Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies

Arbustini, Eloisa; Grasso, Maurizia; Ansaldi, Silvia; Malattia, Clara; Pilotto, Andrea; Porcu, Emanuele; Disabella, Eliana; Marziliano, Nicola; Pisani, Angela; Lanzarini, Luca; Mannarino, Savina; Larizza, Daniela; Mosconi, Mario; Antoniazzi, Elena; Zoia, M. C.; Meloni, Giulia; Magrassi, Lorenzo; Brega, Agnese; Bedeschi, Maria Francesca; Torrente, Isabella; Mari, Francesca; Tavazzi, Luigi

doi:10.1002/humu.9377

Cited by 86 publications

(88 citation statements)

References 26 publications

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“…Moreover, we were likely not biased by having a skewed percentage of mutation type because the missense mutation frequency (53.3%) in our overall cohort was similar to that observed in previous studies (50-59%). 6,13,17 Furthermore, 18% of the patients in the cohort displayed mutations in exons 1-10, which is in agreement with previous works. 12,16 Another potential limitation to our study is that our data may have been biased when younger or older patients were included in the analyses because of lower and higher frequencies of cardiovascular events, respectively.…”

Section: Discussionsupporting

confidence: 92%

“…11 Others have not reported an association with truncating mutations or cysteine mutations and cardiovascular manifestations. 6,[12][13][14] One reason that others may not have observed an association is because of the way the data were analyzed, for example, lumping dilatation and dissection and/or mitral valve prolapse together, including in the analysis patients who are too young to manifest cardiovascular events, and/or including patients who were older and more likely to manifest cardiovascular events.…”

Section: Discussionmentioning

confidence: 99%

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Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events

Baudhuin

Kotzer

Lagerstedt

2015

Genetics in Medicine

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Original research article introduction FBN1 mutations are most commonly associated with Marfan syndrome (MFS), an autosomal dominant connective tissue disorder typically involving the ocular, skeletal, and cardiovascular systems; MFS less frequently involves the skin, integument, lung, muscle, and adipose tissue. Cardiovascular manifestations, which are the major cause of morbidity and early mortality in MFS, include aortic dilatation at the level of the sinus of Valsalva, predisposition for aortic dissection, mitral valve and tricuspid valve prolapse, and enlargement of the proximal pulmonary artery.In MFS, an age-dependent association with the occurrence of an aortic event (aortic dissection or prophylactic aortic surgery) has been demonstrated in 16% of 30-year-olds and 74% of 60-year-olds having an aortic event.1 A sex-dependent association has also been observed: aortic events occur at an earlier age in males than in females. 1Hundreds of mutations have been identified in FBN1-many of them unique to individual families. Missense mutations are the most common type of FBN1 mutation, the majority of which are cysteine substitutions. FBN1 mutations have been shown to occur across the gene with limited genotypephenotype correlations, with the exception of the association of early onset, severe (previously termed "neonatal") MFS and mutations in exons 24 through 32, as well as the association of ectopia lentis with missense mutations. A study investigating genotype-phenotype correlations with cardiovascular features did not observe significant differences with mutation type (e.g., frameshift versus missense) but did observe a higher probability of ascending aortic dilatation, aortic event, and mitral valve prolapse in patients with mutations altering a cysteine residue. 1The type of FBN1 mutation identified and its likelihood of being pathogenic are recognized as important factors when making a diagnosis of MFS and later clinical decisions. Some have argued that truncating and splicing mutations may be associated with a milder disease course. Accordingly, we evaluated 179 consecutive probands with FBN1 mutations to evaluate this important clinical issue. MAtEriALS And MEtHodS Study populationProband samples (n = 179) with a pathogenic or likely pathogenic FBN1 variant and detailed clinical information received over a 4.25-year period were included in this study. Each patient was examined by his or her referring physician. For Mayo Clinic patients, phenotypic information was extracted from the patients' electronic medical record. For patients external to the Mayo Clinic, phenotypic information was provided by the referring provider via a requisition form specific to FBN1, which included age, sex, suspected diagnosis, family history, and phenotypic features, including those related to the Ghent (2010 revised) nosology criteria. Purpose: Marfan syndrome is a systemic disorder that typically involves FBN1 mutations and cardiovascular manifestations. We investigated FBN1 genotype-phenotype correlations with aortic eve...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events

