NOTCH2 was first reported in relation to autosomal dominant Alagille syndrome-NOTCH2 in 2006 (McDaniel et al., PMID: 16773578). Alagille syndrome-NOTCH2 is a multisystem disorder with a high degree of variability in clinical manifestations and severity, even among members of the same family. Manifestations include, but are not limited to, bile duct paucity, congenital cardiac defects, butterfly vertebrae, posterior embryotoxon, characteristic facial features, and renal abnormalities.
NOTCH2 has been noted to be associated with the following disease entities: Alagille syndrome 2 (MIM: 610205), Hajdu-Cheney syndrome (MIM: 102500), and Serpentine Fibula-Polycystic Kidney Syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, Alagille syndrome-NOTCH2 was split from the other two assertions, and Hajdu-Cheney syndrome and Serpentine Fibula-Polycystic Kidney Syndrome were lumped into a single entity, Hajdu-Cheney syndrome-NOTCH2, which has been curated separately. Hajdu-Cheney syndrome-NOTCH2 is caused by protein truncating variants in exon 34 that escape nonsense-mediated decay and remove only the PEST domain, which are postulated to act through a gain of function mechanism. Alagille syndrome is caused by variants upstream of those implicated in Hajdu-Cheney syndrome, and the mechanism of pathogenicity appears to be haploinsufficiency.
Seventeen variants (missense, nonsense, frameshift, large deletion, canonical splice site) that have been reported in 17 probands in 9 publications (PMIDs: 16773578, 31343788, 22209762, 26858187, 28776642, 36458146, 33077891, 36201396, 36447191) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by expression studies, and a mouse model (PMIDs: 15307138, 11171333).
In summary, there is Definitive evidence supporting the relationship between NOTCH2 and autosomal dominant Alagille syndrome-NOTCH2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date February 26, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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