Submission Details

Autosomal dominant

05/19/2019

The NOTCH2 gene is located on chromosome 1 at 1p12 and encodes the notch receptor 2 protein, a single transmembrane domain protein integral to the conserved notch signalling pathway. Notch signalling occurs via cell to cell communication and is involved in determining the cellular fate of diverse cell types, which in turn regulates the homeostatsis of many tissue types. NOTCH2 was first reported in relation to autosomal dominant Alagille syndrome in 2006 (16773578; McDaniell et al. 2006). At least eight unique variants, including seven missense variants and one stop gained variant have been reported. Evidence supporting this gene-disease relationship includes case-level data, and experimental data. Variants in this gene have been reported in at least eight probands in three publications (16773578: McDaniell et al. 2006; 22209762: Kamath et al. 2012; 22488849; Lin et al. 2012). Variants in two cases occurred de novo. Mechanism of disease unclear, where variant level functional data is available, missense variants disrupted the Notch signalling pathway (NSP). This gene-disease relationship is supported by functional and animal model experimental data. The NOTCH1 ligand, JAG1 is associated with autosomal dominant Alagille syndrome (28794168: Siebel et al. 2017). NOTCH 2 is expressed in tissues consistent with the disease phenotype and is localised to cells adjacent to those expressing JAG1 (11171333: McCright et al. 2001) . Mice expressing a hypomorphic Notch2 allele recapitulate some features of Alagille syndrome, as do mice which a heterozygous for both the Notch2 hypomorphic allele and a JAG1 null allele (11171333: McCright et al. 2001; 11861489: McCright et al. 2002). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

16773578 22209762 22488849 11861489 28794168 11171333