Sequencing of NOTCH1 gene in an Italian population with bicuspid aortic valve: Preliminary results from the GISSI OUTLIERS VAR study.
Adult
Alleles
Amino Acid Substitution
Aortic Valve
/ abnormalities
Aortic Valve Stenosis
/ genetics
Bicuspid Aortic Valve Disease
Exons
Female
Heart Valve Diseases
Heterozygote
Homozygote
Humans
Introns
Italy
Longitudinal Studies
Male
Middle Aged
Mutation, Missense
Penetrance
Prospective Studies
Receptor, Notch1
/ genetics
Sequence Analysis, DNA
Bicuspid aortic valve
Clinical biomarkers
Genetic variant
NOTCH1 gene
Polymorphism
Journal
Gene
ISSN: 1879-0038
Titre abrégé: Gene
Pays: Netherlands
ID NLM: 7706761
Informations de publication
Date de publication:
05 Oct 2019
05 Oct 2019
Historique:
received:
22
03
2019
revised:
13
06
2019
accepted:
08
07
2019
pubmed:
23
7
2019
medline:
28
8
2019
entrez:
23
7
2019
Statut:
ppublish
Résumé
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.
Sections du résumé
BACKGROUND
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
METHODS
66 BAV patients from the GISSI VAR study were genotyped for the NOTCH1 gene.
RESULTS
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
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.
Identifiants
pubmed: 31330235
pii: S0378-1119(19)30620-1
doi: 10.1016/j.gene.2019.143970
pii:
doi:
Substances chimiques
NOTCH1 protein, human
0
Receptor, Notch1
0
Types de publication
Clinical Trial
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
143970Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.