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Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families

Kerstjens-Frederikse, W. S., van de Laar, I. M. B. H., Vos, Y. J., Verhagen, J. M. A., Berger, R. M. F., Lichtenbelt, K. D., Wassink-Ruiter, J. S. K., van der Zwaag, P. A., Sarvaas, G. J. D. M., Bergman, K. A., Bilardo, C. M., Roos-Hesselink, J. W., Janssen, J. H. P., Frohn-Mulder, I. M., van Spaendonck-Zwarts, K. Y., Melle, van, J. P., Hofstra, R. M. W. & Wessels, M. W., Sep-2016, In : Genetics in Medicine. 18, 9, p. 914-923 10 p.

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  • Cardiovascular malformations caused by NOTCH1 mutations do not keep left

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DOI

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.

Original languageEnglish
Pages (from-to)914-923
Number of pages10
JournalGenetics in Medicine
Volume18
Issue number9
Publication statusPublished - Sep-2016

    Keywords

  • aortic coarctation, aortic valve, bicuspid, hypoplastic left heart syndrome, NOTCH1, HYPOPLASTIC LEFT-HEART, BICUSPID AORTIC-VALVE, ADAMS-OLIVER SYNDROME, CARDIAC ANOMALIES, NEURAL CREST, DISEASE, VARIANTS, HAPLOINSUFFICIENCY, IDENTIFICATION, INTEGRATION

ID: 30762488