Diagnostic yield and novel candidate genes by exome sequencing in 166 children with intrahepatic cholestasis

Abstract Background & Aims: Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first months of life. Methods: We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis，and re-analyzed phenotype and WES data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. Results: Overall, we identified disease causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) were metabolic liver diseases, 9 (17%) were syndromic cholestasis, 9 (17%) were progressive familial intrahepatic cholestasis, 3 (6%) were bile acid synthesis defects, 3(6%) were infantile liver failure and 10 (19%) were phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G>A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By reanalyzing WES data, two patients were newly solved, which had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved trio families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice model. Conclusions: In a single center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Rigorous analysis of WES data of well-phenotyped patients with intrahepatic cholestasis leads to a broader understanding of gene-specific phenotypic spectra as well as monogenic candidate gene identification.