Novel LTBP3 mutations associated with thoracic aortic aneurysms and dissections

Abstract Background Thoracic aortic aneurysm and dissection (TAAD) is a hidden-onset but life-threatening disorder with high clinical variability and genetic heterogeneity. In recent years, an increasing number of genes have been identified to be related to TAAD. However, some genes remain uncertain because of limited case reports and/or functional studies. LTBP3 was such an ambiguous gene that was previously known for dental and skeletal dysplasia and then noted to be associated with TAAD. More research on individuals or families harboring variants in this gene would be helpful to obtain full knowledge of the disease and clarify its association with TAAD. Methods A total of 266 TAAD probands with no causative mutations in known genes had been performed wholeexome sequencing (WES) to identify potentially pathogenic variants. In this study, rare LTBP3 variants were the focus of analysis. Results Two compound heterozygous mutations, c.625dup (p.Leu209fs) and c.1965del (p.Arg656fs), in LTBP3 were identified in a TAAD patient along with short stature and dental problems, which was the first TAAD case with biallelic LTBP3 null mutations in an Asian population. Additionally, several rare heterozygous LTBP3 variants were also detected in other sporadic TAAD patients. Conclusion The identification of LTBP3 mutations in TAAD patients in our study provided more clinical evidence to support its association with TAAD, which broadens the gene spectrum of LTBP3. LTBP3 should be considered to be incorporated into the routine genetic analysis of heritable aortopathy, which might help to fully understand its phenotypic spectrum and improve the diagnostic rate of TAAD.

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Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Genes ◽

10.3390/genes12020183 ◽

2021 ◽

Vol 12 (2) ◽

pp. 183

Author(s):

Tyler J. Creamer ◽

Emily E. Bramel ◽

Elena Gallo MacFarlane

Keyword(s):

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Aortic Aneurysms ◽

Gene Products ◽

Molecular Processes ◽

Thoracic Aortic Aneurysms ◽

Pathogenic Variants ◽

The Matrix ◽

Life Threatening ◽

Causal Variants

Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

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Ultrasound diagnosis of dissecting thoracic aortic aneurysms: procedure with a handheld device and a video-illustrated case

Tropical Doctor ◽

10.1177/0049475520959906 ◽

2021 ◽

Vol 51 (1) ◽

pp. 10-15

Author(s):

Kenneth V Iserson ◽

Sri Devi Jagjit ◽

Balram Doodnauth

Keyword(s):

Aortic Dissection ◽

Correct Diagnosis ◽

Signs And Symptoms ◽

Aortic Aneurysms ◽

Thoracic Aortic Aneurysms ◽

Handheld Device ◽

Thoracic Aortic Dissection ◽

Threatening Condition ◽

Life Threatening ◽

Handheld Ultrasound

Acute thoracic aortic dissection is an uncommon, although not rare, life-threatening condition. With protean signs and symptoms that often suggest more common cardiac or pulmonary conditions, it can be difficult to diagnose. Ultrasound has proven useful in making the correct diagnosis. This case demonstrates that training gained using standard ultrasound machines can be easily and successfully adapted to newer handheld ultrasound devices. The examination technique using the handheld device is illustrated with photos and a video.

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Surgical treatment for secondary aortoesophageal fistula

Journal of Cardiothoracic Surgery ◽

10.1186/s13019-020-01293-x ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Kayo Sugiyama ◽

Toru Iwahashi ◽

Nobusato Koizumi ◽

Toshiya Nishibe ◽

Toshiki Fujiyoshi ◽

...

Keyword(s):

Open Repair ◽

Rare Condition ◽

Aortic Aneurysms ◽

Total Arch Replacement ◽

University Hospital ◽

Aortoesophageal Fistula ◽

Thoracic Aortic Aneurysms ◽

Life Threatening ◽

Tokyo Medical ◽

Medical University

Abstract Background Aortoesophageal fistula (AEF) is a relatively rare condition that is often life-threatening. Secondary AEF is a complication of previous surgery, which can be more critical and challenging than primary AEF. The number of secondary AEF is increasing due to increase in the number of thoracic endovascular aortic repair (TEVAR). Although TEVAR has become a successful alternative surgical strategy for thoracic aortic aneurysms, secondary AEF after TEVAR might be critical than other secondary AEF because of severe adhesion between the esophagus and residual thoracic aortic wall. Methods This study analyzed six patients with secondary AEF who were treated at Tokyo Medical University Hospital between 2011 and 2016. These participants included four patients who had undergone TEVAR and two who had undergone total arch replacement. Results Although they were subsequently hospitalized for a long period, open surgical repair was completed in two patients who had undergone total arch replacement. TEVAR alone was performed in two patients who had undergone TEVAR and they were discharged without major complications shortly. Combined repair of TEVAR as a bridge to open surgery was planned for two patients who had undergone TEVAR. However, reconstruction of the aorta and esophagus could not be completed in these patients due to severe adhesions, and they died during hospitalization. Conclusions Definitive open repair was successfully performed in patients with secondary AEF after total arch replacement. However, in the patients with secondary AEF after TEVAR, severe adhesion between the aorta and esophagus led to difficulty in performing a successful definitive open repair. The strategy for secondary AEF should, therefore, be decided considering the etiology of secondary AEF. In secondary AEF after TEVAR, definitive open repair is difficult to complete because of catastrophic complication, and palliative treatment using TEVAR without reconstruction of aorta and esophagus can be an alternative.

