Journal of Human Genetics https://doi.org/10.1038/s10038-020-0811-1 ARTICLE New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin Hamoud Alhebbi 1 ● Abdul Ali Peer-Zada 2 ● Abdulrahman A. Al‐Hussaini 3,4 ● Sara Algubaisi 1 ● Awad Albassami 1 ● Nasser AlMasri 5 ● Yasir Alrusayni 6 ● Ibrahim M. Alruzug 7 ● Essa Alharby 8 ● Manar A. Samman 2 ● Syed Zubair Ayoub 2 ● Sateesh Maddirevula 9 ● Roy W. A. Peake 10 ● Fowzan S. Alkuraya 4,9 ● Sami Wali 1 ● Naif A. M. Almontashiri 8,11 Received: 25 March 2020 / Revised: 15 June 2020 / Accepted: 14 July 2020 © The Author(s), under exclusive licence to The Japan Society of Human Genetics 2020 Abstract Biallelic variants in the USP53 gene have recently been reported to segregate with normal gamma glutamyltransferase (GGT) cholestasis. Using whole-exome sequencing (WES), we detected two USP53 homozygous variants (c.951delT; p. Phe317fs and c.1744C>T; p. Arg582*) in five additional cases, including an unpublished cousin of a previously described family with intractable itching and normal GGT cholestasis. Three patients, a child and two adults, presented with recurrent episodes of normal GGT cholestasis, consistent with a diagnosis of benign recurrent intrahepatic cholestasis (BRIC). Cholangiopathic changes, possibly autoimmune in origin, were recognized in some patients. Additional phenotypic details in one patient included an enlarged left kidney, and speech/developmental delay. Notably, two patients exhibited a complete response to rifampicin, and one responded to ursodeoxycholic acid (UDCA). Two adult patients were suspected to have autoimmune liver disease and treated with steroids. This report describes new cases of USP53 disease presenting with normal GGT cholestasis or BRIC in three children and two adults. We also describe the novel finding of a dramatic response to rifampicin. The association of cholangiopathy with normal GGT cholestasis provides a diagnostic challenge and remains poorly understood. Introduction Hereditary cholestasis is a heterogeneous group of autosomal recessive liver disorders in which the production and release of bile acids from hepatocytes is impaired. A number of clinical conditions including progressive familial intrahepatic cholestasis (PFIC) can lead to pediatric cholestasis and pro- gress to cirrhosis and end-stage liver disease before adulthood [1]. The diagnostic yield of genetic testing in cases of pediatric cholestasis currently ranges from 25 to 50%. However, this is expected to increase as more candidate genes are discovered and confirmed [1]. We recently reported the association of several novel loci with pediatric cholestatic liver disease [2, 3]. Benign recurrent intrahepatic cholestasis (BRIC) is characterized by recurrent episodes of cholestasis mani- festing by jaundice, pruritus, anorexia, fatigue, and stea- torrhea. Episodes can be spontaneous or triggered by infection or pregnancy and can last from weeks to months [4, 5]. Familial cases of BRIC affecting children and adults are caused by mutations in ATP8B1 (BRIC1) [4–6], ABCB11 (BRIC2) [7], TJP2 [8], and MYO5B [9]. The USP53 gene encodes a non-protease protein homolog of the ubiquitin-specific peptidase family [10]. The USP53 protein is expressed at high levels in the kidney and inner ear, with medium expression in liver and brain tissues [2, 11]. USP53, a tight junction (TJ) protein, co-localizes and interacts at the cellular TJs with other tight junction proteins 1 and 2 (TJP1 and TJP2). Mutations in the TJP2 gene are known to cause familial hypercholanemia [8, 12], normal GGT cho- lestasis (PFIC4) [8, 13], BRIC [8], intrahepatic cholestasis of pregnancy (ICP) [14], cirrhosis in adults [14], hepatocellular carcinoma [14–16], and deafness [17, 18]. A missense variant These authors contributed equally: Hamoud Alhebbi, Abdul Ali Peer- Zada, Abdulrahman A. Al‐Hussaini * Sami Wali swali@psmmc.med.sa * Naif A. M. Almontashiri nmontashri@taibahu.edu.sa Extended author information available on the last page of the article Supplementary information The online version of this article (https:// doi.org/10.1038/s10038-020-0811-1) contains supplementary material, which is available to authorized users. 1234567890();,: 1234567890();,: