title: Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies.
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.
authors.affiliation: Cardiovascular Genetic Laboratory-Transplant Research Area-GISM (Interdisciplinary Group for Marfan Syndrome), IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy. e.arbustini@smatteo.pv.it
authors.forename: Eloisa
authors.initials: E
authors.lastname: Arbustini
authors.forename: Maurizia
authors.initials: M
authors.lastname: Grasso
authors.forename: Silvia
authors.initials: S
authors.lastname: Ansaldi
authors.forename: Clara
authors.initials: C
authors.lastname: Malattia
authors.forename: Andrea
authors.initials: A
authors.lastname: Pilotto
authors.forename: Emanuele
authors.initials: E
authors.lastname: Porcu
authors.forename: Eliana
authors.initials: E
authors.lastname: Disabella
authors.forename: Nicola
authors.initials: N
authors.lastname: Marziliano
authors.forename: Angela
authors.initials: A
authors.lastname: Pisani
authors.forename: Luca
authors.initials: L
authors.lastname: Lanzarini
authors.forename: Savina
authors.initials: S
authors.lastname: Mannarino
authors.forename: Daniela
authors.initials: D
authors.lastname: Larizza
authors.forename: Mario
authors.initials: M
authors.lastname: Mosconi
authors.forename: Elena
authors.initials: E
authors.lastname: Antoniazzi
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Zoia
authors.forename: Giulia
authors.initials: G
authors.lastname: Meloni
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Magrassi
authors.forename: Agnese
authors.initials: A
authors.lastname: Brega
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Bedeschi
authors.forename: Isabella
authors.initials: I
authors.lastname: Torrente
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
authors.forename: Luigi
authors.initials: L
authors.lastname: Tavazzi
mesh_terms: D000293:Adolescent; D000328:Adult; D020816:Amino Acid Motifs; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis / Q000235:genetics*; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines