Heterozygous NOTCH1 deletion associated with variable congenital heart defects

Area of Science:

• Genetics
• Cardiology
• Developmental Biology

Background:

• Pathogenic variants in the NOTCH1 gene are linked to congenital cardiac anomalies but exhibit incomplete penetrance.
• NOTCH1 whole gene deletions are rare, and their association with cardiac defects is less understood.

Purpose of the Study:

• To investigate the role of NOTCH1 gene deletions in congenital heart defects.
• To describe familial cases of NOTCH1 deletion and their associated cardiac phenotypes.
• To assess the penetrance and expressivity of NOTCH1 deletions in congenital heart disease.

Main Methods:

• Case reporting of four individuals from two families with NOTCH1 gene deletions.
• Clinical phenotyping of congenital heart defects.
• Immunohistochemical staining of cardiac tissue to assess NOTCH1 expression levels.

Main Results:

• Four cases of NOTCH1 gene deletion were identified in two families, associated with a range of congenital heart defects, including bicuspid aortic valve and complex anomalies.
• This is the first report of familial NOTCH1 deletion, demonstrating apparently high, potentially complete, penetrance.
• Reduced NOTCH1 expression was observed in the ventricular outflow tracts of affected cardiac tissue.

Conclusions:

• NOTCH1 gene deletion, leading to haploinsufficiency, is associated with both mild and severe congenital heart defects.
• Familial NOTCH1 deletions appear to have higher penetrance compared to other NOTCH1 pathogenic variants.
• These findings expand the understanding of NOTCH1's role in cardiac development and disease.