Genetic abnormalities in bicuspid aortic valve root phenotype: preliminary results†

Girdauskas, Evaldas; Geist, Lisa; Disha, Kushtrim; Kazakbaev, Iliaz; Gross, T. M. Sequeira; Schulz, Stefan; Ungelenk, Martin; Kuntze, Thomas; Reichenspurner, Hermann; Kurth, Ingo

doi:10.1093/ejcts/ezx065

Cited by 43 publications

(42 citation statements)

References 23 publications

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“…In accordance to these findings, subsequent studies showed that the prevalence of NOTCH1 missense variants was in the range of 10%-18% in BAV patients with concomitant ascending aortic aneurysms (see Table 1) [10][11][12]. These potentially deleterious NOTCH1 variants were mostly absent in the tricuspid aortic valve (TAV) control groups without aortopathy.…”

Section: Genetic Signaling Pathways and Bicuspid Aortopathymentioning

confidence: 62%

Unravelling the Pathogenetic Mechanisms in Congenital Aortopathies: Need for an Integrative Translational Approach

Girdauskas

Kaemmerer

Kodolitsch

2020

JCM

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Congenital heart disease (CHD)-associated aortopathy is a very heterogeneous entity with a wide spectrum of clinical presentations. The pathogenesis of aortopathy is still incompletely understood, and, therefore, the best prevention and management strategy is currently unknown. The most common entity of CHD-associated aortopathies is bicuspid aortic valve (BAV)-associated aortic disease (so called bicuspid aortopathy) that is found in 50%–60% of BAV individuals. BAV aortopathy has been reported in association with an increased risk of aortic events, especially aortic dissection and sudden cardiac death. Risk stratification of adverse aortic events is still very rudimentary and considers only the maximal aortic diameter, which makes it unsuitable for an individual risk prediction. This introductory Editorial highlights the unmet clinical need for more integrative and translational research to unravel pathogenetic pathways in the development of CHD-associated aortopathies, integrating recently identified genetic lesions and knowledge on circulating biomarkers and microstructural changes in the diseased aorta.

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Section: Genetic Signaling Pathways and Bicuspid Aortopathymentioning

confidence: 62%

Unravelling the Pathogenetic Mechanisms in Congenital Aortopathies: Need for an Integrative Translational Approach

Girdauskas

Kaemmerer

Kodolitsch

2020

JCM

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“…This bicuspid aortic valve subtype lacks other clinical features of the Marfan syndrome, but it shares some of its pathogenic and genetic features. Such aortic phenotypes have been described for decades in conjunction with, but also independently of their etiology, as 'annuloaortic ectasia' [24], or as 'forme fruste' of Marfan syndrome [25], Today, this bicuspid aortic phenotype has been associated with nucleotide sequence variants in the FBN1 gene [26,27], but also with other genes known to cause genetic aortic diseases [27].…”

Section: Aortic Valve Diseasementioning

confidence: 99%

Features of Marfan syndrome not listed in the Ghent nosology – the dark side of the disease

Kodolitsch

Demolder

Girdauskas

et al. 2019

Expert Review of Cardiovascular Therapy

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Introduction: The revised Ghent nosology presents the classical features of Marfan syndrome. However, behind its familiar face, Marfan syndrome hides less well-known features. Areas covered: The German Marfan Organization listed unusual symptoms and clinical experts reviewed the literature on clinical features of Marfan syndrome not listed in the Ghent nosology. Thereby we identified the following features: (1) bicuspid aortic valve, mitral valve prolapse, pulmonary valve prolapse, tricuspid valve prolapse, (2) heart failure and cardiomyopathy, (3) supraventricular arrhythmia, ventricular arrhythmia, and abnormal repolarization, (4) spontaneous coronary artery dissection, anomalous coronary arteries, and atherosclerotic coronary artery disease, tortuosity-, aneurysm-, and dissection of large and medium-sized arteries, (5) restrictive lung disease, parenchymal lung disease, and airway disorders, (6) obstructive-and central sleep apnea, (7) liver and kidney cysts, biliary tract disease, diaphragmatic hernia, and adiposity, (8) premature labor, and urinary incontinence, (9) myopathy, reduced bone mineral density, and craniofacial manifestations, (10) atrophic scars, (11) caries, and craniomandibular dysfunction, (12) headache from migraine and spontaneous cerebrospinal fluid leakage, (13) cognitive dysfunction, schizophrenia, depression, fatigue, and pain, (14) and activated fibrinolysis, thrombin, platelets, acquired von Willebrand disease, and platelet dysfunction. Expert commentary: Future research, nosologies, and guidelines may consider less well-known features of Marfan syndrome. ARTICLE HISTORY

