Heart failure and sudden cardiac death in heritable thoracic aortic disease caused by pathogenic variants in the <i><scp>SMAD</scp>3</i> gene

Backer, Julie De; Braverman, Alan C.

doi:10.1002/mgg3.396

Cited by 8 publications

(8 citation statements)

References 24 publications

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“…From more than 300 patients reported in literature with SRD, only 133 of them were described with precise clinical data to be included in our genotype-phenotype correlations study (Arno et al, 2012;Arroyave, Carretero, & Gruosso, 2018;Backer & Braverman, 2018;Campens et al, 2015;Kaadan et al, 2018;Laar et al, 2012;Nevidomskyte et al, 2017;Overwater et al, 2018;Proost et al, 2015;Regalado et al, 2011;Schepers et al, 2018;Wischmeijer et al, 2013;Ye et al, 2013). Six out of these 133 patients bearing splice variants in SMAD3 (Campens et al, 2015;Nevidomskyte et al, 2017;Overwater et al, 2018) were not included in our analysis because the underlying pathogenic mechanism of these variants could not be predicted with certainty.…”

Section: Discussionmentioning

confidence: 99%

“…Pathogenic heterozygous variants in the SMAD3 gene are a rare cause of connective tissue disorder. To our knowledge, 132 families have been reported in the literature with 102 different variants (Arno et al, ; Arroyave et al, ; Aubart et al, ; Backer & Braverman, ; Campens et al, ; Collins, Flor, Tang, Bange, & Zarate, ; Hostetler et al, ; Kaadan et al, ; Kfoury, Chen, & Lin, ; Laar et al, ; Nevidomskyte et al, ; Overwater et al, ; Proost et al, ; Regalado et al, ; Schepers et al, ; Wischmeijer et al, ; Ye et al, ) and four total or partial deletions of SMAD3 (Hostetler et al, ; Schepers et al, ). In this work, we report 22 additional patients from 8 families, showing high variability in terms of expression and penetrance of SMAD3 pathogenic variants even at pediatric age (Hostetler et al, ; Laar et al, ; Wischmeijer et al, ).…”

Section: Discussionmentioning

confidence: 99%

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Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature

Chesneau

Edouard

Dulac

et al. 2020

Molec Gen & Gen Med

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BackgroundPathogenic SMAD3 variants are responsible for a cardiovascular phenotype, mainly thoracic aortic aneurysms and dissections. Precocious identification of the vascular risk such as aortic dilatation in mutated patients has a major impact in terms of management, particularly to avoid dissection and sudden death. These vascular damages are classically associated with premature osteoarthritis and skeletal abnormalities. However, variable expressivity and incomplete penetrance are common with SMAD3 variants.MethodsTo investigate the clinical variability observed within SMAD3 patients, we reviewed the phenotypic and genetic data of 22 new patients from our Centre and of 133 patients reported in the literature. From this cohort of 155 mutated individuals, we first aimed to delineate an estimated frequency of the main clinical signs associated with SMAD3 pathogenic variants and, then, to look for genotype‐phenotype correlations, mainly to see if the aortic phenotype (AP) could be predicted by the SMAD3 variant type.ResultsWe showed, herein, the absence of correlation between the SMAD3 variant type and the occurrence of an AP in patients.ConclusionTherefore, this report brings additional data for the genotype‐phenotype correlations of SMAD3 variants and the need to explore in more detail the effects of genetic modifiers that could influence the phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature

Chesneau

Edouard

Dulac

et al. 2020

Molec Gen & Gen Med

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“…Shortly thereafter, a case report describing a patient carrying a pathogenic variant in TGFBR1 with heart failure necessitating heart transplant was published (80). Several other case reports mentioned both heart failure and SCD in patients carrying variants in other genes: TGFB2, TGFBR2 and SMAD3 (81)(82)(83)(84). Myocardial disease with left ventricular hypertrophy in 16% and VE in 19% of the patients carrying variants in SMAD3 was already reported in one of the first case series characterizing patients with pathogenic variants this gene (85).…”

Section: Evidence Of Cardiomyopathy and Arrhythmia In Other Htadmentioning

confidence: 99%

Cardiomyopathy in Genetic Aortic Diseases

Muiño-Mosquera

Backer

2021

Front. Pediatr.

