Search for correlations between <i>FBN1</i> genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome

Rand‐Hendriksen, Svend; Tjeldhorn, Lena; Lundby, Rigmor; Semb, Svein Ove; Offstad, Jon; Andersen, Kai; Geiran, Odd; Paus, Benedicte

doi:10.1002/ajmg.a.31759

Cited by 32 publications

(49 citation statements)

References 38 publications

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“…[15][16][17] Our data suggest that this is not the case, specifically our observation that the vast majority of early aortic events occurred in patients with a truncating (or splicing) variant. Therefore, instead of having a milder course of disease, as is commonly thought, patients with truncating or splicing variants may have a less clinically apparent MFS phenotype as compared with patients with missense variants, which also has been previously suggested by Schrijver et al 10 For example, one patient in our cohort was a 24-year-old woman with a splicing variant (predicted to result in protein truncation; c.4337-2A>G; Table 3) who died from an aortic dissection shortly after giving birth.…”

Section: Discussionmentioning

confidence: 71%

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: Discussionmentioning

confidence: 71%

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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“…All the patients were assessed for all subsets of the Ghent criteria (Ghent 1) 1 by the same group of physicians. [10][11][12][13][14][15][16] For assessing fulfilment of the major cardiovascular criterion in the Ghent nosology, information was collected about previous surgery related to dilatation or dissection of the ascending aorta, and electrocardiographic evidence of dilatation of the ascending aorta was recorded. 1,13 The assessment of fulfilment of the Ghent criteria included sequencing of the entire coding region of the gene FBN1 and searching for large deletions or duplications.…”

Section: Study Populationmentioning

confidence: 99%

“…1,13 The assessment of fulfilment of the Ghent criteria included sequencing of the entire coding region of the gene FBN1 and searching for large deletions or duplications. 12,13,16 mR or ct of the aorta and pulmonary artery This study was a substudy of the Norwegian Marfan Study. In this substudy, MR imaging of the aorta and the pulmonary artery was performed except when MR was contraindicated, in which case CT images were obtained instead.…”

Section: Study Populationmentioning

confidence: 99%

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The pulmonary artery in patients with Marfan syndrome: a cross-sectional study

Lundby

Rand‐Hendriksen

Hald

et al. 2012

Genetics in Medicine

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Purpose:The objectives of this study were to establish the prevalence of pulmonary artery dilatation in Marfan syndrome using modern radiological methods and to correlate the diameter of the vessel with aortic disease. methods: Magnetic resonance or computed tomography imaging of the pulmonary artery and aorta was performed in 87 patients with proven Marfan syndrome. Diameters of the root and trunk of the pulmonary artery and of the aortic root were measured perpendicular to the long axes of the vessels. Pulmonary artery diameters were measured on axial images, and aortic diameters were assessed on oblique sagittal images. Results:As compared with normal values in the literature, 47 of the 87 patients (54%) had widening of the trunk of the pulmonary artery (≥30 mm). Of these 47, 15% had no sign of disease of the ascending aorta. The mean (SD) ratio between the diameters of the root and trunk of the pulmonary artery was 1.18 (0.155). Multivariate analysis showed that surgery of the ascending aorta and high body surface area were associated with dilatation of the trunk of the pulmonary artery.conclusions: Pulmonary artery dilatation is present in a high proportion of patients with Marfan syndrome as assessed using cutoff values based on measurements in the normal population. Severe disease of the ascending aorta correlates significantly with pulmonary artery trunk dilatation in patients with Marfan syndrome. 2012:14(11):922-927 Genet Med

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“…The assessment included sequencing of the entire coding region of the gene FBN1 and a search for large deletions or duplications. 22,23 …”

Section: Study Populationmentioning

confidence: 99%

Dural Ectasia in Marfan Syndrome: A Case Control Study

Lundby

Rand‐Hendriksen²,

Hald³

et al. 2009

AJNR Am J Neuroradiol

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Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome

Cited by 32 publications

References 38 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

The pulmonary artery in patients with Marfan syndrome: a cross-sectional study

Dural Ectasia in Marfan Syndrome: A Case Control Study

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