Alagille Syndrome Panel

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 in infancy or early childhood. Phenotypes vary greatly among affected individuals, even within the same family.

Alagille syndrome is an autosomal dominant disorder caused by defects in JAG1 or NOTCH2. The JAG1 gene (26 coding exons) encodes the ligand for the receptor Notch 1 in the Notch signaling pathway. Alagille syndrome is most often 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.

JAG1 pathogenic variants were found in 232 out of 247 (94%) patients with clinically well-defined Alagille syndrome overall (Warthen et al. 2006). Given that large deletions and duplications affecting JAG1 were found to be about 5% (Warthen et al. 2006; Li et al. 2015), the mutation detection rate of JAG1 via sequencing is expected to be approximately 90%. NOTCH2 defects are a minor cause for Alagille syndrome, accounting for less than 6% of all cases (McDaniell et al. 2006).

The prevalence of large deletions and duplications affecting the JAG1 gene 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.

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

This panel typically provides 93.3% 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 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.