (NGS). Disease features at presentation and follow-up were collected from available medical records.

Results: By WES, we identified 3 patients with homozygous mutations in USP53. Screening of USP53 in a larger set of patients identified 4 additional patients with homozygous mutations in USP53. Six of the 7 patients had deletion mutations, and 1 had a missense mutation; 3 of the patients were siblings, all bearing a deletion that also disrupted neighboring MYOZ2. Age of onset ranged from early infancy to adolescence. Cholestasis tended to be biochemically mild and intermittent, and responsive to medication. Liver fibrosis was, however, present in all 4 patients who were biopsied, and splenomegaly was apparent in 5 of 7 at last ultrasound.

Conclusions: Two groups recently identified patients with liver disease and mutation in USP53. We have now identified biallelic mutation in USP53 in 7 further patients with cholestasis, from 5 families. Most individuals had evidence of chronic liver disease, and long-term follow-up is recommended.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Carrier Proteins
  • Child
  • Child, Preschool
  • Cholestasis* / genetics
  • Cholestasis, Intrahepatic* / diagnosis
  • Cholestasis, Intrahepatic* / genetics
  • Exome Sequencing
  • Homozygote
  • Humans
  • Infant
  • Muscle Proteins
  • Mutation
  • Ubiquitin-Specific Proteases / deficiency*
  • Ubiquitin-Specific Proteases / genetics


  • Carrier Proteins
  • MYOZ2 protein, human
  • Muscle Proteins
  • USP53 protein, human
  • Ubiquitin-Specific Proteases