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BMC Gastroenterology

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Open Access 01-12-2018 | Research article

Spectrum of genomic variations in Indian patients with progressive familial intrahepatic cholestasis

Authors: Anjali Sharma, Ujjal Poddar, Shikha Agnihotry, Shubha R. Phadke, Surender K. Yachha, Rakesh Aggarwal

Published in: BMC Gastroenterology | Issue 1/2018

Abstract

Background

Progressive familial intrahepatic cholestasis (PFIC) is caused by variations in ATP8B1, ABCB11 or ABCB4 genes. Data on genetic variations in Indian patients with PFIC are lacking.

Methods

Coding and splice regions of the three genes were sequenced in unrelated Indian children with PFIC phenotype. The variations identified were looked for in parents, 30 healthy persons and several variation databases, and their effect was assessed in-silico.

Results

Among 25 children (aged 1–144 months), nine (36%) had unique major genomic variations (ATP8B1: 4, ABCB11: 3 and ABCB4: 2). Seven had homozygous variations, which were assessed as ‘pathogenic’ or ‘likely pathogenic’. These included: (i) four amino acid substitutions (ATP8B1: c.1660G > A/p.Asp554Asn and c.2941G > A/p.Glu981Lys; ABCB11: c.548 T > C/p.Met183Thr; ABCB4: c.431G > A/p.Arg144Gln); (ii) one 3-nucleotide deletion causing an amino acid deletion (ATP8B1: c.1587_1589delCTT/p.Phe529del); (iii) one single-nucleotide deletion leading to frame-shift and premature termination (ABCB11: c.1360delG/p.Val454Ter); and (iv) a complex inversion of 4 nucleotides with a single-nucleotide insertion leading to frame-shift and premature termination (ATP8B1: c.[589_592inv;592_593insA]/p.Gly197LeufsTer10). Two variations were found in heterozygous form: (i) a splice-site variation likely to cause abnormal splicing (ABCB11: c.784 + 1G > C), and (ii) a nucleotide substitution that created a premature stop codon (ABCB4: c.475C > T/p.Arg159Ter); these were considered as variations of uncertain significance. Three of the nine variations were novel.

Conclusions

Nine major genomic variations, including three novel ones, were identified in nearly one-third of Indian children with PFIC. No variation was identified in nearly two-thirds of patients, who may have been related to variations in promoter or intronic regions of the three PFIC genes, or in other bile-salt transport genes.

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Title: Spectrum of genomic variations in Indian patients with progressive familial intrahepatic cholestasis
Authors: Anjali Sharma
Ujjal Poddar
Shikha Agnihotry
Shubha R. Phadke
Surender K. Yachha
Rakesh Aggarwal
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Gastroenterology / Issue 1/2018
Electronic ISSN: 1471-230X
DOI: https://doi.org/10.1186/s12876-018-0835-6

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