title: 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.
authors: Centre de Génétique, Centre Hospitalier Universitaire, Dijon, France. laurence.faivre@chu-dijon.fr
authors: L
authors: L
authors: Faivre
authors: G
authors: G
authors: Collod-Beroud
authors: B L
authors: BL
authors: Loeys
authors: A
authors: A
authors: Child
authors: C
authors: C
authors: Binquet
authors: E
authors: E
authors: Gautier
authors: B
authors: B
authors: Callewaert
authors: E
authors: E
authors: Arbustini
authors: K
authors: K
authors: Mayer
authors: M
authors: M
authors: Arslan-Kirchner
authors: A
authors: A
authors: Kiotsekoglou
authors: P
authors: P
authors: Comeglio
authors: N
authors: N
authors: Marziliano
authors: H C
authors: HC
authors: Dietz
authors: D
authors: D
authors: Halliday
authors: C
authors: C
authors: Beroud
authors: C
authors: C
authors: Bonithon-Kopp
authors: M
authors: M
authors: Claustres
authors: C
authors: C
authors: Muti
authors: H
authors: H
authors: Plauchu
authors: P N
authors: PN
authors: Robinson
authors: L C
authors: LC
authors: Adès
authors: A
authors: A
authors: Biggin
authors: B
authors: B
authors: Benetts
authors: M
authors: M
authors: Brett
authors: K J
authors: KJ
authors: Holman
authors: J
authors: J
authors: De Backer
authors: P
authors: P
authors: Coucke
authors: U
authors: U
authors: Francke
authors: A
authors: A
authors: De Paepe
authors: G
authors: G
authors: Jondeau
authors: C
authors: C
authors: Boileau
mesh_terms: D000293:Adolescent; D000328:Adult; D004815:Epidermal Growth Factor / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis*; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D017434:Protein Structure, Tertiary / Q000235:genetics; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000235:genetics; D054392:Adipokines
chemical_list: D004815:Epidermal Growth Factor; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines
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