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Mapping Semaphorins and Netrins in the Pathogenesis of Human Thoracic Aortic Aneurysms

International Journal of Molecular Sciences ◽

10.3390/ijms20092100 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2100

Author(s):

Alebrahim ◽

Nayak ◽

Ward ◽

Ursomanno ◽

Shams ◽

...

Keyword(s):

Internal Thoracic Artery ◽

Aortic Aneurysms ◽

Axonal Guidance ◽

Full Spectrum ◽

Thoracic Aortic Aneurysms ◽

Persistent Inflammation ◽

Novel Association ◽

Life Threatening ◽

Ecm Degradation ◽

Matrix Degrading Enzymes

Thoracic aortic aneurysm (TAA) is a complex life-threatening disease characterized by extensive extracellular matrix (ECM) fragmentation and persistent inflammation, culminating in a weakened aorta. Although evidence suggests defective canonical signaling pathways in TAA, the full spectrum of mechanisms contributing to TAA is poorly understood, therefore limiting the scope of drug-based treatment. Here, we used a sensitive RNA sequencing approach to profile the transcriptomic atlas of human TAA. Pathway analysis revealed upregulation of key matrix-degrading enzymes and inflammation coincident with the axonal guidance pathway. We uncovered their novel association with TAA and focused on the expression of Semaphorins and Netrins. Comprehensive analysis of this pathway showed that several members were differentially expressed in TAA compared to controls. Immunohistochemistry revealed that Semaphorin4D and its receptor PlexinB1, similar to Netrin-1 proteins were highly expressed in damaged areas of TAA tissues but faintly detected in the vessel wall of non-diseased sections. It should be considered that the current study is limited by its sample size and the use of internal thoracic artery as control for TAA for the sequencing dataset. Our data determines important neuronal regulators of vascular inflammatory events and suggest Netrins and Semaphorins as potential key contributors of ECM degradation in TAA.

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SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105583 ◽

2019 ◽

Vol 56 (4) ◽

pp. 252-260 ◽

Cited By ~ 14

Author(s):

Ellen M Hostetler ◽

Ellen S Regalado ◽

Dong-Chuan Guo ◽

Nadine Hanna ◽

Pauline Arnaud ◽

...

Keyword(s):

Age Of Onset ◽

Cumulative Risk ◽

Aortic Disease ◽

Aortic Aneurysms ◽

Thoracic Aortic Disease ◽

Thoracic Aortic Aneurysms ◽

Missense Variants ◽

Variant Type ◽

Pathogenic Variants ◽

Reduced Penetrance

BackgroundPathogenic variants in SMAD3 cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with SMAD3 variants.MethodsAortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique SMAD3 variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.ResultsAortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed.ConclusionsSMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying SMAD3 variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with SMAD3 variants support gene-specific management of this disorder.

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The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective

Biomolecules ◽

10.3390/biom10020182 ◽

2020 ◽

Vol 10 (2) ◽

pp. 182 ◽

Cited By ~ 5

Author(s):

Nicolai P. Ostberg ◽

Mohammad A. Zafar ◽

Bulat A. Ziganshin ◽

John A. Elefteriades

Keyword(s):

Genetic Basis ◽

Surgical Intervention ◽

Clinical Manifestations ◽

Aortic Aneurysms ◽

Screening Tests ◽

Cellular Mechanisms ◽

Biomechanical Stress ◽

Thoracic Aortic Aneurysms ◽

Aortic Aneurysm And Dissection ◽

History Of

Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural history of TAAD has shown a clear genetic basis for the disease. Here, we review both the cellular mechanisms and clinical manifestations of syndromic and non-syndromic TAAD. We particularly focus on genes that have been linked to dissection at diameters <5.0 cm, the current lower bound for surgical intervention. Genetic screening tests to identify patients with TAAD associated mutations that place them at high risk for dissection are also discussed.

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Novel TGFBR2 and Known Missense SMAD3 Mutations: Two Case Reports of Thoracic Aortic Aneurysms

The Annals of Thoracic Surgery ◽

10.1016/j.athoracsur.2014.02.068 ◽

2015 ◽

Vol 99 (1) ◽

pp. 303-305 ◽

Cited By ~ 4

Author(s):

Paola Panesi ◽

Ilenia Foffa ◽

Saverio Sabina ◽

Lamia Ait Ali ◽

Maria Grazia Andreassi

Keyword(s):

Case Reports ◽

Aortic Aneurysms ◽

Thoracic Aortic Aneurysms

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Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD)

Genetics in Medicine ◽

10.1038/s41436-019-0444-y ◽

2019 ◽

Vol 21 (9) ◽

pp. 2015-2024 ◽

Cited By ~ 7

Author(s):

Pauline Arnaud ◽

Nadine Hanna ◽

Louise Benarroch ◽

Mélodie Aubart ◽

Laurence Bal ◽

...

Keyword(s):

Genetic Diversity ◽

Aortic Aneurysms ◽

Thoracic Aortic Aneurysms ◽

Pathogenic Variants

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Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

Neurology Genetics ◽

10.1212/nxg.0000000000000558 ◽

2021 ◽

Vol 7 (2) ◽

pp. e558

Author(s):

Daphne J. Smits ◽

Rachel Schot ◽

Martina Wilke ◽

Marjon van Slegtenhorst ◽

Marie Claire Y. de Wit ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Splice Variants ◽

Brain Mri ◽

Cerebellar Vermis ◽

Compound Heterozygous ◽

Loss Of Function ◽

Functional Studies ◽

Pathogenic Variants ◽

Whole Exome

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

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