关键词: 遗传性疾病, USP53, 胆汁淤积

Abstract: Background：USP53 gene deficiency disease is a newly discovered rare genetic disorder characterized by cholestasis. Few cases have been reported and more cases need to be accumulated to fully describe the clinical and genetic features. Objective：To investigate the clinical and genetic characteristics of children with USP53 gene deficiency. Design：Case series report. Methods：This retrospective study enrolled children with USP53 gene deficiency who were admitted to the Children's Hospital of Fudan University from January 2019 to December 2022.The clinical data were collected and analyzed. Medical literature published before December 2022 was searched with the keywords of USP53, ubiquitin-specific peptidase 53 and cholestasis in PubMed, Wanfang database and China National Knowledge Infrastructure. Main outcome measures：USP53 gene variation sites and clinical phenotypes. Results：Six patients with USP53 gene deficiency were enrolled (3 males and 3 females). All 6 patients presented with jaundice onset at infancy and liver function tests showed low GGT cholestasis. Whole exome sequencing (WES) were performed and compound heterozygous or homozygous USP53 gene variants were found in these patients. After treatment with ursodeoxycholic acid and cholestyramine, jaundice in 5 cases was completely regressed and liver function tests were normal followed up to the age of 7 to 34 months. One case presented at the with jaundice age of 5 months and completely regressed at last follow-up(12 months) with high total bile acid（257 μmol·L-1）. A total of 3 compound heterozygous and 3 homozygous USP53 gene variants were found through WES in these 6 patients (c.1012C>T in 3 patients, c.1558C>T and c.1426C>T in 2 patients). Except for c.725C>G, which was classified as a variant of uncertain clinical significance, other variants were classified as pathogenic variants. Among all the variants, c.1815_1816dupTA and c.725C>G were novel, which have never been reported before. Thirty-three of 38 USP53-deficient patients presented with jaundice, cholestasis and pruritus and other symptoms including hearing loss (4 cases), speech and developmental delay (2 cases), heart failure (1 case), hypocalcemia (1 case), hypothyroidism (1 case), leukocytosis and thrombocytosis (1 case) and fundus oculi lesion (1 case). A total of 25 pathogenic variants in five types were reported, including nine frameshift variants, six nonsense variants, five missense variants, three splice site mutations and two gross deletion variants. Conclusions：USP53-deficient patients often present with jaundice and cholestasis, and the prognosis is good. Among all the USP53 variants, frameshift variants and nonsense variants are common.

Key words: Genetic disease, USP53, Cholestasis