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Heterozygous NOTCH1 deletion associated with variable congenital heart defects
Author(s) -
Roifman Maian,
Chung Brian Hon Yin,
Reid Diane Myles,
Teitelbaum Ronni,
Martin Nicole,
Nield Lynne E.,
Thompson Megan,
Shan Patrick,
Chitayat David
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13948
Subject(s) - penetrance , haploinsufficiency , variable expression , expressivity , bicuspid aortic valve , biology , genetics , phenotype , gene , gene dosage , gene expression , medicine , aortic valve
Pathogenic heterozygous variants in the NOTCH1 gene are known to be associated with both left and right‐sided congenital cardiac anomalies with strikingly incomplete penetrance and variable phenotypic expressivity. De novo NOTCH1 whole gene deletion has been reported rarely in the literature and its association with cardiac defects is less well established. Here, we report four cases of NOTCH1 gene deletion from two families associated with a spectrum of congenital heart defects from bicuspid aortic valve to complex cardiac anomalies. This is the first description of a familial NOTCH1 deletion, showing apparently high penetrance, which may be unique to this mechanism of disease. Immunohistochemical staining of cardiac tissue demonstrated reduced levels of NOTCH1 expression in both the left and right ventricular outflow tracts. These cases suggest that haploinsufficiency caused by NOTCH1 gene deletion is associated with both mild and severe cardiac defects, similar to those caused by pathogenic variants in the gene, but with apparently higher, if not complete, penetrance.