title: Genotype impacts survival in Marfan syndrome.
abstract: The aorta in Marfan syndrome (MFS) patients is variably affected. We investigated the assumed genotype-effect on protein production as a risk factor for a severe aortic phenotype in adult MFS patients.
  
  
  
  We collected clinical and genetic data from all 570 adults with MFS who had been included in the Dutch CONgenital CORvitia registry since the start in 2001. Mean age was 36.5 ± 13.5 years (51.2% male, 28.9% prior aortic surgery, 8.2% prior aortic dissection). Patients were prospectively followed for a mean duration of 8.2 ± 3.1 years. Men had more frequently aortic surgery at baseline (38.0 vs. 19.4%, P < 0.001) and during follow-up (24.0 vs. 15.1%, P = 0.008) compared with women. After 10-year follow-up cumulative survival was 93.8% and dissection-free survival was 84.2%. We found a pathogenic FBN1 mutation in 357 patients, of whom 146 patients (40.9%) were positive for a mutation causing haploinsufficiency (reduced fibrillin-1 protein) and 211 (59.1%) for a mutation leading to a DN effect (abnormal fibrillin-1 protein). Corrected for age, sex, and previous aortic complications, patients with a haploinsufficient (HI) mutation had a 2.5-fold increased risk for cardiovascular death (hazard ratio, HR: 2.5, 95% CI: 1.0-6.1, P = 0.049), a 2.4-fold increased risk for the combined endpoint comprising death and dissection (HR: 2.4, 95% CI: 1.4-4.2, P < 0.001) and a 1.6-fold increased risk for any aortic complication compared with patients with a DN mutation (HR: 1.6, 95% CI 1.1-2.3, P = 0.014).
  
  
  
  Marfan syndrome patients with an HI mutation are at increased risk for cardiovascular death and aortic dissection compared with patients with a DN mutation.
authors.affiliation: Department of Cardiology, Academic Medical Center Amsterdam, B2-240, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.|Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors.forename: Romy
authors.initials: R
authors.lastname: Franken
authors.affiliation: Department of Cardiology, Academic Medical Center Amsterdam, B2-240, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.|Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.|Department of Radiology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Groenink
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Vivian
authors.initials: V
authors.lastname: de Waard
authors.affiliation: Department of Cardiology, Academic Medical Center Amsterdam, B2-240, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Helena M A
authors.initials: HM
authors.lastname: Feenstra
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Scholte
authors.affiliation: Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Maarten P
authors.initials: MP
authors.lastname: van den Berg
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.affiliation: Department of Cardiology, st. Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Janneke
authors.initials: J
authors.lastname: Timmermans
authors.affiliation: Department of Cardiology, Academic Medical Center Amsterdam, B2-240, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands b.j.mulder@amc.uva.nl.|Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors.forename: Barbara J M
authors.initials: BJ
authors.lastname: Mulder
mesh_terms: D000328:Adult; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005838:Genotype; D006801:Humans; D008297:Male; D008382:Marfan Syndrome; D008840:Microfilament Proteins
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins
keywords: Aortic aneurysm; Aortic dissection; FBN1 mutation; Marfan syndrome; Survival