The clinical spectrum of complete FBN1 allele deletions

Hilhorst‐Hofstee, Yvonne; Hamel, B.C.J.; Verheij, Joanne; Rijlaarsdam, María; Mancini, Grazia M.S.; Cobben, Jan-Hein; Giroth, Cindy; Ruivenkamp, Claudia; Hansson, Kerstin; Timmermans, Janneke; Moll, Henriëtte A.; Breuning, Martijn H.; Pals, Gerard

doi:10.1038/ejhg.2010.174

Cited by 64 publications

(59 citation statements)

References 43 publications

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“…10,16,17 However, several others have stressed the importance of haploinsufficiency in the pathogenesis of MFS, as observed in mouse model studies and because of the identification of patients with classic MFS and full-gene deletions. 23,24 It was also observed that variable disease expression in patients with premature termination codon mutations appeared to correlate with variable expression of the normal FBN1 allele and not with variable rates of nonsense-mediated decay. 24 In recent years, it has come to light that the fibrillin-1-related mechanisms leading to MFS pathogenesis include not only its effect on extracellular matrix structure through microfibrillar formation and elastin association but also its effect on transforming growth factor (TGF)-β regulation and homeostasis.…”

Section: Discussionmentioning

confidence: 87%

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: 87%

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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“…Contrary to a premise put forth by Franken et al, 1 HI-type mutations (including entire FBN1 allele deletions) are not more likely to be associated with phenotypic homogeneity, but rather have proven capable of association with phenotypes ranging from particularly mild (even subdiagnostic) presentations without cardiovascular involvement in adulthood to classic MFS, although particularly severe pediatric disease has not been described. 21,23,24 Taken together, these data suggest tremendous overlap between phenotypes induced by DN-and HI-type FBN1 mutations, with a context-dependent potential for greater severity in the former.…”

Section: Phenotype-genotype Correlations In Mfsmentioning

confidence: 82%

Potential Phenotype–Genotype Correlation in Marfan Syndrome

Dietz

2015

Circ Cardiovasc Genet

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A recent emphasis on individualized medicine reflects a desire to transition currently prevailing evidence-based practices (What works best for the average patient?) to more informed and tailored approaches (What will work best for this patient or subgroup?). It has been both expected and realized that genotypic information will contribute prominently to this endeavor. In this issue of Circulation Cardiovascular Genetics, Franken et al 1 report that the angiotensin receptor blocker (ARB) losartan is particularly effective at suppressing aortic root aneurysm progression in patients with Marfan syndrome (MFS) that are heterozygous for mutations in the fibrillin-1 gene (FBN1) that create a premature termination codon, when compared with other mutation classes expected to express abnormal protein from the mutant allele. Given the intuitive importance of this finding, it is worth exploring its potential biological foundations, while also considering alternative explanations. Article see p 383 Proposed Pathogenesis of MFSMFS is an autosomal-dominant systemic disorder of connective tissue with prominent involvement of the ocular, skeletal, and cardiovascular systems, including a strong predisposition for eye lens dislocation (ectopia lentis) and myopia, long-bone overgrowth and other skeletal deformity, and progressive aortic root dilatation and tear (dissection), respectively. The condition is caused by heterozygous mutations in FBN1 that encodes the extracellular matrix protein fibrillin-1. Fibrillin-1 monomers aggregate to form complex extracellular structures called microfibrils and an extracellular deficiency of microfibrils is thought to be the sentinel event in MFS pathogenesis. Missense mutations are the most common type causing MFS, with particularly high frequency of substitutions that either destroy or create cysteine residues in repetitive epidermal growth factor-like or latent transforming growth factor-β (TGF-β)-binding protein-like domains that each have 6 or 8 obligate cysteines with predictable spacing, respectively, that are required for proper intradomain folding. The FBN1 mutational repertoire also includes all other types of mutations, including insertions/deletions (indels) or altered splicing events that alter the coding sequence but maintain the open reading frame and events that create a premature termination codon, including nonsense and frameshift mutations and out-of-frame perturbations of splicing. Finally, a small subset of patients with MFS show large deletions that remove most or all of the disrupted allele. Premature termination codon mutations in FBN1 that disrupt the open reading frame before the distal portion of the penultimate are expected and observed to induce instability and efficient clearance of the mutant mRNA through nonsense-mediated mRNA decay, effectively precluding the production of much (or any) abnormal fibrillin-1 protein. Cell lines and tissues from patients and mouse models with MFS show diminished matrix deposition of fibrillin-1, with levels <50% threshold predict...

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“…The 4.25-Mb deletion in patient 42 contained the FBN1 gene, explaining the observed Marfan phenotype. 22 Five out of forty-six (11%) patients with a two-breakpoint chromosome rearrangement had a cryptic imbalance related to their reciprocal translocation. No imbalances were found related to inversions (n¼6).…”

Section: Resultsmentioning

confidence: 99%