Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies.

Eloisa Arbustini, Maurizia Grasso, Silvia Ansaldi, Clara Malattia, Andrea Pilotto, Emanuele Porcu, Eliana Disabella, Nicola Marziliano, Angela Pisani, Luca Lanzarini, Savina Mannarino, Daniela Larizza, Mario Mosconi, Elena Antoniazzi, M. Cristina Zoia, Giulia Meloni, Lorenzo Magrassi, Agnese Brega, Maria Francesca Bedeschi, Isabella TorrenteFrancesca Mari, Luigi Tavazzi

Research output: Contribution to journalArticlepeer-review

Abstract

Marfan Syndrome (MFS) is an autosomal dominant disorder of the connective tissue due to mutations of Fibrillin-1 gene (FBN1) in more than 90% of cases and Transforming Growth Factor-Beta-Receptor2 gene (TGFB2R) in a minority of cases. Genotyping is relevant for diagnosis and genotype-phenotype correlations. We describe the FBN1 genotypes and related phenotypes of 81 patients who were referred to our attention for MFS or Marfan-like phenotypes. Patients underwent multidisciplinary pertinent evaluation in the adult or paediatric setting, according to their age. The diagnosis relied on Ghent criteria. To optimise DHPLC analysis of the FBN1 gene, all coding regions of the gene were directly sequenced in 19 cases and 10 controls: heterozygous amplicons were used as true positives. DHPLC sensitivity was 100%. Then, DHPLC was used to screen 62 other cases. We identified 74 FBN1 mutations in 81 patients: 64 were novel and 17 known. Of the 81 mutations, 41 were missense (50.6%), 27, either nonsense or frameshift mutations and predicted a premature termination codon (PTC) (33%), 11 affected splice sites (13.6%), and two predicted in-frame deletions (2.5%). Most mutations (67.9%) occurred in cbEGF-like modules. Genotype was clinically relevant for early diagnosis and conclusion of the diagnostic work-up in patients with incomplete or atypical phenotypes.

Original languageEnglish
Pages (from-to)494
Number of pages1
JournalHuman Mutation
Volume26
Issue number5
Publication statusPublished - Nov 2005

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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