Alagille Syndrome Testing

Alagille syndrome (ALGS) is an inherited multisystem disorder, primarily affecting the liver, heart, eyes, skeletal system, and characteristic facial features.  Characteristics are highly variable, even within the same family.  Confirming a diagnosis molecularly can help patients and their providers make informed decisions about management.

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Alagille syndrome (ALGS) is an inherited multisystem disorder, primarily affecting the liver, heart, eyes, skeletal system, and characteristic facial features.  Characteristics are highly variable, even within the same family.  Confirming a diagnosis molecularly can help patients and their providers make informed decisions about management.

Disease Name 
Alagille Syndrome
Arteriohepatic Dysplasia
Syndromic Bile Duct Paucity
Disease Information 

Alagille syndrome (ALGS) is an inherited multisystem disorder with an estimated incidence of at least 1/70,000 live births worldwide. However, due to the variability of the condition, not all people are diagnosed at birth. It is believed that the actual incidence is about 1 in 30,000 to 1 in 50,000 births, but many go undiagnosed until later in life.1 An accurate diagnosis can help identify a need for patients to receive referrals to other sub-specialties, such as ophthalmology, nephrology, gastroenterology, and cardiology.1 Diagnostic criteria require bile duct paucity (present in about 90% of patients), and three of the following five major characteristics: structural cardiac abnormality (often pulmonic stenosis or tetralogy of Fallot), specific ocular findings (especially posterior embryotoxon), butterfly vertebrae or other skeletal abnormalities, and distinctive facial features.2  Less frequent findings include functional and structural abnormalities of the kidneys, pancreatic insufficiency, and vascular abnormalities. Most patients are diagnosed in infancy. Mortality is 10%, with early deaths typically due to cardiac or severe liver disease and later mortality due to vascular problems.3

ALGS usually is usually caused by autosomal dominantly inherited mutations in the JAG1 gene (also called JAGGED1). Penetrance is high, but diagnosis may be complicated by the large proportion of de novo mutations (50-70%) and highly variable severity and clinical expression, even within the same family.2  Therefore, evaluation of first-degree relatives of a patient could be considered once a diagnosis is suspected or made.1

 

Testing Benefits & Indication 

Molecular testing for Alagille syndrome provides a highly sensitive tool for:

  • Diagnostic confirmation in symptomatic individuals
  • Testing of at-risk family members who are asymptomatic or have subclinical features
  • Reproductive risk assessment for family members
  • Prenatal testing of at-risk pregnancies
Test Description 

Our Alagille syndrome genetic testing includes next generation sequencing (NGS) and deletion/duplication analysis of the JAG1 gene. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and NGS. Additional Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.4 This test targets detection of DNA sequence mutations in all coding domains, and well into the 5’ and 3’ ends of all the introns and untranslated regions. Gross deletion/duplication analysis is performed via multiplex ligation probe amplification (MLPA, MRC Holland).

Mutation Detection Rate 

Genetic testing detects mutations in ~95% of clinically affected patients. Full gene sequence analysis is expected to detect mutations in ~88% of affected patients. Additional testing for gross deletions and duplications detects mutations in ~7% of patients (clinical sensitivity).1 Ambry's Alagille syndrome testing can detect >99.9% of described mutations in the JAG1 gene, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Note for Transfusion Patients: Wait at least two weeks after a packed cell or platelet transfusion, and at least four weeks after a whole blood transfusion prior to blood draw.

Turnaround Time 
TEST CODE TECHNIQUE TURNAROUND TIME (days)
1640 JAG1 Gene Sequence Analysis and Deletion / Duplication 14-28 

 

Genes 
JAG1
References 
  1. Leonard LD, et al. Clinical utility gene card for: Alagille Syndrome (ALGS). Eur J Hum Genet. 2014 Mar;22(3).
  2. Spinner NB, et al. Alagille Syndrome. GeneReviews. 2000, updated 2013. Pagon RA, Adam MP, Ardiner HH ., editors. Seattle (WA): University of Washington, Seattle; 1993-2014.
  3. Emerick KM, et al. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999; 29:822-829.
  4. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.