LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections

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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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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Novel LTBP3 mutations associated with thoracic aortic aneurysms and dissections

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-02143-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Guoyan Zhu ◽

Mingyao Luo ◽

Qianlong Chen ◽

Yinhui Zhang ◽

Kun Zhao ◽

...

Keyword(s):

Case Reports ◽

Asian Population ◽

Aortic Aneurysms ◽

Compound Heterozygous ◽

Thoracic Aortic Aneurysms ◽

Functional Studies ◽

Pathogenic Variants ◽

Aortic Aneurysm And Dissection ◽

Life Threatening ◽

Full Knowledge

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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