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Progressive Familial Intrahepatic Cholestasis (PFIC) and Alagille syndrome Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
ABCB11 81479,81479
ABCB4 81479,81479
ATP8B1 81479,81479
JAG1 81407,81406
NOTCH2 81479,81479
TJP2 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10229Genes x (6)81479 81406(x1), 81407(x1), 81479(x10) $990 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Chansonette Badduke, PhD

Clinical Features and Genetics

Clinical Features

Jaundice and pruritus are the major features of cholestasis, which can present as the hallmark features in progressive familial intrahepatic cholestasis (PFIC) or as features in other inherited disorders such as Alagille syndrome

PFIC is a group of autosomal recessive liver disorders due to defects in bile secretion and is characterized by intrahepatic cholestasis with disease onset usually in infancy and childhood (Srivastava 2014; Davit-Spraul et al. 2009). Four types of PFIC have been classified in terms of causative genes involved in the hepatocellular transport system. FIC1 (familial intrahepatic cholestasis protein 1 deficiency (PFIC1) is caused by pathogenic variants in ATP8B1. BSEP (bile salt export pump) deficiency (PFIC2) is caused by pathogenic variants in ABCB11. PFIC3 is caused by reduced biliary phospholipid secretion due to pathogenic variants in ABCB4. The most recently identified PFIC4 is caused by abnormal tight junctions between adjacent hepatocytes and biliary canaliculi in liver tissue due to TJP2 defects (Sambrotta et al. 2014). PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyl transferase (GGT) activity is normal in PFIC1 and PFIC2 patients, elevated in PFIC3 patients and low in PFIC4 patients.

Defects in PFIC-associated genes ATP8B1 and ABCB11 can also cause a milder type of liver disease called benign recurrent intrahepatic cholestasis (BRIC) (Klomp et al. 2004; Beauséjour et al. 2011). BRIC is an autosomal recessive disorder characterized by intermittent episodes of cholestasis without progression to liver failure.

Alagille syndrome is characterized by cholestasis (caused by abnormalities in the bile ducts), congenital heart defects (featured by pulmonic stenosis), ophthalmic findings (featured by posterior embryotoxon), vertebral defects (featured by butterfly vertebrae), and characteristic facies (including deep-set eyes with moderate hypertelorism, a broad forehead, a prominent pointed chin, and a long straight nose with a bulbous tip) (Emerick et al. 1999). Symptoms can start from infancy or early childhood. Phenotypes vary greatly among affected individuals even within the same family.


Progressive familial intrahepatic cholestasis (PFIC) is inherited in an autosomal recessive manner. Defects in four genes encoding proteins associated with hepatocellular transport system have been found to cause PFIC: ATP8B1, ABCB11, ABCB4 and TJP2 (Srivastava et al. 2014; Davit-Spraul et al. 2009; Sambrotta et al. 2014).

The ATP8B1 gene (27 coding exons) encodes the FIC1 protein, which is a member of the P-type cation transport ATPase family. Pathogenic defects in ATP8B1 include missense, nonsense, splicing site variants, small indels and exon-level large deletions (Human Gene Mutation Database). In addition to PFIC1, recessive ATP8B1 pathogenic variants can also cause benign recurrent intrahepatic cholestasis-1 (BRIC1).

The ABCB11 (27 coding exons) gene encodes the bile salt export pump protein (BSEP), which is a member of the superfamily of ATP-binding cassette (ABC) transporters. Pathogenic defects in ABCB11 include missense, nonsense, splicing site variants and small indels and exon-level large deletions (Human Gene Mutation Database). In addition to PFIC2, recessive ABCB11 pathogenic variants can also cause benign recurrent intrahepatic cholestasis-2 (BRIC2).

The ABCB4 gene (27 coding exons) encodes the multi-drug resistant 3 protein (MDR3), which is also a member of the superfamily of ATP-binding cassette (ABC) transporters. Pathogenic defects in ABCB4 include missense, nonsense, splicing site variants, small indels and exon-level large deletions (Human Gene Mutation Database).

The newly found fourth PFIC gene TJP2 (23 coding exons) encodes the tight junction protein 2, which is involved in the organization of epithelial and endothelial intercellular junctions. Pathogenic defects in TJP2 include missense, nonsense, splicing site variants, small indels and exon-level large deletions (Human Gene Mutation Database). TJP2 defects can also cause familial hypercholanemia, which is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption (Carlton et al. 2003).

Alagille syndrome is caused by defects in the JAG1 or NOTCH2 gene. The JAG1 gene (26 coding exons) encodes the ligand for the receptor Notch 1 in the Notch signaling pathway. Alagille syndrome is mainly caused by dominant JAG1 pathogenic variants (Oda et al. 1997; Warthen et al. 2006). Pathogenic defects in JAG1 include missense, nonsense, splicing site variants, small indels and large deletions/duplications (Human Gene Mutation Database).

