• Test code: 04215
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit

Invitae Alagille Syndrome Panel

Test description

This test analyzes two genes, JAG1 and NOTCH2, which are associated with Alagille syndrome (ALGS), a multisystem disorder that is characterized by liver disease (bile duct paucity and cholestasis), congenital heart defects, eye findings, vertebral defects, and characteristic facial features. The clinical presentation of ALGS can be highly variable. Renal and pancreatic abnormalities are also evident in some individuals.

Identification of a genetic change related to ALGS can impact medical management, provide a predicted outcome for the patient, and indicate the recurrence risk. Genetic testing can provide important insight for individuals who are at risk of having ALGS but do not present with obvious symptoms, as they may be at risk of having congenital heart defects or developing bile duct paucity.

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Primary panel (2 genes)

Alagille syndrome (ALGS) is a multisystemic disorder characterized by liver disease (bile duct paucity and cholestasis), congenital heart defects that primarily involve the pulmonary arteries, ophthalmic findings, butterfly vertebra, and characteristic facial features. Approximately 90% of individuals with ALGS present with bile duct paucity, which is the primary manifestation associated with this syndrome. Renal, neurovasculature, and pancreatic abnormalities are also evident in some individuals.

More than 90% of individuals with ALGS have a congenital heart defect ranging from benign heart murmurs to significant structural defects. The most common heart defect is pulmonic stenosis; other defects that involve the pulmonary outflow tract and vasculature are common as well. Tetralogy of fallot (TOF), ventricular septal defect (VSD), atrial septal defect (ASD), aortic stenosis, and coarctation of the aorta have also been observed in patients with ALGS. The variation in the presentation of ALGS is largely dependent on the severity of the liver disease and congenital heart defect. Both the liver disease and cardiac complications can be life-threatening if they are not identified and managed appropriately.

More than 94% of individuals who meet clinical diagnostic criteria for ALGS have an identifiable disease-causing change in JAG1 and 1-2% of individuals may have a pathogenic variant in NOTCH2.

ALGS is inherited in an autosomal dominant pattern, with approximately 50%-70% of cases resulting from a de novo pathogenic variant.

ALGS syndrome exhibits reduced penetrance. Approximately 50% of patients meet clinical diagnostic criteria for ALGS. Due to the wide range of variable expression, individuals with a mild liver disease or benign heart defects may be diagnosed later in life or not at all.

The incidence of Alagille syndrome has been reported as approximately 1:70,000 live births. Recent reports suggest this is an underestimate and that the incidence may actually be 1:30,000 to 1:50,000 live births.

ALGS has a variable clinical presentation, so identifying the genetic cause of ALGS in one individual enables testing of related asymptomatic adults who could be at risk of having ALGS and developing cardiac or liver problems. Individuals with subclinical or mild hepatic disease may not be diagnosed until later in life, and a related congenital heart defect may not be revealed until then. Molecular analysis may provide an individual with an earlier diagnosis, enabling medical management to be modified and allowing for earlier medical interventions.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
JAG1 NM_000214.2
NOTCH2* NM_024408.3

NOTCH2: Analysis is not offered for exons 1-4.