Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome or Related Phenotypes and FBN1 Mutations: An International Study

Abstract

Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

“…Only few examples exist in which the corresponding phenotype could reliably be predicted from the mutations. 48 Recently, network modeling has been introduced in order to explain how specific mutations may lead to distinct phenotypes. 44,46,[49][50][51] In a specific network model called the edgetic perturbation model, a mutation is considered to alter molecular interactions either due to edgetic perturbations or due to node removal ( Figure 4).…”

The clinical spectrum of complete FBN1 allele deletions

“…Other mutations are frameshift, splice-site and nonsense mutations. 11 Deletions of single and multiple exons can be detected using appropriate methods, such as multiplex ligation-dependent probe amplification (MLPA), cDNA or Southern blot analyses. Most of these deletions are associated with a severe or classical Marfan phenotype.…”

Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene

“…7 -11 The detection of a mutation, thus long, difficult and costly, cannot be offered to all suspected Marfan patients even in countries, in which state funding is available for wide molecular diagnosis. Therefore, we recommended earlier 11 that FBN1 molecular analysis be performed in newly suspected MFS when two systems are involved with at least one major diagnostic criterion (as described in the Ghent nosology). In patients found to harbor a mutation, this recommendation allows for diagnosis of MFS.…”

“…However, FBN1 molecular analysis must also be performed in the illdefined group of type I fibrillinopathies, as they carry an increased risk of cardiovascular disease. 11 Therefore, the question arises of when to perform FBN1 gene mutation screening in patients with incomplete phenotypes. To answer this question, we first compiled the molecular data obtained from the screening of the FBN1 gene in 586 probands, which had been addressed to our laboratory for molecular diagnosis.…”