TY - JOUR
T1 - Cardiovascular malformations caused by NOTCH1 mutations do not keep left
T2 - data on 428 probands with left-sided CHD and their families
AU - Kerstjens-Frederikse, Wilhelmina S
AU - van de Laar, Ingrid M B H
AU - Vos, Yvonne J
AU - Verhagen, Judith M A
AU - Berger, Rolf M F
AU - Lichtenbelt, Klaske D
AU - Klein Wassink-Ruiter, Jolien S
AU - van der Zwaag, Paul A
AU - du Marchie Sarvaas, Gideon J
AU - Bergman, Klasien A
AU - Bilardo, Catia M
AU - Roos-Hesselink, Jolien W
AU - Janssen, Johan H P
AU - Frohn-Mulder, Ingrid M
AU - van Spaendonck-Zwarts, Karin Y
AU - van Melle, Joost P
AU - Hofstra, Robert M W
AU - Wessels, M W
PY - 2016
Y1 - 2016
N2 - PURPOSE: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome.METHODS: NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested.RESULTS: In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)).CONCLUSION: Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted.
AB - PURPOSE: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome.METHODS: NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested.RESULTS: In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)).CONCLUSION: Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted.
KW - aortic coarctation; aortic valve; bicuspid; hypoplastic left heart syndrome; NOTCH1
U2 - 10.1038/gim.2015.193
DO - 10.1038/gim.2015.193
M3 - Article
C2 - 26820064
SN - 1098-3600
VL - 18
SP - 914
EP - 923
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 9
ER -