A New Homozygous ABCB4 Mutation Identified in Two Chinese Siblings Based on Exome Sequencing

Rong Fu Xiumin Zhang

doi:10.4172/2157-7412.1000243

Abstract

Background: Many pediatric cholestatic liver diseases show unspecific symptoms, laboratory tests and histological features. A complete genetic background check is necessary to identify the genetic determinants as well as the diagnosis and differential diagnosis. Method: The whole genome exome sequencing was performed in two Chinese sister siblings with unspecific cholestasis and the data was analyzed. Results: A homozygous mutation, c.2176C-T transition (p.P726L) in exon 17 of ABCB4, was identified. Further study indicated that there are mutant alleles in the genome of their non consanguineous parents. The final diagnosis is progressive familial intrahepatic cholestasis (PFIC), type 3. Conclusion: As a rare hereditary cholestatic liver disease, PFIC shares many similar features with other hereditary or acquired liver disease and requires a wide range of differential diagnosis. Exome sequencing is a useful tool for mapping this kind of monogenic disease mutation and plays a very important role in genetic counseling and prenatal diagnosis.Background: Many pediatric cholestatic liver diseases show unspecific symptoms, laboratory tests and histological features. A complete genetic background check is necessary to identify the genetic determinants as well as the diagnosis and differential diagnosis. Method: The whole genome exome sequencing was performed in two Chinese sister siblings with unspecific cholestasis and the data was analyzed. Results: A homozygous mutation, c.2176C-T transition (p.P726L) in exon 17 of ABCB4, was identified. Further study indicated that there are mutant alleles in the genome of their non consanguineous parents. The final diagnosis is progressive familial intrahepatic cholestasis (PFIC), type 3. Conclusion: As a rare hereditary cholestatic liver disease, PFIC shares many similar features with other hereditary or acquired liver disease and requires a wide range of differential diagnosis. Exome sequencing is a useful tool for mapping this kind of monogenic disease mutation and plays a very important role in genetic counseling and prenatal diagnosis.

Highlights

Cholestasis is a common manifestation of hepatic disease in pediatric patients and a wide range of differential diagnosis, especially inherited diseases, need to be considered
Because inherited syndromes of intrahepatic cholestasis commonly resulted from mutations in the genes including SERPINA1, JAG1, ATP8B1, ABCB11 and ABCB4, we simultaneously focused on these genes to investigate possible variants
Given that non-synonymous variants were more likely to be the pathogenic mutations and unlikely to be present in general group, so we filtered them against several public database mentioned in methods and the number of the candidate variants was reduced to about 400

Summary

Introduction

Cholestasis is a common manifestation of hepatic disease in pediatric patients and a wide range of differential diagnosis, especially inherited diseases, need to be considered. Many of these entities have overlapped symptoms, histological findings as well as laboratory features. Under this kind of situations, genetic background assay is very important for a precise final diagnosis. In this study we utilized exome sequencing in blood samples of two Chinese siblings who presented with cholestasis phenotypes to identify the underlying genetic defects responsible for the disease and confirm the clinical diagnosis. A complete genetic background check is necessary to identify the genetic determinants as well as the diagnosis and differential diagnosis

Methods

Results

Discussion

Conclusion