Genetic Dissection of Marfan Syndrome and Related Connective Tissue Disorders: An Update 2012

Hoffjan, Sabine

doi:10.1159/000339441

Cited by 41 publications

(38 citation statements)

References 141 publications

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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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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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“…Since many patients carrying FBN1 mutations may develop classic MFS over time, genotype information is essential for the diagnosis or exclusion of MFS [Sheikhzadeh et al, 2012], despite the fact that knowledge about a specific FBN1 mutation seems to have little prognostic value for an individual patient and cannot reliably guide individual management [Hoffjan, 2012]. In our case, although the FBN1 C538P mutation seems not to favor the progression of aortic root dilatation, periodic echocardiograms should be performed to prevent the risk of aortic dissection in the follow-up.…”

Section: Discussionmentioning

confidence: 99%

A Novel Fibrillin 1 Gene Mutation Leading to Marfan Syndrome with Minimal Cardiac Features

et al. 2014

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Marfan syndrome is an autosomal dominant disorder of the connective tissue, characterized by early development of thoracic aortic aneurysms and/or dissections, accompanied by ocular and/or skeletal involvement, and is caused by mutations in the fibrillin 1 (FBN1) gene. We report on a patient with ectopia lentis and a nonprogressive aortic root dilatation who presented with a novel mutation affecting a conserved cysteine residue present in a calcium-binding epidermal growth factor-like domain of FBN1 (ENSP00000325527, p.Cys538Phe; Chr15:48,805,751 G>T), as revealed by complete sequencing of the FBN1 gene exons and flanking sequences. Identification of the mutation led to genetic screening of apparently asymptomatic family members, allowing the detection of characteristic ocular phenotypes in the absence of typical cardiac Marfan features. This finding stresses the importance of genetic screening of asymptomatic relatives for FBN1 gene mutation carriers.

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“…The differential diagnosis of a tall, young person with Marfan-like skeletal features includes homocystinuria, Stickler syndrome, Ehlers-Danlos syndrome (EDS), Loeys-Dietz syndrome (LDS) and MASS phenotype (the acronym represents the following manifestations: a prolapsed mitral valve, myopia, aortic root enlargement, and skeletal and skin manifestations) [6,12,17,18].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, approximately one-fourth of MFS cases are caused by de-novo mutations. It has been demonstrated that fibrillin-1 microfibrils participate in the regulation of transforming growth factor β (TGF-β) [5,6]. Normally, in a healthy individual TGF-β is bound to connective tissue by fibrillin-1.…”

Section: Introductionmentioning

confidence: 99%

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Marfan syndrome – typical musculoskeletal abnormalities, rare occurrence in children

Żuber¹,

Solakiewicz²,

Turowska-Heydel³

et al. 2014

Reumatologia

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Słowa kluczowe: zespół Marfana, choroby układowe tkanki łącznej, mutacja fibryliny-1, diagnostyka. S t r e s z c z e n i eZespół Marfana (MFS) jest chorobą tkanki łącznej, genetycznie uwarunkowaną, dziedziczoną w sposób autosomalny dominujący. Przyczyną choroby jest mutacja w genie fibryliny 1 (FBN1) znajdują-cym się na chromosomie 15, w wyniku aktywowania transformują-cego czynnika wzrostu β. Ponieważ MFS dotyczy większości narzą-dów i tkanek, pacjenci z tą chorobą stanowią niejednorodną grupę pod względem objawów klinicznych. W przebiegu MFS dochodzi do zmian i zaburzeń funkcji w obrębie układu mięśniowo-szkieletowego, narządu wzroku, serca i naczyń krwionośnych. Z uwagi na duże ryzyko wystąpienia powikłań sercowo-naczyniowych oraz ocznych, które są wynikiem stopniowego poszerzania aorty i ektopii soczewki, rokowanie w tej chorobie może być niepomyślne. W artykule przedstawiono przypadek zespołu Marfana z typowymi zaburzeniami układu mięśniowo-szkieletowego.

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Genetic Dissection of Marfan Syndrome and Related Connective Tissue Disorders: An Update 2012

Cited by 41 publications

References 141 publications

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

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

A Novel Fibrillin 1 Gene Mutation Leading to Marfan Syndrome with Minimal Cardiac Features

Marfan syndrome – typical musculoskeletal abnormalities, rare occurrence in children

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