NOTCH2-Related Disorders via the NOTCH2 Gene

Dominant-acting defects in the NOTCH2 gene can cause two different clinical conditions: Alagille syndrome and Hajdu-Cheney syndrome (including serpentine fibula-polycystic kidney syndrome). Both are autosomal dominant multisystemic disorders.

Alagille syndrome is characterized by cholestasis (caused by abnormalities in the bile ducts), congenital heart defects (pulmonic stenosis), ophthalmic findings (posterior embryotoxon), vertebral defects (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.

Hajdu-Cheney syndrome is characterized by severe and progressive bone loss throughout the body (Simpson et al. 2011). Patients develop acroosteolysis and generalized osteoporosis over time. Common features include compression fractures of the spinal bones, abnormal curvature of the spine, abnormal long bones in the arms and legs, short stature, abnormal skull bones, and dysmorphic facies. Other variable features include joint and dental abnormalities, hearing loss, renal cysts, excess body hair, and cardiovascular anomalies. Phenotypes vary greatly among affected individuals even within the same family. Of note, serpentine fibula-polycystic kidney syndrome (SFPKS) was once classified as a distinct disease entity, but has been later recognized within the phenotypic spectrum of Hajdu-Cheney syndrome due to clinical and molecular similarities (Gray et al. 2012; Narumi et al. 2013).

Alagille syndrome and Hajdu-Cheney syndrome are autosomal dominant disorders caused by defects in the NOTCH2 gene (McDaniell et al. 2006; Isidor et al. 2011; Simpson et al. 2011). The NOTCH2 gene has 34 coding exons that encode Notch2, a member of the Notch family of receptors. Notch2 signaling is important for the development of cells destined to many organs.

Genetic defects in NOTCH2 found to date include missense, nonsense, splicing mutations and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving NOTCH2 have not been reported. Pathogenic variants in the NOTCH2 gene can be transmitted within a family or arise de novo.

Alagille syndrome can be caused by different types of NOTCH2 variants throughout the gene. However, Hajdu-Cheney syndrome (including serpentine fibula-polycystic kidney syndrome) is exclusively caused by truncated pathogenic variants clustered in the last exon (near the carboxyl terminus) of the gene. The mutant mRNA products escape nonsense-mediated decay and the resulting truncated Notch2 proteins cause disease through a gain-of-function.

Alagille syndrome is mostly caused by defects in the JAG1 gene, which encodes the Notch signaling pathway ligand Jagged1.

NOTCH2 defects are a minor cause of Alagille syndrome, accounting for less than 6% of all cases (McDaniell et al. 2006).

NOTCH2 defects should be detected in near 100% of Hajdu-Cheney syndrome (including serpentine fibula-polycystic kidney syndrome) cases if a clinical diagnosis is strongly indicated.

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

This test provides full coverage of most coding exons of the NOTCH2 gene 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 full coverage as >20X NGS reads or Sanger sequencing.

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.