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Increased frequency of double and triple heterozygous gene variants in children with intrahepatic cholestasis.

ABSTRACT: AIM:Single gene mutations cause syndromes of intrahepatic cholestasis, but previous multi-gene mutation screening in children with idiopathic cholestasis failed to fulfill diagnostic criteria in approximately two-thirds of children. In adults with fibrosing cholestatic disease, heterozygous ABCB4 mutations were present in 34% of patients. Here, we hypothesized that children with idiopathic cholestasis have a higher frequency of heterozygous non-synonymous gene sequence variants. METHODS:We analyzed the frequency and types of variants in 717 children in whom high-throughput sequencing of the genes SERPINA1, JAG1, ATP8B1, ABCB11 and ABCB4 was performed as part of an evaluation for idiopathic intrahepatic cholestasis cholestasis. The frequency of non-synonymous variants (NSV) was compared with those of 1092 control subjects enrolled in the 1000 Genome Project. RESULTS:The frequency of NSV in single genes was similar between disease (25%) and controls (26%, P?=?0.518). In contrast, double or triple NSV in two or more genes were more frequent in disease (n?=?7%) than controls (n?=?4.7%, P?=?0.028). Detailed review of clinical and laboratory information in a subgroup of double or triple heterozygous patients revealed variable ?-glutamyltransferase levels and severity of pruritus, with liver biopsies showing stage 2-3 fibrosis. CONCLUSION:Children with idiopathic intrahepatic cholestasis have a higher frequency of double or triple NSV in SERPINA1, JAG1, ATPB1, ABCB11 or ABCB4. These findings raise the potential role for gene-gene relationships in determining the phenotype of cholestatic liver disease in children.

SUBMITTER: Goldschmidt ML

PROVIDER: S-EPMC4816673 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Increased frequency of double and triple heterozygous gene variants in children with intrahepatic cholestasis.

Goldschmidt Monique L ML Mourya Reena R Connor Jessica J Dexheimer Phillip P Karns Rebekah R Miethke Alexander A Sheridan Rachel R Zhang Kejian K Bezerra Jorge A JA

Hepatology research : the official journal of the Japan Society of Hepatology 20150714 4

<h4>Aim</h4>Single gene mutations cause syndromes of intrahepatic cholestasis, but previous multi-gene mutation screening in children with idiopathic cholestasis failed to fulfill diagnostic criteria in approximately two-thirds of children. In adults with fibrosing cholestatic disease, heterozygous ABCB4 mutations were present in 34% of patients. Here, we hypothesized that children with idiopathic cholestasis have a higher frequency of heterozygous non-synonymous gene sequence variants.<h4>Metho ...[more]

PMID: 26126923

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Project description:BackgroundIntrahepatic cholestasis of pregnancy (ICP) can cause adverse pregnancy outcomes, such as spontaneous preterm delivery and stillbirth. It is a complex disease influenced by multiple factors, including genetics and the environment. Previous studies have reported that functioning nuclear receptor subfamily 1 group H member 4 (NR1H4) plays an essential role in bile acid (BA) homeostasis. However, some novel variants and their pathogenesis have not been fully elucidated. Therefore, this research aimed to investigate the genetic characteristics of the NR1H4 gene in ICP.MethodsIn this study, we sequenced the entire coding region of NR1H4 in 197 pregnant women with ICP disease. SIFT and PolyPhen2 were used to predict protein changes. Protein structure modelling and comparisons between NR1H4 reference and modified protein structures were performed by SWISS-MODEL and Chimera 1.14rc, respectively. T-tests were used to analyse the potential significant differences between NR1H4 mutations and wild types for 29 clinical features. Fisher's test was conducted to test the significance of differences in mutation frequencies between ICP and the three databases.ResultsWe identified four mutations: two novel missense mutations, p.S145F and p.M185L; rs180957965 (A230S); and rs147030757 (N275N). The two novel missense mutations were absent in 1029 controls and three databases, including the 1000 Genomes Project (1000G_ALL), Exome Aggregation Consortium (ExAC) and ChinaMAP. Two web-available tools, SIFT and PolyPhen2, predicted that these mutations are harmful to the function of the protein. Moreover, compared to the wild-type protein structure, the NR1H4 p.S145F and p.M185L protein structure showed a slight change in the chemical bond in two zinc finger structures. Combined clinical data indicate that the mutation group had higher levels of total bile acid (TBA) than the wild-type group. Therefore, we hypothesized that these two mutations altered the protein structure of NR1H4, which impaired the function of NR1H4 itself and its target gene and caused an increase in TBA.ConclusionsTo our knowledge, this is the first study to identify the novel p.S145F and p.M185L mutations in 197 ICP patients. Our present study provides new insights into the genetic architecture of ICP involving the two novel NR1H4 mutations.

Project description:Intrahepatic cholestasis represents a heterogeneous group of disorders that begin during childhood, most commonly manifesting as neonatal cholestasis, and lead to ongoing liver dysfunction in children and adults. For children, inherited pathogenic factors of cholestasis have gained increasing attention owing to the rapid development of molecular biology technology. However, these methods have their advantages and disadvantages in terms of simplicity, sensitivity, specificity, time required and expense. In the present study, an effective, sensitive and economical method is recommended, termed high-resolution melting (HRM) analysis and direct sequencing, based on general polymerase chain reaction, to detect mutations in disease?causing genes. As one type of inherited intrahepatic cholestasis, progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by pathogenic mutations in the ABCB11 gene, HRM was used to detect mutations in the ABCB11 gene in the present study, and the diagnosis for PFIC2 was made by comprehensive analysis of genetic findings and clinical features. Furthermore, the characteristics of mutations and single nucleotide polymorphisms (SNPs) in the ABCB11 gene were elucidated. A total of 14 types of mutations/polymorphisms were identified in 20 patients from mainland China, including six missense mutations (p.Y337H, p.Y472C, p.R696W, p.Q931P, p.D1131V and p.H1198R), one nonsense mutation (p.R928X) and seven SNPs (p.D36D/rs3815675, p.F90F/rs4148777, p.Y269Y/rs2287616, p.I416I/rs183390670, p.V444A/rs2287622, p.A865V/rs118109635 and p.A1028A/rs497692). Five mutations were novel. The majority of the mutations were different from those detected in other population groups. A total of 4/20 patients (1/5) were diagnosed to be PFIC2 by combining genetic findings with the clinical features. Polymorphisms V444A and A1028A, with an allele frequency of 74.5 and 67.2%, respectively, were highly prevalent in the mainland Chinese subjects. No differences were found between the patients with cholestasis and the control subjects. Efficient genetic screening facilitates the clinical diagnosis of genetic disorders. The present study demonstrated that HRM analysis was efficient and effective in detecting mutations and expanded the known spectrum of ABCB11 gene mutations.

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Increased frequency of double and triple heterozygous gene variants in children with intrahepatic cholestasis.

Publications

Increased frequency of double and triple heterozygous gene variants in children with intrahepatic cholestasis.

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