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Twelve novel FBN1 mutations in Marfan syndrome and Marfan related phenotypes test the feasibility of FBN1 mutation testing in clinical practice
  1. D J Halliday1,
  2. S Hutchinson2,
  3. L Lonie3,
  4. J A Hurst1,
  5. H Firth4,
  6. P A Handford2,
  7. P Wordsworth3
  1. 1Department of Clinical Genetics, The Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK
  2. 2Division of Molecular and Cellular Biochemistry, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
  3. 3Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
  4. 4Department of Medical Genetics, Cambridge University, Cambridge CB2 2QQ, UK
  1. Correspondence to:
 Dr D J Halliday, Department of Clinical Genetics, The Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK;

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Marfan syndrome (MFS) is one of the major heritable disorders of connective tissue with a prevalence of between 1 in 5-10 000.1,2 It is characterised by features in the cardiovascular, ocular, and musculoskeletal systems and the Ghent criteria form a useful framework for its diagnosis.3 Mutations in FBN1 encoding the extracellular matrix protein fibrillin-1 classically cause MFS.4 Fibrillin-1, comprising multiple repeating subunits, of which the most common is the calcium binding epidermal growth factor (cbEGF) domain, is a key component of 10-12 nm microfibrils.5

Mutation detection has not been performed routinely in MFS because of the size and complexity of FBN1, which contains 65 exons extending over 200 kb of genomic DNA.5,6 Mutations are nearly always specific to each family and to date ∼300 mutations have been reported.7–10FBN1 mutations have been found in 20-80% of patients with MFS depending upon the clinical selection of patients and the mutation detection method used.11–17FBN1 mutations have been reported in a wide range of phenotypes in the Marfan spectrum1; neonatal MFS is associated with some FBN1 mutations in exons 24-3218; mutations of various types throughout FBN1 have been associated with classical MFS8; and FBN1 mutations have also been reported in many of the non-classical Marfan related phenotypes.1 The Ghent criteria propose that an FBN1 mutation is only of help diagnostically if it has been previously found in a person who independently meets the criteria for diagnosis of MFS.3

Other than mutations causing neonatal MFS, which occur in exons 24-32, correlation between genotype and phenotype is poor. The majority of patients with cysteine substitutions have classical MFS, and cysteine substitutions in exons 26-32 appear to be associated with classical disease manifesting early in life. …

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