Analysis of gene mutations in children with cholestasis of undefined etiology.
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.


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.
Matte
Ursula
U
Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil.
Mourya
Reena
R
Cincinnati Children's Hospital Medical Center.
Miethke
Alexander
A
Cincinnati Children's Hospital Medical Center.
Liu
Cong
C
Cincinnati Children's Hospital Medical Center.
Kauffmann
Gregory
G
Cincinnati Children's Hospital Medical Center.
Moyer
Katie
K
Cincinnati Children's Hospital Medical Center.
Zhang
Kejian
K
Cincinnati Children's Hospital Medical Center.
Bezerra
Jorge A
JA
Cincinnati Children's Hospital Medical Center.
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000293:Adolescent; D002135:Calcium-Binding Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002779:Cholestasis / Q000175:diagnosis / Q000235:genetics*; D003937:Diagnosis, Differential; D020022:Genetic Predisposition to Disease / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D000072099:Serrate-Jagged Proteins; D000515:alpha 1-Antitrypsin / Q000235:genetics
C093491:ABCB11 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C043392:SERPINA1 protein, human; D000072099:Serrate-Jagged Proteins; D000515:alpha 1-Antitrypsin; C095122:multidrug resistance protein 3; D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human