TY - JOUR

T1 - Variants in the NOTCH1 gene in patients with aortic coarctation

AU - Freylikhman, Olga

AU - Tatarinova, Tatyana

AU - Smolina, Natalia

AU - Zhuk, Sergey

AU - Klyushina, Alexandra

AU - Kiselev, Artem

AU - Moiseeva, Olga

AU - Sjoberg, Gunnar

AU - Malashicheva, Anna

AU - Kostareva, Anna

PY - 2014/9/1

Y1 - 2014/9/1

N2 - BACKGROUND AND OBJECTIVE: Malformations of the left ventricular outflow tract are one of the most common forms of congenital heart disorders. Recently, it has been shown that mutations in the NOTCH1 gene can lead to bicuspid aortic valve, aortic aneurysm, and hypoplastic left heart syndrome. The aim of our study was to estimate the frequency of NOTCH1 gene mutations/substitutions in patients with aortic coarctation, isolated or combined with bicuspid aortic valve.DESIGN AND PATIENTS: The study included 51 children with coarctation. Detailed family history was obtained for every study subject, and echocardiographic data were obtained for the relatives when available. We applied a strategy of targeted mutation screening for 10 out of 34 exons of the NOTCH1 gene by direct sequencing. Control DNA was obtained from 200 healthy donors.RESULTS: In more than half of the cases, coarctation was combined with bicuspid aortic valve, and in approximately half of the cases, it was combined with hypoplasia of the aortic arch or descending aorta. Familial history of congenital heart disease was observed in 34.3% of the cases. In total, 29 variants of the NOTCH1 gene were identified in the patient group and in the control subjects. Four of those variants led to amino acid exchange, of which only one, R1279H, was identified in both the patient group and in the controls. This variant was significantly overrepresented in the patients with aortic coarctation compared with those in the control group (P < .05). We conclude that the R1279H substitution in the NOTCH1 gene is significantly overrepresented in patients with aortic coarctation and, therefore, may represent a disease-susceptibility allele.

AB - BACKGROUND AND OBJECTIVE: Malformations of the left ventricular outflow tract are one of the most common forms of congenital heart disorders. Recently, it has been shown that mutations in the NOTCH1 gene can lead to bicuspid aortic valve, aortic aneurysm, and hypoplastic left heart syndrome. The aim of our study was to estimate the frequency of NOTCH1 gene mutations/substitutions in patients with aortic coarctation, isolated or combined with bicuspid aortic valve.DESIGN AND PATIENTS: The study included 51 children with coarctation. Detailed family history was obtained for every study subject, and echocardiographic data were obtained for the relatives when available. We applied a strategy of targeted mutation screening for 10 out of 34 exons of the NOTCH1 gene by direct sequencing. Control DNA was obtained from 200 healthy donors.RESULTS: In more than half of the cases, coarctation was combined with bicuspid aortic valve, and in approximately half of the cases, it was combined with hypoplasia of the aortic arch or descending aorta. Familial history of congenital heart disease was observed in 34.3% of the cases. In total, 29 variants of the NOTCH1 gene were identified in the patient group and in the control subjects. Four of those variants led to amino acid exchange, of which only one, R1279H, was identified in both the patient group and in the controls. This variant was significantly overrepresented in the patients with aortic coarctation compared with those in the control group (P < .05). We conclude that the R1279H substitution in the NOTCH1 gene is significantly overrepresented in patients with aortic coarctation and, therefore, may represent a disease-susceptibility allele.

KW - Aortic Coarctation

KW - Bicuspid Aortic Valve

KW - Genetic Variant

KW - NOTCH1

UR - http://www.scopus.com/inward/record.url?scp=85027936771&partnerID=8YFLogxK

U2 - 10.1111/chd.12157

DO - 10.1111/chd.12157

M3 - Article

C2 - 24418111

VL - 9

SP - 391

EP - 396

JO - Congenital Heart Disease

JF - Congenital Heart Disease

SN - 1747-079X

IS - 5

ER -