Sequencing of NOTCH1 gene in an Italian population with bicuspid aortic valve: Preliminary results from the GISSI OUTLIERS VAR study

• Published in: Gene Vol. 715; p. 143970
• Main Authors: Pileggi, Silvana, De Chiara, Benedetta, Magnoli, Michela, Franzosi, Maria Grazia, Merlanti, Bruno, Bianchini, Francesca, Moreo, Antonella, Romeo, Gabriella, Russo, Claudio Francesco, Rizzo, Stefania, Basso, Cristina, Martinelli, Luigi, Maseri, Attilio
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.10.2019
• Subjects: Adult; Alleles; Amino Acid Substitution; Aortic Valve - abnormalities; Aortic Valve Stenosis - genetics; Bicuspid aortic valve; Bicuspid Aortic Valve Disease; Clinical biomarkers; Exons; Female; Genetic variant; Heart Valve Diseases; Heterozygote; Homozygote; Humans; Introns; Italy; Longitudinal Studies; Male; Middle Aged; Mutation, Missense; NOTCH1 gene; Penetrance; Polymorphism; Prospective Studies; Receptor, Notch1 - genetics; Sequence Analysis, DNA; Italy; NOTCH1 gene; trans-thoracic echocardiography; Biobanking and BioMolecular resources Research Infrastructure; Analysis of Variance; GISSI Group; Genetic variant; Bicuspid aortic valve; Clinical biomarkers; epithelial-to mesenchyme transition; trans-esophageal echocardiography; polymerase chain reaction; Polymorphism
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2019.143970

Bicuspid aortic valve (BAV) formation is genetically determined, with reduced penetrance and variable expressivity. NOTCH1 is a proven candidate gene and its mutations have been found in familial and sporadic cases of BAV. 66 BAV patients from the GISSI VAR study were genotyped for the NOTCH1 gene. We identified 63 variants, in heterozygous and homozygous states. Fifty-two are common polymorphisms present in almost all patients. Eleven variants are new and never yet reported: two are non-synonymous substitutions, Gly540Asp in exon 10 and Glu851Gln in exon 16; one is in the 3’UTR region and seven in introns, one corresponds to a T allele insertion in intron 27. We selected four statistically noteworthy and seven new variants identified in six BAV patients and correlated them with clinical and demographic variables and with imaging and histological parameters. Preliminary data show that four were BAV patients with isolated stenosis in patients over 60 aged. These variants may correlate with a later need for surgery for the presence of stenosis and not aortic valve regurgitation or ascending aortic aneurysm. Completing the genotyping of 62 BAV patients we found 11 new variants in the NOTCH1 gene never yet reported. These findings confirm that the identification of new, clinically remarkable biomarkers for BAV requires a deeper genetic understanding of the NOTCH1 gene variants, which could be targeted by future diagnostic and therapeutic strategies. •Our preliminary genetic characterization of the BAV population of the GISSI VAR study corroborates the role of NOTCH1 gene mutations as proven candidate for familial and sporadic cases of BAV.•The GISSI VAR study is first study with 4 groups based on echographic BAV classification and aortic disease.•Among the 63 identified variants in the NOTCH1 gene, eleven are new and never yet reported in literature.•New variants may correlate with a later need for surgery for the presence of stenosis.