Low‐GGT intrahepatic cholestasis associated with biallelic USP53 variants: clinical, histological, and ultrastructural characterization

BACKGROUND AND AIMS: In about 20% of children with cholestasis and normal or low serum gamma-glutamyltransferase (GGT) activity, no etiology is identified. We sought new genes implicated in pediatric hepatobiliary disease. METHODS: We conducted whole exome sequencing in 69 children evaluated at our center from 2011 to 2018 who had low-GGT cholestasis and in whom homozygous / compound heterozygous predictedly pathogenic variants (PPV) in ATP8B1, ABCB11, NR1H4, MYO5B, or TJP2 were not found. Clinical records and findings on light microscopy and transmission electron microscopy of liver-biopsy materials were reviewed. RESULTS: In 7 patients from 7 unrelated families, biallelic PPV (10 in total) were found in USP53, recently associated with intrahepatic cholestasis. Seven variants were classified as pathogenic: one canonical splicing, c.569+2T>C, and six nonsense or frameshifting: c.169C>T (p.Arg57Ter), c.581delA (p.Arg195GlufsTer38), c.831_832insAG (p.Val279GlufsTer16), c.1012C>T (p.Arg338Ter), c.1426C>T (p.Arg476Ter), and c.1558C>T (p.Arg520Ter). Three were likely pathogenic: c.297G>T (p.Arg99Ser), c.395A>G (p.His132Arg), and c.878G>T (p.Gly293Val). In all patients, jaundice began at age <7mo. Cholestasis was transient, with documented resolution of hyperbilirubinemia in all (oldest patient now aged 5y) except one, who was lost to follow-up. Light microscopy identified intralobular cholestasis, giant-cell change of hepatocytes, and perisinusoidal-perihepatocytic and portal-tract fibrosis. Ultrastructural study revealed elongated hepatocyte-hepatocyte tight junctions. One patient was deaf. CONCLUSION: USP53 interacts with the tight-junction constituent TJP2. TJP2 mutation can cause low-GGT intrahepatic cholestasis, with elongated hepatocyte-hepatocyte tight junctions, as well as deafness. Our findings extend a preliminary report of USP53 disease and indicate that USP53 mutation may generate a partial phenocopy of TJP2 disease. (250 words).