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Bile salt export pump deficiency disease: two novel, late onset, ABCB11 mutations identified by next generation sequencing

Giovanni Vitale, Martina Pirillo, Vilma Mantovani, Elena Marasco, Adelia Aquilano, Nesrine Gamal, Paola Francalanci, Fabio Conti, Pietro Andreone


Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive cholestatic diseases of childhood and represents the main indication for liver transplantation at this age; PFIC2 involves ABCB11 gene, that encodes the ATPdependent canalicular bile salt export pump (BSEP). Benign intrahepatic cholestasis (BRIC) identifies a group of diseases involving the same genes and characterized by intermittent attacks of cholestasis with no progression to liver cirrhosis. Diagnosis with standard sequencing techniques is expensive and available only at a few tertiary centers. We report the application of next generation sequencing (NGS) in the diagnosis of the familial intrahepatic cholestasis with a parallel sequencing of three causative genes. We identified the molecular defects in ABCB11 gene in two different probands who developed a severe cholestatic disease of unknown origin. In the first patient a compound heterozygosity for the novel frameshift mutation p.Ser1100GlnfsX38 and the missense variant p.Glu135Lys was detected. In the second patient, triggered by contraceptive therapy, we identified homozygosity for a novel missense variant p.Ala523Gly. In conclusion, these mutations seem to have a late onset and a less aggressive clinical impact, acting as an intermediate form between BRIC and PFIC.

Key words. Progressive familial intrahepatic cholestasis, Benign intrahepatic cholestasis, Cholestatic diseases, Gamma-glutamiltranspeptidase, Alkaline phosphatase

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The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for the Study of the Liver and the Canadian Association for the Study of the Liver

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