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

Abstract

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...

Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome

“…In addition, a study by Aoyama et al had already demonstrated in 1995 that mutations leading to a very low deposition of the fibrillin-1 protein (HI) were associated with shortened event-free survival and more severe cardiovascular complications 6. Moreover, among patients with Ghent-positive MFS, a higher frequency of HI- FBN1 mutations was found in patients with cardiovascular events (79%) versus patients without an event (48%, p=0.0039), even at a younger age, compared with patients with a DN- FBN1 mutation 5. Finally, we recently confirmed that patients with an HI- FBN1 mutation are at increased risk for hard clinical endpoints, including aortic dissection and death, compared with those with a DN- FBN1 mutation 15.…”

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

“…Most mutations are considered to act in a dominant negative way exemplified by missense mutations, or through haploinsufficiency due to nonsense-mediated mRNA decay (NMD) mostly caused by splice-site, frameshift, and nonsense mutations. Although some studies suggest higher probabilities of ectopia lentis in patients with cysteine substitutions 27) and aortic events with truncating/splicing variants, 28) further studies are needed to confirm these relationships.…”

Marfan Syndrome and Related Disorders: 25 Years of Gene Discovery

“…Cysteine-destroying or cysteine-creating mutations are commonly associated with ectopia lentis (Schrijver et al, 1999). Haploinsufficient mutations, on the other hand, more frequently correlate with aortic events at young ages as well as pectus carinatum, dural ectasia, and skin striae (Baudhuin et al, 2015;Franken et al, 2015). Additionally, the vast majority of the mutations in exons 24-32 are linked to either neonatal MFS or other severe marfanoid presentations (Tiecke et al, 2001).…”