Genes Tested:

ABCB11, ABCB4, ATP8B1, JAG1, TJP2

Description

Inherited intrahepatic cholestasis is a heterogeneous group of disorders typically presenting as neonatal jaundice and leading to persistent liver dysfunction in children and adults. Although some of these conditions are associated with extrahepatic symptoms and varying laboratory and pathologic findings, there remains considerable clinical overlap between these disorders.

Indications

  • Confirmation of diagnosis in a patient with chronic cholestasis of unknown etiology
  • Screening for Alagille Syndrome
  • Screening for Progressive Familial Intrahepatic Cholestasis (PFIC)

Testing Methodology

This test is performed by enrichment of the coding exons, flanking intronic and untranslated regions (5’ and 3’), as well as known pathogenic variants (HGMD 2018.1) in the promoter and deep intronic regions of the genes specified above using oligonucleotide probe hybridization followed by next-generation sequencing with >50X coverage at every target base. All pathogenic and novel variants, as well as variants of unknown (indeterminate) significance, as determined bioinformatically, are confirmed by Sanger sequencing. Regions with <50X will be filled in by Sanger sequencing. A detailed non-coding variant list is available upon request.

Test Sensitivity

Analytical Sensitivity: The sensitivity of DNA sequencing is over 99% for the detection of nucleotide base changes, small deletions and insertions in the regions analyzed.

Limitations: Variants in regulatory regions and non-reported variants in untranslated regions may not be detected by this test. Large deletions involving entire single exons or multiple exons, large insertions and other complex genetic events will not be identified using NGS methodology. Rare primer site variants may lead to erroneous results.

Turnaround Time

28 days

How to Order

Download Heritable Liver Disease requisition. Single gene sequencing, deletion/duplication analysis and targeted variant analysis is also available for all genes in the Jaundice Panel.

References

Colliton, R.P., L. Bason, et al. (2001) "Mutation Analysis of Jagged1 (JAG1) in Alagille Syndrome Patients." Human Mutation 17(2): 151-2.

Colombo, C., P. Vajro, et al. (2011) "Clinical Features and Genotype-Phenotype Correlations in Children with Progressive Familial Intrahepatic Cholestasis Type 3 Related to ABCB4 Mutations." Journal of Pediatric Gastroenterology and Nutrition 52(1): 73–83.

Davit-Spraul, A., M. Fabre, et al. (2010) "ATP8B1 and ABCB11 Analysis in 62 Children with Normal Gamma-Glutamyl Transferase Progressive Familial Intrahepatic Cholestasis (PFIC): Phenotypic Differences between PFIC1 and PFIC2 and Natural History." Hepatology (Baltimore, Md.) 51(5): 1645-55.

Guegan, K., K. Stals, et al. (2012) "JAG1 Mutations Are Found in Approximately One Third of Patients Presenting with Only One or Two Clinical Features of Alagille Syndrome." Clinical Genetics 82(1): 33-40.

Kamath, B.M., K.M. Loomes, et al. (2010) "Medical Management of Alagille Syndrome." Journal of Pediatric Gastroenterology and Nutrition 50(6): 580-6.

Klomp, L.W.J., J.C. Vargas, et al. (2004) "Characterization of Mutations in ATP8B1 Associated with Hereditary Cholestasis." Hepatology (Baltimore, Md.) 40(1): 27–38.

Kohsaka, T., Z.-R. Yuan, et al. (2002) "The Significance of Human Jagged 1 Mutations Detected in Severe Cases of Extrahepatic Biliary Atresia." Hepatology (Baltimore, Md.) 36(4 Pt 1): 904-12.

Matte, U., R. Mourya, et al. (2010) "Analysis of Gene Mutations in Children with Cholestasis of Undefined Etiology." Journal of Pediatric Gastroenterology and Nutrition 51(4): 488-93.

Morotti, R.A., F.J. Suchy, et al. (2011) "Progressive Familial Intrahepatic Cholestasis (PFIC) Type 1, 2, and 3: A Review of the Liver Pathology Findings." Seminars in Liver Disease 31(1): 3–10.

Sambrotta, M., S. Strautnieks, et al. (2014) "Mutations in TJP2 Cause Progressive Cholestatic Liver Disease." Nature Genetics 46(4): 326–8.

Turnpenny, P.D. and S. Ellard (2012) "Alagille Syndrome: Pathogenesis, Diagnosis and Management." European Journal of Human Genetics: EJHG 20(3): 251-7.

Van der Woerd, W.L., S.W.C. van Mil, et al. (2010) "Familial Cholestasis: Progressive Familial Intrahepatic Cholestasis, Benign Recurrent Intrahepatic Cholestasis and Intrahepatic Cholestasis of Pregnancy." Best Practice & Research. Clinical Gastroenterology 24(5): 541–53.

Van Mil, S.W.C., W.L. van der Woerd, et al. (2004) "Benign Recurrent Intrahepatic Cholestasis Type 2 Is Caused by Mutations in ABCB11." Gastroenterology 127(2): 379-84.