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Genetic aortic diseases are a group of illnesses characterized by aortic aneurysms or dissection in the presence of an underlying genetic defect. They are part of the broader spectrum of heritable thoracic aortic disease, which also includes those cases of aortic aneurysm or dissection with a positive family history but in whom no genetic cause is identified. Aortic disease in these conditions is a major cause of mortality, justifying clinical and scientific emphasis on the aorta. Aortic valve disease and atrioventricular valve abnormalities are known as important additional manifestations that require careful follow-up and management. The archetype of genetic aortic disease is Marfan syndrome, caused by pathogenic variants in the Fibrillin-1 gene. Given the presence of fibrillin-1 microfibers in the myocardium, myocardial dysfunction and associated arrhythmia are conceivable and have been shown to contribute to morbidity and mortality in patients with Marfan syndrome. In this review, we will discuss data on myocardial disease from human studies as well as insights obtained from the study of mouse models of Marfan syndrome. We will elaborate on the various phenotypic presentations in childhood and in adults and on the topic of arrhythmia. We will also briefly discuss the limited data available on other genetic forms of aortic disease.

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“…25,26 Variable bioinformatic approaches using traditional RNA sequencing (RNA-seq) have helped us gain a better understanding regarding the altered expression of genes in CVD and HF patients, compared to healthy individuals. [27][28][29] However, previous studies were not able to identify the variant mutations associated with these genes. A more integrated gene expression and variant analysis is required to reduce the high-risk mortality of CVD patients by creating more personalized treatments.…”

Section: Introductionmentioning

confidence: 98%

“…Despite significant advancements in CVD diagnostics, prevention and treatment, approximately half of the affected CVD patients reportedly die within 5 years of receiving a diagnosis due to the complex multifactorial aetiology of CVDs involving both genetic and environmental agents 25,26 . Variable bioinformatic approaches using traditional RNA sequencing (RNA‐seq) have helped us gain a better understanding regarding the altered expression of genes in CVD and HF patients, compared to healthy individuals 27–29 . However, previous studies were not able to identify the variant mutations associated with these genes.…”

Section: Introductionmentioning

confidence: 99%

Investigating genes associated with cardiovascular disease among heart failure patients for translational research and precision medicine

Ahmed

Zeeshan

Persaud

et al. 2023

Clinical and Translational Dis

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Background Cardiovascular disease (CVD) is a leading cause of premature mortality in the United States and the world. CVD comprises several complex and mostly heritable conditions, which range from myocardial infarction to congenital heart disease. The risk factors contributing to the development of CVD and response to therapy in an individual patient are highly variable. Here, we report our findings from an integrative analysis of gene expression, disease‐causing gene variants and associated phenotypes among CVD populations, with a focus on high‐risk heart failure (HF) patients. Methods We built a cohort using electronic health records of consented patients with available samples and then performed high‐throughput whole genome and RNA sequencing of key genes responsible for HF and other CVD pathologies. Our in‐depth gene expression analysis revealed differentially expressed genes associated with HF and other CVDs. We performed a variant analysis of whole genome sequence data of CVD patients and identified genes with altered gene expression with functional and non‐functional mutations in these genes. Results Our results highlight the importance of investigating the mechanisms of CVD progression through multi‐omics datasets. Next, we performed splice mutation and variant distribution analysis of genes associated with HF and other CVD. We implemented Jensen–Shannon divergence (JSD)‐based method and identified HBA1, FADD, ADRB2, NPPB, ADRB1, ADB and NPPC genes with the greatest variance based on their JSD scores. Our study provided evidence that applying integrative data analysis approach involving genomics and transcriptomics data will not only help understand the pathophysiology of CVD diseases but also reduce heterogeneity in disease subtypes.

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Heart failure and sudden cardiac death in heritable thoracic aortic disease caused by pathogenic variants in the SMAD3 gene

Cited by 8 publications

References 24 publications

Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature

Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature

Cardiomyopathy in Genetic Aortic Diseases

Investigating genes associated with cardiovascular disease among heart failure patients for translational research and precision medicine

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