Rapid detection of gene mutations responsible for non-syndromic aortic aneurysm and dissection using two different methods: resequencing microarray technology and next-generation sequencing

Sakai, Haruko; Suzuki, Shinichi; Mizuguchi, Takeshi; Imoto, Kiyotaka; Yamashita, Yūki; Doi, Hiroshi; Kikuchi, Masakazu; Tsurusaki, Yoshinori; Saitsu, Hirotomo; Miyake, Noriko; Masuda, Munetaka; Matsumoto, Naomichi

doi:10.1007/s00439-011-1105-7

Cited by 17 publications

(11 citation statements)

References 33 publications

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“…Over half (57%) of the variants identified were novel, and most were classified as uncertain. Pathogenic mutations were identified in ACTA2 [Milewicz et al, ], FBN1 [Collod‐Beroud et al, ; Sakai et al, ], SMAD3 [Wischmeijer et al, ], and TGFBR1 [Loeys et al, ] while VUS [Collod‐Beroud et al, ; Rommel et al, ; Arno et al, ] was identified in all 10 genes in the panel (Table and Fig. ).…”

Section: Resultsmentioning

confidence: 99%

Clinical utility of a next generation sequencing panel assay for Marfan and Marfan‐like syndromes featuring aortopathy

Wooderchak-Donahue

VanSant-Webb

Tvrdik

et al. 2015

American J of Med Genetics Pt A

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Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.

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Section: Resultsmentioning

confidence: 99%

Clinical utility of a next generation sequencing panel assay for Marfan and Marfan‐like syndromes featuring aortopathy

Wooderchak-Donahue

VanSant-Webb

Tvrdik

et al. 2015

American J of Med Genetics Pt A

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“…Moreover, one of the failing regions, TGFBR1 exon 1, was also excluded from our previous NGS test, which included three TAA genes (FBN1, TGFBR1, and TGFBR2), and which used a multiplex PCR approach for sample enrichment [Baetens et al, 2011). Compared with this previous multiplex PCR-based test and to a test based on pooling of PCR fragments prior to NGS [Sakai et al, 2012], we have achieved the following improvements: an increase in the number of simultaneously sequenced genes, an increase in design flexibility, a decrease in cost per sample and shorter turnaround times. In addition, if we compare our assay to whole-exome sequencing, we can conclude that we obtained a higher target base coverage (99.5% > 30x vs. 88.5% > 30x), half the number of (partially) failed exons, an increased number of samples per run, and a 10-fold shorter turnaround time.…”

Section: Discussionmentioning

confidence: 99%

Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes

et al. 2015

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At least 14 causative genes have been identified for both syndromic and nonsyndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world. Molecular confirmation of the diagnosis is increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor-intensive. To circumvent these problems, we developed a TAA gene panel for next-generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex ligation-dependent probe amplification identified large deletions in six of the remaining samples, whereas false-negative results were excluded by Sanger sequencing of FBN1, TGFBR1, and TGFBR2 in the last four samples. Subsequently, we screened 55 syndromic and nonsyndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the six following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), two in NOTCH1, and seven in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes.

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“…It is clear that the imbalance of the homeostasis between collagens and MMPs/TIMPs system is a key responsible for extracellular matrix (ECM) degeneration and structure and functions of aorta, and therefore may contribute to the pathogenesis of AD (Barbour et al, 2007;Theruvath et al, 2012;Tsamis et al, 2013). However, to date, except for gene COL3A1, no pathogenic genes in collagens and MMP/TIMPs system have been demonstrated in AD patients (Sakai et al, 2012;Smith 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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Rapid detection of gene mutations responsible for non-syndromic aortic aneurysm and dissection using two different methods: resequencing microarray technology and next-generation sequencing

Cited by 17 publications

References 33 publications

Clinical utility of a next generation sequencing panel assay for Marfan and Marfan‐like syndromes featuring aortopathy

Clinical utility of a next generation sequencing panel assay for Marfan and Marfan‐like syndromes featuring aortopathy

Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes

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

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