UvA-DARE ( Digital Academic Repository ) Marfan syndrome : Getting to the root of the problem

AIMS 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. METHODS AND RESULTS 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). CONCLUSION Marfan syndrome patients with an HI mutation are at increased risk for cardiovascular death and aortic dissection compared with patients with a DN mutation.

[1]  F. Setacci,et al.  The risk for type B aortic dissection in Marfan syndrome. , 2015, The Journal of cardiovascular surgery.

[2]  A. Zwinderman,et al.  Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome , 2015, Circulation. Cardiovascular genetics.

[3]  M. Gross,et al.  The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele. , 2015, Human molecular genetics.

[4]  L. Baudhuin,et al.  Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events , 2014, Genetics in Medicine.

[5]  A. Zwinderman,et al.  Diagnosis and genetics of Marfan syndrome , 2014 .

[6]  V. Aboyans,et al.  [2014 ESC Guidelines on the diagnosis and treatment of aortic diseases]. , 2014, Kardiologia polska.

[7]  P. Robinson,et al.  Observational Cohort Study of Ventricular Arrhythmia in Adults with Marfan Syndrome Caused by FBN1 Mutations , 2013, PloS one.

[8]  P. Robinson,et al.  FBN1 gene mutation characteristics and clinical features for the prediction of mitral valve disease progression. , 2013, International Journal of Cardiology.

[9]  G. Pals,et al.  The clinical spectrum of complete FBN1 allele deletions , 2011, European Journal of Human Genetics.

[10]  Helmut Baumgartner,et al.  ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). , 2010, European heart journal.

[11]  Laurence Faivre,et al.  The revised Ghent nosology for the Marfan syndrome , 2010, Journal of Medical Genetics.

[12]  Marc K. Halushka,et al.  Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome , 2006, Science.

[13]  B. Mulder,et al.  CONCOR, an initiative towards a national registry and DNA-bank of patients with congenital heart disease in the Netherlands: Rationale, design, and first results , 2005, European Journal of Epidemiology.

[14]  Jessica Geubtner,et al.  Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. , 2004, The Journal of clinical investigation.

[15]  Gabor Matyas,et al.  Update of the UMD‐FBN1 mutation database and creation of an FBN1 polymorphism database , 2003, Human mutation.

[16]  Uta Francke,et al.  Premature termination mutations in FBN1: distinct effects on differential allelic expression and on protein and clinical phenotypes. , 2002, American journal of human genetics.

[17]  U. Francke,et al.  Multi-exon deletions of the FBN1 gene in Marfan syndrome , 2001, BMC Medical Genetics.

[18]  U. Francke,et al.  Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. , 1999, American journal of human genetics.

[19]  R. Hennekam,et al.  Survival and complication free survival in Marfan’s syndrome: implications of current guidelines , 1999, Heart.

[20]  R E Pyeritz,et al.  Revised diagnostic criteria for the Marfan syndrome. , 1996, American journal of medical genetics.

[21]  P. Byers,et al.  Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene. , 1996, American journal of medical genetics.

[22]  U. Francke,et al.  Fibrillin abnormalities and prognosis in Marfan syndrome and related disorders. , 1995, American journal of medical genetics.

[23]  H. Dietz,et al.  Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. , 1993, Genomics.

[24]  Ada Hamosh,et al.  Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene , 1991, Nature.