Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype–phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy

Turner, Claire; Emery, Herschell S.; Collins, Amanda; Howarth, Rachel J; Yearwood, Catharina; Cross, Esther; Duncan, Philippa; Bunyan, Dave; Harvey, John F.; Foulds, Nicola

doi:10.1002/ajmg.a.32593

Cited by 36 publications

(26 citation statements)

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“…This includes missense, frame-shift, nonsense and splice-site mutations and indels including whole-exon or even whole-gene deletions (Faivre et al 2009;Turner et al 2009). This repertoire strongly suggests loss of function of the fibrillin-1 protein as the relevant mechanism; a prediction confirmed using mouse models .…”

Section: The Tgf-b Pathway In Marfan Syndromementioning

confidence: 99%

The Genetic Basis of Aortic Aneurysm

Lindsay

Dietz

2014

Cold Spring Harbor Perspectives in Medicine

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Gene identification in human aortic aneurysm conditions is proceeding at a rapid pace and the integration of pathogenesis-based management strategies in clinical practice is an emerging reality. Human genetic alterations causing aneurysm involve diverse gene products including constituents of the extracellular matrix, cell surface receptors, intracellular signaling molecules, and elements of the contractile cytoskeleton. Animal modeling experiments and human genetic discoveries have extensively implicated the transforming growth factor-b (TGF-b) cytokine-signaling cascade in aneurysm progression, but mechanistic links between many gene products remain obscure. This chapter will integrate human genetic alterations associated with aortic aneurysm with current basic research findings in an attempt to form a reconciling if not unifying model for hereditary aortic aneurysm.A mong the myriad blood vessels within the body, the large capacitance arteries adjacent to the heart are unique in structure, function, and in their capacity for derangement in disease states. The clear enrichment of involvement of the proximal ascending thoracic aorta, and more specifically the sinuses of Valsalva, in inherited forms of thoracic aortic aneurysm (TAA) has been historically attributed to the unique functional demands and hemodynamic environment of this aortic segment. The aorta is a relatively unique organ in that its critical functional components are located in the extracellular space, whereas the cellular components of the aorta may act primarily to support the development and homeostasis of the supporting matrix. Cardiovascular surgeons show this interesting biology in common surgical practice. Large aortic segments are routinely replaced entirely with synthetic materials such as Dacron, demonstrating the dispensability of aortic cellular components for minimal critical function (to serve as a conduit and distribution network for blood flow). Despite its seemingly simple nature, the aorta has evolved into a complex organ with spatial variation in structure. During cardiac systole, the proximal ascending aorta has the ability to accept pressure and volume loads (capacitance) and to transmit them distally during diastole through recoil (elastance) with the least loss of energy. These requirements are reflected by variation in the major compoEditors:

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Section: The Tgf-b Pathway In Marfan Syndromementioning

confidence: 99%

The Genetic Basis of Aortic Aneurysm

Lindsay

Dietz

2014

Cold Spring Harbor Perspectives in Medicine

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“…Mutations in the first 15 exons of FBN1 are infrequent but tend to be associated with ectopia lentis [Turner et al, 2009]. Missense mutations in exons 2-17 are associated with severe eye pathology [Jin et al, 2007;Evangelisti et al, 2010] or isolated ectopia lentis [Adès et al, 2004].…”

Section: Discussionmentioning

confidence: 99%

“…Clear genotype-phenotype correlations have been made between mutations in exons 24-32 and severe neonatal Marfan syndrome [Palz et al, 2000;Attanasio et al, 2008;Turner et al, 2009], and with increased risk for cardiovascular manifestations at a later age [Faivre et al, 2007]. Genotype-phenotype correlations are less strong for rare variants found in the C-terminal region of fibrillin, perhaps indicating the involvement of interacting proteins in disease pathogenesis.…”

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confidence: 98%

“…According to several reports [Palz et al, 2000;Comeglio et al, 2007], missense mutations within exons 59-65 present with a relatively mild Marfan phenotype, with a lower risk of aortic involvement. Turner et al [2009] reported a trend toward a lack of ectopia lentis. In contrast, other studies [Arbustini et al, 2005;Rand-Hendriksen et al, 2007] failed to associate missense mutations within this region with a milder cardiovascular phenotype.…”