The NOTCH2 gene (34 coding exons) encodes the receptor Notch 2 in the Notch signaling pathway. Dominant NOTCH2 pathogenic variants can cause both Alagille syndrome (McDaniell et al. 2006) and the skeletal disorder Hajdu-Cheney syndrome (Simpson et al. 2011). NOTCH2 defects are a minor cause for Alagille syndrome, accounting for less than 6% of all cases (McDaniell et al. 2006). Genetic defects of NOTCH2 found to date include missense, nonsense, splicing variants and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions/duplication involving NOTCH2 have not been reported.

Clinical Sensitivity - Sequencing with CNV PGxome

Detection rate of pathogenic variants in each gene of this panel in a large cohort of patients with cholestasis of undefined etiology is unknown. However, in a study of 51 subjects with cholestasis of undefined etiology, Matte et al. found causative variants in JAG1, ATP8B1, ABCB11, or ABCB4 in 14 patients (27%) (Matte et al. 2010). ATP8B1 and ABCB11 causative variants were found in 12 (21%) and 36 (63%) respectively of 57 families affected by PFIC with normal gamma-glutamyl transferase (GGT) activity (Davit-Spraul et al. 2010). In a cohort study of 68 unrelated PFIC3 patients, ABCB4 causative variants were found at both alleles in 13 patients (19%) and only one allele in 5 patients (7%) (Degiorgio et al. 2007). Out of 29 families that had chronic cholestatic liver disease with low GGT and that did not have causative variants in ABCB11 or ATP8B1, TJP2 pathogenic variants were found in 8 families (27.6%) (Sambrotta et al. 2014).

Large deletions and duplications have been reported in each of the four PFIC genes, but these are the rare type of genetic defect in these genes. Only limited cases have been reported in each gene (Human Gene Mutation Database). In contrast, large deletions are more common in ABCB4; about 4% (4/102) of patients were found to have a large deletion in a study of ABCB4 relevant cholestasis (Pasmant et al. 2012).

The prevalence of large deletions and duplications in JAG1 was found to be about 5% in Alagille syndrome (Warthen et al. 2006; Li et al. 2015). Large deletions encompassing the entire JAG1 gene are the major type of copy number change affecting this gene (Warthen et al. 2006; Li et al. 2015; Kamath et al. 2009). Large deletions/duplication involving NOTCH2 have not been reported.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 97.2% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

This test does not currently include coverage for exons 1 to 4 of the NOTCH2 gene because of high sequence similarity to one or more additional chromosomal regions. So far, no pathogenic variants have been reported in these exons.

Indications for Test

Candidates for this test are patients with cholestasis indicative of PFIC or Alagille syndrome. This test especially aids in a differential diagnosis of similar phenotypes by analyzing multiple genes simultaneously.


Official Gene Symbol OMIM ID
ABCB11 603201
ABCB4 171060
ATP8B1 602397
JAG1 601920
NOTCH2 600275
TJP2 607709
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test



  • Beauséjour et al. 2011. PubMed ID: 21766090
  • Carlton V.E. et al. 2003. Nature Genetics. 34: 91-6. PubMed ID: 12704386
  • Davit-Spraul A. et al. 2010. Hepatology. 51: 1645-55. PubMed ID: 20232290
  • Davit-Spraul et al. 2009. PubMed ID: 19133130
  • Degiorgio et al. 2007. PubMed ID: 17726488
  • Emerick K.M. et al. 1999. Hepatology (baltimore, Md.). 29: 822-9. PubMed ID: 10051485
  • Human Gene Mutation Database (Bio-base).
  • Kamath B.M. et al. 2009. Human Mutation. 30: 371-8. PubMed ID: 19058200
  • Klomp L.W. et al. 2004. Hepatology. 40: 27-38. PubMed ID: 15239083
  • Li L. et al. 2015. Plos One. 10: e0130355. PubMed ID: 26076142
  • Matte et al. 2010. PubMed ID: 20683201
  • McDaniell R. et al. 2006. American Journal of Human Genetics. 79: 169-73. PubMed ID: 16773578
  • Oda T. et al. 1997. Nature Genetics. 16: 235-42. PubMed ID: 9207787
  • Pasmant E. et al. 2012. European Journal of Human Genetics. 20: 277-82. PubMed ID: 21989363
  • Sambrotta et al. 2014. PubMed ID: 24614073
  • Simpson M.A. et al. 2011. Nature Genetics. 43: 303-5. PubMed ID: 21378985
  • Srivastava. 2014. PubMed ID: 25755532
  • Warthen D.M. et al. 2006. Human Mutation. 27: 436-43. PubMed ID: 16575836


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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