NOTCH2 – Alagille syndrome type 2

Alagille syndrome (AGS) is a multisystem autosomal dominant disorder characterized by bile duct paucity, cholestasis, congenital heart defects, vertebral anomalies, posterior embryotoxon and characteristic facies. While pathogenic variants in Gene Symbol account for the majority of cases, a subset (~1–2%) of AGS patients harbor heterozygous mutations in Gene Symbol (MONDO:0007318). Initial identification of NOTCH2 as a second disease gene came from screening 11 JAG1-negative probands, revealing mutations segregating in two families with five affected individuals (PMID:16773578). Subsequent cohort studies of 8 additional NOTCH2-mutant individuals corroborated its role in AGS (PMID:22209762).

Genetic evidence supports an autosomal dominant inheritance with highly variable expressivity. To date, 13 probands with heterozygous NOTCH2 variants have been reported (7 loss-of-function, 1 splice site, 3 missense) across ten unrelated families (PMID:16773578; PMID:22209762). Segregation of truncating alleles in two families provided additional support for pathogenicity (5 affected relatives) and confirmed that haploinsufficiency underlies disease mechanism.

The variant spectrum includes frameshift and nonsense mutations (e.g., c.6007C>T (p.Arg2003Ter)), a splice acceptor change (c.5930-1G>A), and extracellular missense substitutions (p.Cys444Tyr) distributed throughout functional domains. Recurrent truncating alleles such as c.6007C>T (p.Arg2003Ter) emphasize the critical role of the PEST domain in receptor turnover.

Functional assays and animal models demonstrate concordant pathogenicity. A hypomorphic mouse Notch2 allele recapitulates renal glomerular and cardiac defects, mirroring AGS features, and double heterozygotes with Jag1 display synergistic glomerulopathy (PMID:11171333). In vitro reporter assays of missense, nonsense and splice variants show reduced Notch signalling consistent with loss of function (PMID:22209762).

Phenotypic variability is marked by universal liver involvement and high prevalence of renal anomalies, with somewhat lower penetrance of vertebral and facial features compared to JAG1-mutant patients. Posterior embryotoxon, peripheral pulmonary stenosis, and bile duct paucity are common hallmarks guiding diagnosis in NOTCH2-positive cases.

In summary, heterozygous NOTCH2 variants cause AGS type 2 through haploinsufficiency with strong genetic and functional support. NOTCH2 testing is recommended in JAG1-negative patients with clinical features of AGS to enable accurate diagnosis, guide management, and inform genetic counseling.

References

• American Journal of Human Genetics • 2006 • NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway PMID:16773578
• Journal of Medical Genetics • 2012 • NOTCH2 mutations in Alagille syndrome PMID:22209762
• Development (Cambridge, England) • 2001 • Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation PMID:11171333

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