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“…21 This initial report was followed by many others, describing an association between variations in NOTCH1 and BAV, BAV/TAA, hypoplastic left heart syndrome (HLHS), aortic valve stenosis, and coarctation. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Most of the identified variants in these reports are missense variants, In 2016, a large scale screening of 428 probands with left-sided CHD (LS-CHD), confined to aortic valve stenosis, BAV, coarctation of the aorta, and HLHS, revealed the presence of 14 NOTCH1 mutations, including splicing mutations, truncating mutations and a whole gene deletion ( Figure 2, Table S1). 39 A specific frameshift mutation reported in this study (p.Ser2486Leufs*21) is located within the last exon and is therefore predicted to escape nonsense mediated decay (NMD) of the mutant mRNA transcript.…”

Section: Congenital Heart Diseasementioning

confidence: 99%

“…Truncating NOTCH1 mutations were identified in 2 families, members of whom presented with various aortic and cardiac anomalies, including BAV, CAVD, aortic stenosis, aortic insufficiency, TAA, Tetralogy of Fallot (TOF), ventricular septal defect (VSD), mitral atresia, hypoplastic left ventricle, and double‐outlet right ventricle (Figure ) . This initial report was followed by many others, describing an association between variations in NOTCH1 and BAV, BAV/TAA, hypoplastic left heart syndrome (HLHS), aortic valve stenosis, and coarctation . Most of the identified variants in these reports are missense variants, which do not replace or create critical cysteine or other conserved residues in the EGF‐like domains.…”

Section: Introductionmentioning

confidence: 99%

Overlapping but distinct roles for NOTCH receptors in human cardiovascular disease

et al. 2018

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The NOTCH signalling pathway is an essential pathway, involved in many cellular processes, including cell fate decision, cell proliferation, and cell death and important in the development of most organs. Mutations in genes encoding components of the NOTCH signalling pathway lead to a spectrum of congenital disorders. Over the past decades, mutations in human NOTCH signalling genes have been identified in several diseases with cardiovascular involvement. NOTCH1 mutations have been described in bicuspid aortic valve disease, left-sided congenital heart disease, and Adams-Oliver syndrome. NOTCH2 mutations lead to the development of Alagille syndrome, while mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. To date, mutations in NOTCH4 have not been associated with cardiovascular disease. This review focuses on the mutations described in NOTCH1, NOTCH2, and NOTCH3 and their associated cardiovascular phenotypes.

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Genetic abnormalities in bicuspid aortic valve root phenotype: preliminary results†

Abstract: Our preliminary study demonstrates a high prevalence and a wide spectrum of rare genetic variants in patients with the BAV root phenotype, indicative of the potentially congenital origin of associated aortopathy in this specific BAV cohort.

Cited by 43 publications

References 23 publications

Unravelling the Pathogenetic Mechanisms in Congenital Aortopathies: Need for an Integrative Translational Approach

Unravelling the Pathogenetic Mechanisms in Congenital Aortopathies: Need for an Integrative Translational Approach

Features of Marfan syndrome not listed in the Ghent nosology – the dark side of the disease

Overlapping but distinct roles for NOTCH receptors in human cardiovascular disease

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