Novel pathogenic<i>SMAD2</i>variants in five families with arterial aneurysm and dissection: further delineation of the phenotype

Cannaerts, Elyssa; Kempers, Marlies; Maugeri, Alessandra; Marcelis, Carlo; Gardeitchik, Thatjana; Richer, Julie; Micha, Dimitra; Beauchesne, Luc; Timmermans, Janneke; Vermeersch, Paul; Meyten, Nathalie; Chénier, Sébastien; Beek, Gerarda van de; Peeters, Nils; Alaerts, Maaike; Schepers, Dorien; Laer, Lut Van; Verstraeten, Aline; Loeys, Bart

doi:10.1136/jmedgenet-2018-105304

Cited by 30 publications

(21 citation statements)

References 28 publications

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“…This advised the subdivision of LDS into multiple classes based on the causative gene (LDS1-5) providing a general indication of the spectrum of disease severity, from most to least severe form: LDS1=LDS2>LDS3>LDS4>LDS5 [6]. Still, there are not enough data on LDS caused by heterozygous mutations in SMAD2 to place this form (LDS6) in this spectrum [13]. Recently, it has been suggested that mutations in genes different from TGFBR1/ 2 may give rise to a phenotypic continuum hard to categorize in clear-cut genotype-phenotype correlations [3,6].…”

Section: Discussionmentioning

confidence: 99%

“…Still, limited numbers are available in literature about genotype-phenotype correlation. To date, 9 (likely) pathogenic variants in SMAD2 have now been described in 15 subjects displaying a broad range of features, including aneurysms, tortuosity of the entire arterial tree, and coronary artery dissections, even in the absence of prominent connective tissue characteristics [13]. Concerning TGFB3 , 15 different variants were reported in 56 individuals presenting with phenotypic overlap between LDS and MFS [12].…”

Section: Discussionmentioning

confidence: 99%

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Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data

Camerota

Ritelli

Wischmeijer

et al. 2019

Genes

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Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-β pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data

Camerota

Ritelli

Wischmeijer

et al. 2019

Genes

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“…A total of 78 and 8 variants in SMAD3 and SMAD2, respectively, have been reported in LDS patients [8], the majority (63 and 87.5%, respectively) of which are located in the MH2 domain, a highly conserved region responsible for the oligomerization of SMAD2 or SMAD3 with SMAD4 and subsequent Smad-dependent activation of downstream transcription. Other than missense variants, previous reports reveal only one SMAD2 nonsense mutation [19], which is located in the linker region. In this study, we identified the second case of a SMAD2 truncating mutation (c.593dupA), which was also in the linker region.…”

Section: Genetic Profilingmentioning

confidence: 95%

Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients

Yang

Luo

et al. 2020

Orphanet J Rare Dis

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Background: Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder for which 6 genes in the TGF-β pathway have been identified as causative. With the widespread use of genetic testing, the range of known clinical and genetic profiles has broadened, but these features have not been fully elucidated thus far. Methods and results: Using gene panel sequencing or whole exome sequencing, we identified 54 unique rare variants in LDS genes in 57 patients with thoracic aneurysms/dissections, including 27 pathogenic mutations (P + LP) and 27 variants of unknown significance (VUS LP + VUS). Genotype-phenotype correlation analysis revealed that carriers with P/LP/ VUS LP variants in TGFBR1/TGFBR2/SMAD3 genes had significantly more severe cardiovascular features (cardiovascular death/dissection) than carriers with VUSs in these 3 genes at an early age and had less favorable eventfree survival. Additionally, carriers with VUS in combination with other risk factors, such as hypertension, might be prone to developing an aortic dissection, as indicated by the fact that 5/8 (62.5%) patients with VUSs in our cohort developed aortic dissections in the presence of hypertension, compared with 25.0% (3/12) in the absence of hypertension (p = 0.047). Conclusions: To date, this was the largest cohort of LDS patients ever reported in China, and the present study expanded the known mutation and phenotypic spectra of LDS, which might help refine our knowledge of LDS.

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“…Notably, different mutations in the TGF-β pathway cause LDS, an autosomal dominant connective tissue disorder. LDS can be classified into six different subtypes, according to the underlying mutation (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, and SMAD2) [21,22,[68][69][70][71][72][73]. LDS patients share many phenotypical characteristics with MFS patients, but LDS vascular pathology is often more aggressive and more widespread, affecting the entire arterial tree.…”

Section: Tgf-β Pathway Genes Associated With Aneurysm Formationmentioning

confidence: 99%

Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment

Dorst

Wagenaar

Pluijm

et al. 2020

Cardiovasc Drugs Ther

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Thoracic aortic aneurysms (TAAs) are permanent pathological dilatations of the thoracic aorta, which can lead to life-threatening complications, such as aortic dissection and rupture. TAAs frequently occur in a syndromic form in individuals with an underlying genetic predisposition, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Increasing evidence supports an important role for transforming growth factor-β (TGF-β) and the renin-angiotensin system (RAS) in TAA pathology. Eventually, most patients with syndromic TAAs require surgical intervention, as the ability of present medical treatment to attenuate aneurysm growth is limited. Therefore, more effective medical treatment options are urgently needed. Numerous clinical trials investigated the therapeutic potential of angiotensin receptor blockers (ARBs) and β-blockers in patients suffering from syndromic TAAs. This review highlights the contribution of TGF-β signaling, RAS, and impaired mechanosensing abilities of aortic VSMCs in TAA formation. Furthermore, it critically discusses the most recent clinical evidence regarding the possible therapeutic benefit of ARBs and β-blockers in syndromic TAA patients and provides future research perspectives and therapeutic implications.

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Novel pathogenicSMAD2variants in five families with arterial aneurysm and dissection: further delineation of the phenotype

Abstract: Taken together, our data suggest that heterozygous loss-of-function variants can cause a wide spectrum of autosomal dominant aortic and arterial aneurysmal disease, combined with connective tissue findings reminiscent of MFS and LDS.

Cited by 30 publications

References 28 publications

Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data

Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data

Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients

Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment

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