Submission Details

NOTCH1 was first reported in relation to autosomal dominant aortic valve disease in 2005 (Garg et al., PMID: 16025100). In 2014, the gene was reported in relation to autosomal dominant Adams-Oliver syndrome (Stittrich et al., PMID: 25132448). In 2016, deleterious variants in the NOTCH1 gene were reported in patients with left-sided congenital heart disease (Kerstjens-Frederikse et al., PMID: 26820064). To date, at least 4000 NOTCH1 variants have been submitted to ClinVar in association with human diseases (PMID: 24234437).

Variants in NOTCH1 have been reported in individuals with the following disease entities: Adams-Oliver Syndrome, congenital heart disease, aortic valve disease including bicuspid aortic valve, and thoracic aortic aneurysm and dissection. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism and inheritance pattern and found considerable interfamilial and intrafamilial variability in cardiac phenotypes. Therefore, the following disease entities have been lumped into one disease entity (NOTCH1-related AOS spectrum disorder).

Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Eleven variants (nonsense and frameshift) that have been reported in eleven probands, with segregation in an additional twenty-two family members, from four publications are included in this curation (PMIDs: 16025100, 25132448, 26820064, 38778082).

This gene-disease relationship is supported by animal models, expression studies, or in vitro functional assay. Expression data from human and mice tissues showed high expression levels of NOTCH1 in cardiac valve and heart tissues with implications of NOTCH1 playing a role in cardiac valve development (PMIDs: 16025100, 23715323). Immunohistochemistry data showed Notch1 intracellular domain expression in both normal human aorta and diseased human aortic aneurysm samples, with expression levels correlating to disease severity (PMID: 29093270). In addition, various strains of mice with Notch1 haploinsufficiency expressed postnatal lethality, bicuspid valve, or dilation of the ascending aorta or aortic root (PMIDs: 27107132, 29093270).

Disease-causing variants in the NOTCH1 gene elicit a spectrum of cardiac and extracardiac phenotypes with incomplete penetrance and extensive intrafamilial variability (PMID: 38778082). Comprehensive evaluation for all potentially affected organ systems should be pursued at the time of diagnosis. Clinical surveillance for thoracic aortic aneurysm is warranted in individuals with NOTCH1 variants as they may be asymptomatic due to incomplete penetrance and age-related manifestation of aortopathy (PMIDs: 20301299, 38778082).

In summary, there is definitive evidence supporting the relationship between NOTCH1 and autosomal dominant NOTCH1-related AOS spectrum disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease GCEP on March 7th 2025 (SOP Version 11).

This gene was originally evaluated by the Heritable Thoracic Aortic Aneurysm and Dissection Expert Panel on April 6th, 2016 in relation to familial thoracic aortic aneurysm and aortic dissection. It was reevaluated on March 7th 2025. As a result of this reevaluation, the classification was changed from Limited assertion for familial thoracic aortic aneurysm and aortic dissection to Definitive assertion for NOTCH1-related AOS spectrum disorder.