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Updated: Jun 10, 2026
Isolation of Neonatal Extrahepatic Cholangiocytes
Published on: June 5, 2014
Analysis of gene mutations in children with cholestasis of undefined etiology
Ursula Matte1, Reena Mourya2, Alexander Miethke2
1Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil.
Insights
Genetic mutation screening identified a molecular diagnosis in 27% of children with idiopathic cholestasis, revealing disease-causing variants in key genes like JAG1 and ATP8B1.
Area of Science:
- Genetics
- Pediatric Gastroenterology
- Molecular Diagnostics
Background:
- Inherited cholestasis syndromes are linked to specific genetic mutations, aiding diagnosis despite similar clinical presentations.
- Idiopathic cholestasis in children presents a diagnostic challenge due to overlapping phenotypes.
- Genetic analysis offers a pathway to molecularly diagnose children with cholestasis of unknown origin.
Purpose of the Study:
- To investigate the utility of targeted gene mutation screening in diagnosing pediatric idiopathic cholestasis.
- To determine the frequency of disease-causing variants in specific genes within this patient cohort.
Main Methods:
- DNA samples from 51 children with idiopathic cholestasis were analyzed using a high-throughput gene chip.
- Mutations in SERPINA1, JAG1, ATP8B1, ABCB11, and ABCB4 genes were screened.
- Sequence variants were correlated with clinical and histopathological data.
Main Results:
- Genetic variants associated with disease phenotypes were identified in 14 subjects (27%), involving JAG1, ATP8B1, ABCB11, or ABCB4.
- These diagnosed cases lacked syndromic features and were indistinguishable by standard biochemical or histopathological markers.
- Additional subjects had heterozygous variants or variants unlikely to cause disease.
Conclusions:
- Gene sequence analysis successfully assigned a molecular diagnosis in 27% of children with idiopathic cholestasis.
- The findings highlight the importance of genetic testing for identifying the etiology of unexplained cholestasis in pediatric patients.
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.
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