Molecular Test Listing

Molecular Requisition
ALAGILLE SYNDROME (Jagged1 Gene)

Alagille syndrome (AGS) is a multi-system developmental disorder that affects 1 in 70,000 live births (when ascertained by neonatal jaundice, true incidence is likely higher) and is one of the most common genetic causes of liver disease in childhood. The disease is characterized by reduction of bile ducts in the liver accompanied by heart defects (most commonly pulmonary valves, artery and its branches). Other symptoms can include posterior embryotoxon (defect in the anterior chamber of the eye), butterfly vertebrae and characteristic “triangular” facial features due to a high broad forehead, wide spaced eyes and a pointed chin. Less frequently there are renal, neurovascular and pancreatic involvement.

 

These conditions have been found to be a result of mutations in the Jagged 1 gene (JAG1) located at chromosome 20p12. The protein acts as a ligand for the Notch proteins that are instrumental in cell fate decision pathways during normal development of the heart, liver, skeleton, face and pancreas.  Inheritance is autosomal dominant; however, 60-70% display de novo mutations. In addition, expression is often variable frequently leading to individuals who only have isolated features and do not meet the classical criterion for Alagille Syndrome. Overall 3-7% of patients show a complete deletion of the gene; the remainder of the patients have a variety of missense and small deletion mutations often resulting in deletions of exons.   

REASONS FOR REFERRAL:

  • Confirmation of the genetic cause of apparent Alagille syndrome.

  • Heart complications in children.
  • Establish a diagnosis in children with one or more Alagille-like symptoms.

 

TESTING METHODOLOGY:

  • Sequencing all 26 exons of the JAG1 gene DNA and the intron/exon borders detects all mutations in the coding sequence of the gene but will not detect the deletion of the entire gene. Specimen required is EDTA whole blood.
  • Sequencing the cDNA generated from JAG1 mRNA all mutations within the coding sequences as well as splicing defects caused by changes buried within the introns. Specimen required is a T25 flask of cultured fibroblasts.

SPECIMEN REQUIREMENTS:

  • Blood EDTA (purple top) tubes: -
    Newborn: minimum 1-2 mL
    Child/Adult: prefer 2 tubes of 3-5 mL

  • Live fibroblasts- Live fibroblasts appropriate to grow in tissue culture:  A skin biopsy can be shipped in transport media at room temperature to arrive the next day (Priority Overnight Mail). Cultured fibroblasts, 2 T25 flasks, can be shipped at room temperature to arrive within 24 hours.

  • Prenatal testing:  Please contact the laboratory for instructions.

  • A Molecular Genetics Laboratory Test Requisition must accompany the specimen. Contact the Molecular Laboratory at 918-502-1721 if further information is needed.

TURNAROUND TIME:  4 –6 weeks