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confidence: 99%

“…FBN1 is located on chromosome 15q21.1 and has 65 exons that encode a protein of 2,871 amino acids [Maslen et al, 1991;Corson et al, 1993;Pereira et al, 1993]. Rare DNA variants that alter single amino acid residues within the coding sequence of the protein (missense mutations) are the cause of 50-66% of cases of Marfan syndrome [Attanasio et al, 2008;Turner et al, 2009]. Though fewer than 15% of documented cases are the result of deletion/insertion mutations [Pepe et al, 2001;Turner et al, 2009], this proportion is expected to increase as high-throughput methodologies that detect these variants become more widespread.…”

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confidence: 99%

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The c.7409G>A (p.Cys2470Tyr) Variant of FBN1: Phenotypic Variability across Three Generations

Potter

Creighton

Armstrong³

et al. 2013

Mol Syndromol

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findings to date. These findings suggest that FBN1 C-terminal missense mutations may not confer the ophthalmological features of Marfan syndrome, but they also confer a more significant risk for cardiovascular pathology than that suggested by previous studies. Furthermore, clinical data from this family supports the previously reported association of dural ectasia with C-terminal mutations. Copyright © 2013 S. Karger AG, Basel Marfan syndrome is an autosomal dominant connective tissue disorder with an incidence of between 1 and 3 per 10,000 individuals [Gray et al., 1994;Ramirez et al., 2007]. The disease predominantly manifests in the cardiovascular, skeletal and ocular systems as well as in the dura mater. Prominent cardiovascular features include dilatation of the aorta and proximal pulmonary artery as well as prolapse of the mitral and tricuspid valves. Musculoskeletal manifestations include joint laxity, chest deformities and overgrowth of tubular bones. Myopia is common and lens displacement is thought to occur in over 60% of affected individuals throughout their lifetime [Maumenee, 1981;Dietz, 1993;Ammash et al., 2008;Datta Kanjilal and Datta, 2009]. The recently revised Ghent Key Words Cardiovascular phenotype · Diagnostic criteria · FBN1 · Marfan syndrome · Novel mutation Abstract Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin gene FBN1 , which encodes an extracellular matrix glycoprotein. Major features of Marfan syndrome occur in the ocular, cardiovascular, and skeletal systems as well as in the dura mater. Approximately 60% of known disease-causing mutations are missense mutations of single amino acid residues. Effects on the cardiovascular system are classically associated with mutations in exons 24-32 of the 65 FBN1 exons and many, though not all, reports associate missense mutations in exons 59-65 with a mild cardiovascular phenotype. Here we present 5 related individuals among whom a c.7409G>A (p.Cys2470Tyr) missense variant in exon 59 of FBN1 is associated with significant cardiovascular features. The index case also had an apparently de novo 46,XX,del(5)(q33.1q33.3) deletion on chromosome 5. This family demonstrates skeletal, dermatological and neurological features consistent with Marfan syndrome but lacks significant ophthalmological

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Ectopia lentis as the presenting and primary feature in Marfan syndrome

Zadeh

Bernstein

Niemi

et al. 2011

American J of Med Genetics Pt A

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Marfan syndrome (MFS) is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems. We report on eight patients, all presenting initially with bilateral ectopia lentis (EL) during early childhood. These individuals did not have systemic manifestations of MFS, and did not fulfill the revised Ghent diagnostic criteria. However, all patients had demonstratable, disease-causing missense mutations in the FBN1 gene. Based on molecular results, cardiovascular imaging was recommended and led to the identification of mild aortic root changes in seven of the eight patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta. The findings presented in this paper validate the necessity of FBN1 gene testing in all individuals presenting with isolated EL. As we observed, these individuals are at increased risk of cardiovascular complications. Furthermore, we also noted that the majority of our patient cohort's mutations occurred in the 5 0 portion of the FBN1 gene, and were found to affect highly conserved cysteine residues, which may indicate a possible genotype-phenotype correlation. We conclude that in patients with isolated features of EL, FBN1 mutation analysis is necessary to aid in providing prompt diagnosis, and to identify patients at risk for potentially life-threatening complications. Additionally, knowledge of the type and location of an FBN1 mutation may be useful in providing further clinical correlation regarding phenotypic progression and appropriate medical management.

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Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype–phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy

Cited by 36 publications

References 26 publications

The Genetic Basis of Aortic Aneurysm

The Genetic Basis of Aortic Aneurysm

The c.7409G>A (p.Cys2470Tyr) Variant of <b><i>FBN1</i></b>: Phenotypic Variability across Three Generations

Ectopia lentis as the presenting and primary feature in Marfan syndrome

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