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

Campens, Laurence; Callewaert, Bert; Mosquera, Laura Muiño; Renard, Marjolijn; Symoens, Sofie; Paepe, Anne De; Coucke, Paul; Backer, Julie De

doi:10.1186/s13023-014-0221-6

Cited by 69 publications

(49 citation statements)

References 48 publications

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“…This emphasizes the extreme allelic heterogeneity of H‐TAD‐related disorders. Young age at diagnosis, a positive family history, and presence of syndromic features were shown to be the strongest predictors for the identification of a disease‐causing variant in the literature ( P = 0.001–0.01) (Campens et al., ). The observation that the mean age at DNA testing in the group of patients with a pathogenic or likely pathogenic variant was 11 years lower than the mean age in the groups without a pathogenic or likely pathogenic variant is in line with this.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…AD usually occurs in non-syndromic and sporadic form (~80%) or in association with hereditary genetic disorders, such as familial thoracic aortic dissection (fTAAD), Marfan syndrome (MFS), the vascular type of Ehlers-Danlos syndrome (EDS), Loeys-Dietz syndrome (LDS), and arterial tortuosity syndrome (ATS) (Goldfinger et al, 2014;Hoffjan, 2012;Khau Van Kien et al, 2004;Ritelli et al, 2009). Although previous genetic studies in familial AD cases have identified several genes (Table S1 in Supporting Information) responsible for this disease, large fraction of clinical cases, especially sporadic cases, still lack genetic targets (Campens et al, 2015;Guo et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection

Zhou

Tan

et al. 2016

Sci. China Life Sci.

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Aortic dissection (AD) is a devastating, heterogeneous condition of aorta. The homeostasis between collagens and matrix metalloproteases (MMPs)/tissue inhibitors of MMPs (TIMPs) system in the extracellular matrix plays an important role for structure and functions of aorta. However, our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited. We analyzed all yet known coding human genes of collagens (45 genes), MMPs/TIMPs (27 genes) in 702 sporadic AD patients and in 163 matched healthy controls, by using massively targeted next-generation and Sanger sequencing. To define the pathogenesis of potential disease-causing candidate genes, we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats. We identified 257 pathogenic or likely pathogenic variants which involved 88.89% (64/72) genes in collagens-MMPs/TIMPs system and accounted for 31.05% (218/702) sporadic AD patients. In them, 84.86% patients (185/218) carried one variant, 12.84% two variants and 2.30% more than two variants. Importantly, we identified 52 novel probably pathogenic loss-of-function (LOF) variants (20 nonsense, 16 frameshift, 14 splice sites, one stop-loss, one initiation codon) in 11.06% (50/452) AD patients, which were absent in 163 controls (P=2.5×10 −5 ). Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems. The Col5a2 −/− rats manifested growth retardation and aortic dysplasia. Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis. aortic dissection, collagen, matrix metalloproteinase, next-generation sequencing, genetic diagnosis Citation:Li, Z., Zhou, C., Tan, L., Chen, P., Cao, Y., Li, C., Li, X., Yan, J., Zeng, H., Wang, D.W., and Wang, D.W. (2017). Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissec. Sci China Life Sci 60, 57-65.

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“…This explains the scarcity of mutations reported in the C-propeptide region. Previously, targeted region capture combined with next-generation sequencing was successfully utilized to uncover pathologic variants of COL3A1 in individuals with aortopathy with unsuspected vEDS (7,27). As with the proband in the present study, they were subject to targeted sequencing primarily based on aortic phenotypes, rather than other syndromic manifestations.…”

Section: Discussionmentioning

confidence: 99%

Identification of a missense mutation of COL3A1 in a Chinese family with atypical Ehlers-Danlos syndrome using targeted next-generation sequencing

Zhang¹,

Han²,

Zhou³

et al. 2016

Molecular Medicine Reports

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Aortopathy represents an important cause of mortality in industrialized countries, with a number of genes identified as predispose factors. It can be difficult to identify the genetic lesions underlying this disorder, particularly when the phenotype is atypical. The present study performed targeted next-generation sequencing of 428 genes associated with cardiovascular diseases in a family with aortopathy, the proband of which presented with abdominal aortic aneurysm rupture only, with tissue fragility noted in surgery. After targeted capture, sequencing and bioinformatics analysis, a missense mutation, p.A1259T, was identified in the collagen type III α1 (COL3A1) gene and co-segregated with the disease in the family. Crystal structure modeling revealed abnormal hydrogen bonds generated by the mutation, which likely affected the spatial structure of the procollagen C-propeptide. Mutations in the procollagen C-propeptide are rare and genotype-phenotype correlation may explain the atypical manifestations of affected individuals. The results of the present study suggested that targeted gene capture combined with next-generation sequencing can serve as a useful technique in the genetic diagnosis of aortopathy, particularly in the content of an atypical phenotype.

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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

Cited by 69 publications

References 48 publications

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

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

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection

Identification of a missense mutation of COL3A1 in a Chinese family with atypical Ehlers-Danlos syndrome using targeted next-generation sequencing

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