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Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD
Wilhelmina S Kerstjens-Frederikse1, Ingrid M B H van de Laar2, Yvonne J Vos1
1Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Insights
NOTCH1 mutations are found in 7% of familial and 1% of sporadic left-sided congenital heart disease (LS-CHD). These mutations can cause a range of heart defects and thoracic aortic aneurysms, warranting early genetic testing.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Left-sided congenital heart disease (LS-CHD) encompasses conditions like aortic valve stenosis and coarctation of the aorta.
- Genetic factors play a significant role in the etiology of congenital heart disease.
- The NOTCH1 gene is implicated in cardiovascular development.
Purpose of the Study:
- To determine the prevalence of NOTCH1 gene mutations in patients with LS-CHD.
- To characterize the phenotypic spectrum associated with NOTCH1 mutations.
- To assess the penetrance and inheritance patterns of NOTCH1 mutations in affected families.
Main Methods:
- Genetic screening of the NOTCH1 gene in 428 probands with nonsyndromic LS-CHD.
- Detailed family history collection and genetic testing of relatives when mutations were identified.
- Phenotypic analysis of mutation carriers, including cardiovascular malformations and thoracic aortic aneurysms.
Main Results:
- NOTCH1 mutations were detected in 3% of all LS-CHD probands, with higher prevalence in familial cases (7%) compared to sporadic cases (1%).
- Mutations included splicing defects, truncations, and whole-gene deletions.
- Phenotypic manifestations in mutation carriers extended beyond LS-CHD to include right-sided congenital heart disease (RS-CHD), conotruncal heart disease (CTD), and thoracic aortic aneurysms (TAAs).
- High penetrance was observed, with 75% of carriers exhibiting cardiovascular malformations, and 25% of identified carriers being asymptomatic.
Conclusions:
- Pathogenic NOTCH1 mutations are a significant cause of LS-CHD, particularly in familial cases.
- The phenotypic spectrum associated with NOTCH1 mutations is broad, including LS-CHD, RS-CHD, CTD, and TAAs.
- Genetic testing of NOTCH1 is recommended for early diagnosis and management of individuals with LS-CHD, RS-CHD, CTD, and TAAs.
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.Genet Med 18 9, 914-923.
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