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

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

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.

Keywords: Genetic variation; Hereditary cholestasis; Polymorphism; Progressive familial intrahepatic cholestasis.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by Ethics Committee of the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. An informed written consent was obtained from one of the parents for each child studied.

Consent for publication

The consent document for study subjects included consent for publication of data (after removing any identifying information).

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Family tree for 9 patients in whom major variations in ATP8B1 (patients PF05, PF20, PF19 and PF18), ABCB11 (patients PF03, PF21 and PF13) or ABCB4 (patients PF25 and PF09) genes were found. Five of these nine  patients had history of consanguinity. Clinical, biochemical and histological findings in these patients are included in Table 3

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