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

Abstract

BackgroundProgressive 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.MethodsCoding 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.ResultsAmong 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.ConclusionsNine 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.Electronic supplementary materialThe online version of this article (10.1186/s12876-018-0835-6) contains supplementary material, which is available to authorized users.

Phenotypic and Molecular Characteristics of Children with Progressive Familial Intrahepatic Cholestasis in South China

“…A net charge alternation can adversely affect the structure and function of the FIC1 protein. Another deletion mutation p.F529del was previously reported in three patients: in homozygous form in a Japanese and an Indian patient, and in compound heterozygous form with a splice mutation in a patient of mixed Caucasian-African American ancestry [ 8 14 15 ]. The codons G446 and F529 were both involved in substrate binding and the related mutations may lead to an impairment of the enzyme activity.…”

“…PFIC1 and PFIC2 represent 2/3 of PFIC cases, whereas PFIC3 represents 1/3 of PFIC cases [ 6 ]. To date, PFIC has been reported in patients of Caucasian, Asian, and African origin [ 7 8 9 10 ]. In this study, we report the clinical features and gene analysis of nine Chinese patients with PFIC.…”

NovelATP8B1Gene Mutations in a Child with Progressive Familial Intrahepatic Cholestasis Type 1

“…Genetic profiles are well known in the ATP8B1 gene (Table 1 [68141718192021]). Generally, nonsense, frame-shift, and large deletion mutations have been seen commonly in PFIC type 1 patients (13%, 26%, and 3%, respectively) in contrast to missense mutations (58%) seen in BRIC [14].…”

Intrahepatic cholestasis in two omani siblings associated with a novel homozygous ATP8B1 mutation, c.379C>G (p.L127V)

“…[456] The mutation type sometimes predicts the cholestasis phenotype. For example, nonsense and frame-shift mutations are more often detected in PFIC1, whereas missense mutations are more frequently identified in BRIC1.…”

“…Distinct ATP8B1 mutations cause PFIC1 in particular demes: in Amish [c.923G>T (p.G308V)], Inuit and Athabascan [c.1660G>A (D554N)] and Indian children (c.[589_592inv; 592_593insA]) or BRIC in northern European children and adults [c.1982T>C (p.I661T)]. [456] The full range of mutations associated with PFIC1/BRIC1 remains undescribed in the various populations of the Middle East and Arabian peninsula.…”