NOTCH1 – Adams-Oliver syndrome

Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by aplasia cutis congenita and terminal limb defects, often accompanied by vascular malformations and cardiac anomalies. Heterozygous pathogenic variants in the NOTCH1 gene have emerged as a major cause of autosomal dominant AOS, implicating dysregulated Notch signaling in its pathogenesis. NOTCH1 testing is therefore critical for definitive diagnosis and familial risk assessment in AOS.

In a cohort of 11 families lacking mutations in ARHGAP31, RBPJ, DOCK6, and EOGT, whole-genome sequencing identified five unrelated probands harboring heterozygous NOTCH1 variants, including de novo missense and coding region alterations (5 probands [PMID:25132448]). One family exhibited a canonical splice-site variant (c.743-1G>T) segregating in an affected father–daughter pair [PMID:25132448]. A subsequent study of 12 AOS probands delineated two kindreds with truncating mutations and segregation as an autosomal dominant trait, plus eight additional unique NOTCH1 mutations in 52 unrelated cases [PMID:25963545]. A sporadic Chinese case revealed a novel de novo in-frame deletion (c.1292_1294del (p.Asn431del)) with pathogenic in silico predictions [PMID:32129674].

The NOTCH1 variant spectrum in AOS encompasses missense substitutions within EGF-like and heterodimerization domains, canonical splice-site changes, frameshift and nonsense alleles. The exemplar missense change c.1285T>C (p.Cys429Arg) occurs in a calcium-binding EGF-like repeat critical for ligand interaction [PMID:25132448]. No recurrent or founder variants have been reported to date, and population databases lack these alleles, supporting their rarity and pathogenicity.

Functional assays demonstrate that loss-of-function NOTCH1 alleles impair receptor maturation and signaling. Quantitative RT-PCR of patient leukocyte RNA confirmed downregulation of Notch targets HEY1 and HES1, while molecular modeling of the p.Asn431del mutation predicts disrupted calcium chelation and reduced ligand affinity [PMID:32129674]. In cellular models, truncating and missense variants lead to decreased NOTCH1 expression and diminished Notch pathway activation [PMID:25963545].

Collectively, these findings support a haploinsufficiency mechanism for NOTCH1-related AOS, consistent with autosomal dominant inheritance and variable expressivity. The clinical validity of the NOTCH1–AOS association is classified as Strong, based on multiple unrelated cases, familial segregation, and concordant functional data.

Key Take-home: NOTCH1 haploinsufficiency is a principal driver of autosomal dominant AOS, and molecular testing of NOTCH1 should be integrated into diagnostic and genetic counseling workflows for affected families.

References

• American Journal of Human Genetics • 2014 • Mutations in NOTCH1 cause Adams-Oliver syndrome PMID:25132448
• Circulation: Cardiovascular Genetics • 2015 • Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies PMID:25963545
• DNA and Cell Biology • 2020 • Novel In-Frame Deletion Mutation in NOTCH1 in a Chinese Sporadic Case of Adams-Oliver Syndrome. PMID:32129674

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