印度进行性家族性肝内胆汁淤积症患者的基因组变异谱
Spectrum of genomic variations in Indian patients with progressive familial intrahepatic cholestasis.
作者信息
Sharma Anjali, Poddar Ujjal, Agnihotry Shikha, Phadke Shubha R, Yachha Surender K, Aggarwal Rakesh
机构信息
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India.
Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India.
出版信息
BMC Gastroenterol. 2018 Jul 4;18(1):107. doi: 10.1186/s12876-018-0835-6.
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.
背景
进行性家族性肝内胆汁淤积症（PFIC）由ATP8B1、ABCB11或ABCB4基因变异引起。目前缺乏关于印度PFIC患者基因变异的数据。
方法
对无亲缘关系的患有PFIC表型的印度儿童的这三个基因的编码区和剪接区进行测序。在父母、30名健康人和几个变异数据库中查找所鉴定出的变异，并在计算机上评估其影响。
结果
在25名儿童（年龄1 - 144个月）中，9名（36%）有独特的主要基因组变异（ATP8B1：4例，ABCB11：3例，ABCB4：2例）。7例有纯合变异，被评估为“致病性”或“可能致病性”。这些变异包括：（i）四个氨基酸替换（ATP8B1：c.1660G＞A/p.Asp554Asn和c.2941G＞A/p.Glu981Lys；ABCB11：c.548T＞C/p.Met183Thr；ABCB4：c.431G＞A/p.Arg144Gln）；（ii）一个导致氨基酸缺失的3核苷酸缺失（ATP8B1：c.1587_1589delCTT/p.Phe529del）；（iii）一个导致移码和提前终止的单核苷酸缺失（ABCB11：c.1360delG/p.Val454Ter）；以及（iv）一个4核苷酸的复杂倒位并伴有一个单核苷酸插入导致移码和提前终止（ATP8B1：c.[589_592inv;592_593insA]/p.Gly197LeufsTer10）。发现两个杂合形式的变异：（i）一个可能导致异常剪接的剪接位点变异（ABCB11：c.784 + 1G＞C），以及（ii）一个产生提前终止密码子的核苷酸替换（ABCB4：c.475C＞T/p.Arg159Ter）；这些被认为是意义不明确的变异。九个变异中有三个是新发现的。
结论
在近三分之一的印度PFIC儿童中鉴定出九个主要基因组变异，包括三个新发现的变异。近三分之二的患者未发现变异，这些患者可能与这三个PFIC基因的启动子或内含子区域变异或其他胆盐转运基因变异有关。
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