Baudhuin

Kotzer

Lagerstedt

2015

Genetics in Medicine

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“…In classical MFS the incidence of ectopia lentis was significantly higher in patients harboring cysteine substitutions in the cbEGF-like modules than in patients with premature termination codon (PTC) mutations (Arbustini et al 2005;Biggin et al 2004;Loeys et al 2004;Rommel et al 2005;Schrijver et al 2002). Furthermore, isolated or predominant ectopia lentis is frequently associated with cysteine substitutions Comeglio et al 2002), suggesting that cysteine residues may have a critical function in suspensory ligaments of the eyes, as previously described (Rommel et al 2005).…”

Section: Pathogenesis Of Marfan Syndromementioning

confidence: 63%

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

2006

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Marfan syndrome (MFS, OMIM #154700) is a hereditary connective tissue disorder, clinically presenting with cardinal features of skeletal, ocular, and cardiovascular systems. In classical MFS, changes in connective tissue integrity can be explained by defects in fibrillin-1, a major component of extracellular microfibrils. However, some of the clinical manifestations of MFS cannot be explained by mechanical properties alone. Recent studies manipulating mouse Fbn1 have provided new insights into the molecular pathogenesis of MFS. Dysregulation of transforming growth factor beta (TGFb) signaling in lung, mitral valve and aortic tissues has been implicated in mouse models of MFS. TGFBR2 and TGFBR1 mutations were identified in a subset of patients with MFS (MFS2, OMIM #154705) and other MFS-related disorders, including LoeysDietz syndrome (LDS, #OMIM 609192) and familial thoracic aortic aneurysms and dissections (TAAD2, #OMIM 608987). These data indicate that genetic heterogeneity exists in MFS and its related conditions and that regulation of TGFb signaling plays a significant role in these disorders.

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“…The exon -intron boundaries of the FBN1 gene had previously been screened using DHPLC. 11 The analysis documented the absence of mutations. The seven exons and flanking regions of the TGFBR2 were amplified using previously reported intron-specific primers, 8 with the exception of three amplicons (exons 1, 2 and 5) for which the two primers were newly designed using the Amplify 1.0 software:…”

Section: Dna Isolation and Pcrmentioning

confidence: 99%

Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects

Disabella¹,

Grasso²,

Marziliano³

et al. 2005

Eur J Hum Genet

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TGF-b-receptor 2 (TGFBR2) gene defects have been recently associated with Marfan syndrome (MFS) with prominent cardio-skeletal phenotype in patients with negative fibrillin-1 (FBN1) gene screening. Four mutations have been identified to date in five unrelated families. We screened TGFBR2 gene by direct automated sequencing in two adult patients diagnosed with MFS according to Ghent criteria, and in one girl clinically suspected as affected on the basis of a major cardiovascular criterion and skeletal involvement, all proven not to carry mutations in the exon -intron boundaries of FBN1 gene. We identified two novel and one known TGFBR2 gene mutations in the three unrelated probands. The D446N was identified in a 4-year-old girl with de novo disease characterized by severe cardiovascular disease and skeletal involvement. The M425V and R460H mutations were identified in two familial, autosomal dominant MFSs, both characterized by major cardio-skeletal signs and absence of major ocular signs. The mutation R460H has been recently reported in a family with thoracic aortic aneurysms and dissection. The three mutations are absent in 192 controls and affect evolutionarily conserved residues of the serine/ threonine kinase domain (exon 5). Our data support the recently reported association between TGFBR2 gene and MFS without major ocular signs (MFS2). The number of genotyped cases however is too low to confirm that major ocular signs are characteristically absent in MFS2. Accordingly, all patients proven or suspected to be affected by MFS with negative FBN1 gene screening could benefit from rapid investigation of the TGFBR2 gene.

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Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies

Cited by 86 publications

References 26 publications

Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events

Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects

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