Silvana Pileggi1, Benedetta De Chiara2, Michela Magnoli3, Maria Grazia Franzosi3, Bruno Merlanti4, Francesca Bianchini5, Antonella Moreo6, Gabriella Romeo7, Claudio Francesco Russo4, Stefania Rizzo8, Cristina Basso8, Luigi Martinelli9, Attilio Maseri10. 1. Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy. Electronic address: silvana.pileggi@marionegri.it. 2. Cardiology IV, "A.De Gasperis" Department, ASST GOM Niguarda, Milan, Italy; School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy. 3. Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy. 4. Cardiac Surgery, "A.De Gasperis" Department, ASST GOM Niguarda, Milan, Italy. 5. ANMCO Research Center, Florence. 6. Cardiology IV, "A.De Gasperis" Department, ASST GOM Niguarda, Milan, Italy. 7. Department of Cardiac, Vascular and Thoracic Sciences, University of Padua, Padua. 8. Cardiovascular Pathology, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua. 9. Cardiothoracic Surgery, ICLAS-Istituto Clinico Ligure Alta Specialità, Rapallo. 10. Heart Care Foundation, Florence.
Abstract
BACKGROUND: 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. METHODS: 66 BAV patients from the GISSI VAR study were genotyped for the NOTCH1 gene. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 66 BAV patients from the GISSI VAR study were genotyped for the NOTCH1 gene. RESULTS: 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. CONCLUSIONS: 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.