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.
Highlights
Progressive familial intrahepatic cholestasis (PFIC) is caused by variations in ATP8B1, ABCB11 or ABCB4 genes
PFIC is classified into three types, namely PFIC1, PFIC2 and PFIC3, based on detection of causative variations in ATP8B1, ABCB11 and ABCB4 genes
In our study of 25 unrelated Indian children with PFIC phenotype, we found pathogenic or likely-pathogenic sequence variations in ATP8B1, ABCB11 or ABCB4 gene in seven and variations of unknown significance in two
Summary
Progressive familial intrahepatic cholestasis (PFIC) is caused by variations in ATP8B1, ABCB11 or ABCB4 genes. Progressive familial intrahepatic cholestasis (PFIC) is a group of heterogeneous liver disorders of childhood with disruption of normal secretion of bile salts and/or phospholipids into the bile [1]. It accounts for nearly 10 to 15% of cases with cholestasis in early childhood, and for a large proportion of pediatric liver transplantation procedures [1]. PFIC is classified into three types, namely PFIC1, PFIC2 and PFIC3, based on detection of causative variations in ATP8B1, ABCB11 and ABCB4 genes, The genomic variations underlying PFIC show geographic heterogeneity. Some of these cases are related to variations in other genes involved in the secretion of bile salts [9]
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