Biallelic Novel Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature.

Introduction: Hereditary cholestasis is a heterogeneous group of liver diseases that mostly show autosomal recessive inheritance. The phenotype of cholestasis is highly variable. Molecular genetic testing offers an useful approach to differentiate different types of cholestasis because some symptoms and findings overlap. Biallelic variants in have recently been reported in cholestasis phenotype.

Methods: In this study, we aimed to characterize clinical findings and biological insights on a novel splice variant causing cholestasis phenotype and provided a review of the literature. We performed whole-exome sequencing and then confirmed it with Sanger sequencing. In addition, as a result of in silico analyses and cDNA analysis, we showed that the USP53 protein in our patient was shortened.

Results: We report a novel splice variant (NM_019050.2:c.238-1G>C) in the gene via whole-exome sequencing in a patient with cholestasis phenotype. This variant was confirmed by Sanger sequencing and was a result of family segregation analysis; it was found to be in a heterozygous state in the parents and the other healthy elder brother of our patient. According to in silico analyses, the change in the splice region resulted in an increase in the length of exon 2, whereas the stop codon after the additional 3 amino acids (VTF) caused the protein to terminate prematurely. Thus, the mature USP53 protein, consisting of 1,073 amino acids, has been reduced to a small protein of 82 amino acids.

Conclusion: We propose a model for the tertiary structure of USP53 for the first time, and together with all these data, we support the association of biallelic variants of the gene with cholestasis phenotype. We also present a comparison of previously reported patients with -associated cholestasis phenotype to contribute to the literature.