The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys–Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD)

Lerner‐Ellis, Jordan; AlDubayan, Saud H.; Hernandez, Amy Lovelette; Kelly, Melissa; Stuenkel, Aaron J.; Walsh, Jennifer; Joshi, Victoria A.

doi:10.1016/j.ymgme.2014.03.011

Cited by 50 publications

(33 citation statements)

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“…This discrepancy may be due to differences in study design and patient ascertainment. Our results are in line with more recent studies performed in similar patient populations [44]. …”

Section: Discussionsupporting

confidence: 94%

“…In addition to previously reported FBN1, TGFBR1/2 , TGFB2 , SMAD3 and ACTA2 mutations [9,12,18,19,24,35,43], we report on a COL3A1 mutation in a nonsyndromic H-TAD patient. The mutation detection rate in the FBN1 gene in the nonsyndromic H-TAD patient group (1.9%) is in line with previously published data [44]. The mutation detection rate in ACTA2 (2.6%) contrasts with what has been reported in the first studies identifying ACTA2 mutations in up to 16% of nonsyndromic H-TAD families [18-20].…”

Section: Discussionsupporting

confidence: 89%

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Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients

Campens

Callewaert

Mosquera

et al. 2015

Orphanet J Rare Dis

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BackgroundHeritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. About one dozen genes are now available for clinical molecular testing. Targeted single gene testing is hampered by significant clinical overlap between syndromic H-TAD entities and the absence of discriminating features in isolated cases. Therefore panel testing of multiple genes has now emerged as the preferred approach. So far, no data on mutation detection rate with this technique have been reported.MethodsWe performed Next Generation Sequencing (NGS) based screening of the seven currently most prevalent H-TAD-associated genes (FBN1, TGFBR1/2, TGFB2, SMAD3, ACTA2 and COL3A1) on 264 samples from unrelated probands referred for H-TAD and related entities. Patients fulfilling the criteria for Marfan syndrome (MFS) were only included if targeted FBN1 sequencing and MLPA analysis were negative.ResultsA mutation was identified in 34 patients (13%): 12 FBN1, one TGFBR1, two TGFBR2, three TGFB2, nine SMAD3, four ACTA2 and three COL3A1 mutations. We found mutations in FBN1 (N = 3), TGFBR2 (N = 1) and COL3A1 (N = 2) in patients without characteristic clinical features of syndromal H-TAD. Six TAD patients harboring a mutation in SMAD3 and one TAD patient with a TGFB2 mutation fulfilled the diagnostic criteria for MFS.ConclusionNGS based H-TAD panel testing efficiently reveals a mutation in 13% of patients. Our observations emphasize the clinical overlap between patients harboring mutations in syndromic and nonsyndromic H-TAD related genes as well as within syndromic H-TAD entities, justifying a widespread application of this technique.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0221-6) contains supplementary material, which is available to authorized users.

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“…This discrepancy may be due to differences in study design and patient ascertainment. Our results are in line with more recent studies performed in similar patient populations [44]. …”

Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 89%

Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients

Campens

Callewaert

Mosquera

et al. 2015

Orphanet J Rare Dis

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“…In this cohort of 810 patients, a pathogenic or likely pathogenic variant was identified in 66 patients (8.1%). Overall, we identified a relatively low number of pathogenic or likely pathogenic variants in our H-TAD cohort compared to pre-vious studies that identified mutations in 10.3% to 35.5% (Campens et al, 2015;Lerner-Ellis et al, 2014;Poninska et al, 2016;Proost et al, 2015;Wooderchak-Donahue et al, 2015;Ziganshin et al, 2015). This wide range is likely to be explained by differences in clinical and demographic characteristics of the study populations and different inclusion criteria used for genetic testing.…”

Section: Discussionmentioning

confidence: 78%

Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders

et al. 2018

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Simultaneous analysis of multiple genes using next‐generation sequencing (NGS) technology has become widely available. Copy‐number variations (CNVs) in disease‐associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H‐TAD)‐associated genes. Eight hundred ten patients suspected of H‐TAD were analyzed by targeted NGS analysis of 21 H‐TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi‐)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H‐TAD patients.

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“…Pathogenic variants in TGFBR2 lead to Loeys–Dietz syndrome (MIM #610168) that closely matches the phenotypic presentation of this patient. Pathogenic variants in FBN1 lead to Marfan syndrome (MIM #154700); however, the variant identified in this patient has been previously reported as a benign polymorphism (Rommel et al 2002, 2005; Lerner-Ellis et al 2014). Pathogenic variants in MYH11 cause familial thoracic aortic aneurysm (MIM #132900) that is typically associated with aortic aneurysms but also strongly associated with patent ductus arteriosus not present in the patient or family members carrying the variant.…”

Section: Resultsmentioning

confidence: 73%

Functional validation reveals the novel missense V419L variant in TGFBR2 associated with Loeys–Dietz syndrome (LDS) impairs canonical TGF-β signaling

Cousin

Zimmermann

Mathison

et al. 2017

Cold Spring Harb Mol Case Stud

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TGF-β-related heritable connective tissue disorders are characterized by a similar pattern of cardiovascular defects, including aortic root dilatation, mitral valve prolapse, vascular aneurysms, and vascular dissections and exhibit incomplete penetrance and variable expressivity. Because of the phenotypic overlap of these disorders, panel-based genetic testing is frequently used to confirm the clinical findings. Unfortunately in many cases, variants of uncertain significance (VUSs) obscure the genetic diagnosis until more information becomes available. Here, we describe and characterize the functional impact of a novel VUS in the TGFBR2 kinase domain (c.1255G>T; p.Val419Leu), in a patient with the clinical diagnosis of Marfan syndrome spectrum. We assessed the structural and functional consequence of this VUS using molecular modeling, molecular dynamic simulations, and in vitro cell-based assays. A high-quality homology-based model of TGFBR2 was generated and computational mutagenesis followed by refinement and molecular dynamics simulations were used to assess structural and dynamic changes. Relative to wild type, the V419L induced conformational and dynamic changes that may affect ATP binding, increasing the likelihood of adopting an inactive state, and, we hypothesize, alter canonical signaling. Experimentally, we tested this by measuring the canonical TGF-β signaling pathway activation at two points; V419L significantly delayed SMAD2 phosphorylation by western blot and significantly decreased TGF-β-induced gene transcription by reporter assays consistent with known pathogenic variants in this gene. Thus, our results establish that the V419L variant leads to aberrant TGF-β signaling and confirm the diagnosis of Loeys–Dietz syndrome in this patient.

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The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys–Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD)

Cited by 50 publications

References 31 publications

Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients

Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients

Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders

Functional validation reveals the novel missense V419L variant in TGFBR2 associated with Loeys–Dietz syndrome (LDS) impairs canonical TGF-β signaling

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