Open AccessAnalysis of Gene Mutations in Children With Cholestasis of Undefined Etiology
Author(s) -
Matte Ursula,
Mourya Reena,
Miethke Alexander,
Liu Cong,
Kauffmann Gregory,
Moyer Katie,
Zhang Kejian,
Bezerra Jorge A
Publication year - 2010
Publication title -
journal of pediatric gastroenterology and nutrition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.206
H-Index - 131
eISSN - 1536-4801
pISSN - 0277-2116
DOI - 10.1097/mpg.0b013e3181dffe8f
Subject(s) - missense mutation , genetics , progressive familial intrahepatic cholestasis , cholestasis , phenotype , jag1 , gene , mutation , allele , nonsense mutation , medicine , biology , notch signaling pathway , transplantation , liver transplantation
Background: The discovery of genetic mutations in children with inherited syndromes of intrahepatic cholestasis allows for diagnostic specificity despite similar clinical phenotypes. Here, we aimed to determine whether mutation screening of target genes could assign a molecular diagnosis in children with idiopathic cholestasis. Patients and Methods: DNA samples were obtained from 51 subjects with cholestasis of undefined etiology and surveyed for mutations in the genes SERPINA1, JAG1, ATP8B1, ABCB11, and ABCB4 by a high‐throughput gene chip. Then, the sequence readouts for all 5 genes were analyzed for mutations and correlated with clinical phenotypes. Healthy subjects served as controls. Results: Sequence analysis of the genes identified 14 (or 27%) subjects with missense, nonsense, deletion, and splice site variants associated with disease phenotypes based on the type of mutation and/or biallelic involvement in the JAG1, ATP8B1, ABCB11 , or ABCB4 genes. These patients had no syndromic features and could not be differentiated by biochemical markers or histopathology. Among the remaining subjects, 10 (or ∼20%) had sequence variants in ATP8B1 or ABCB11 that involved only 1 allele, 8 had variants not likely to be associated with disease phenotypes, and 19 had no variants that changed amino acid composition. Conclusions: Gene sequence analysis assigned a molecular diagnosis in 27% of subjects with idiopathic cholestasis based on the presence of variants likely to cause disease phenotypes.