The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193FBN1 mutations

Abstract

Mutations in the FBN1 gene have been characterised in patients affected by Marfan syndrome and Marfan-related disorders. Starting with genomic DNA, we analysed the FBN1 gene using PCR, SSCP and/or dHPLC analysis, and automatic sequencing of abnormal bands/peaks, in a consecutive series of 508 patients, of which 22 were children less than 5 years old. Our results are comparable with those reported by other groups. In this study we observed 193 mutations, 126 of which previously unreported. A total of 331 relatives (including 51 infants) of 120 probands for whom a family mutation had been identified here or elsewhere, were tested for the presence of that particular mutation. In addition, 4 prenatal tests were carried out. The identification of a mutation allows for early diagnosis, prognosis, genetic counselling, preventive management of carriers and reassurance for unaffected relatives. The importance of knowing in advance the location of the putative family mutation is highlighted by its straightforward application to prenatal and postnatal screening. © 2007 Wiley-Liss, Inc. KEY WORDS: Marfan, MFS, fibrillin-1, FBN1, ectopia lentis, ascending aortic aneurysm INTRODUCTIONMarfan syndrome (MFS; MIM# 154700) is an autosomal dominantly inherited disorder, characterised by highly variable phenotypic manifestations, mainly in skeletal, ocular, cardiovascular and central nervous systems. Other systems can be involved, mainly lungs and skin, but usually with less specific manifestations (De Paepe et al., 1996;Pyeritz and Dietz, 2002).According to the current Gent nosology, a clinical diagnosis of Marfan syndrome requires major criteria (more severe clinical signs) affecting at least two systems and the involvement of a third system with minor criteria (milder clinical signs) (De Paepe et al., 1996).Between 20% and 30% of cases are sporadic, representing new mutations. The incidence of this pleiotropic disease has been reported at 1 in 9,802 in the UK, with a prevalence of 1 in 14,217 (Gray et al., 1994). It is suggested that figures are not influenced by ethnicity or gender (Pyeritz and Dietz, 2002).MFS results from mutations in the FBN1 gene (MIM# 134797), which is more than 200 kb long, made up of 652 Comeglio et al.exons, and has a transcript of approximately 9.7 kb, with a coding region of about 8.6 kb Corson et al., 1993;Biery et al., 1999). FBN1 encodes for a ubiquitous connective tissue microfibrillar protein named fibrillin-1, and is located on chromosome 15q21.1 (Lee et al., 1991;Magenis et al., 1991). Fibrillin-1 is mainly composed of cysteine-rich EGF-like domains, most of them with a consensus sequence for calcium binding (cbEGF-like). Interspersed among these domains are TGFBP domains and other fibrillin-1 specific cysteine-rich hybrid motifs (Pereira et al., 1993). To date, identified mutations are distributed throughout the FBN1 gene, with limited evidence of correlation between the regions of the mutations and the clinical phenotype, reflecting sequence-specific roles in secretion, assembly and extra c...

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

“…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. Furthermore, our data represent a mixture of ethnicities and therefore may unknowingly create a bias because of the potential for the presence of ethnicity-based differences in frequency of mutation type.…”

“…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.…”

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

“…The percentage of missense, splice sites, nonsense mutations, insertions/ duplications, and deletions are roughly comparable with earlier reported mutations. 11,28,29 A slight decrease in deletion mutations to the advantage of point mutations, and particularly nonsense mutations, is observed. These mutations are, as earlier described mutations, spread along the FBN1 gene without specific clustering, sign of a mutation hotspot (Supplementary Table 7).…”

Marfan syndrome masked by Down syndrome?

“…The mutation (IVS 11+5G>A) has been described before in other studies. 5,12 In at least one case, the mutation caused an incomplete MFS. 12 This is consistent with the incomplete MFS in the patient and her father.…”

“…4 Mutations in this gene have also been reported in Marfan-related diseases such as ectopia lentis syndrome and familial ascending aortic aneurysms. 5 In 10% of the cases that fulfil the criteria of MFS, no mutation in the FBN1 gene is identified. Mutations in the transforming growth factor-beta receptor 2 (TGFBR2) on chromosome 3 and TGFBR1 on chromosome 9 have been linked to the Marfan phenotype in some of these patients.…”