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Genotype–phenotype correlations in Marfan syndrome
  1. Benjamin J Landis1,
  2. Gruschen R Veldtman2,
  3. Stephanie M Ware1
  1. 1 Department of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Ringgold Standard Institution, Indianapolis, Indiana, USA
  2. 2 Adult Congenital Heart Disease Program, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  1. Correspondence to Prof Gruschen R Veldtman, Cincinnati Children's Hospital Medical Centre, Adult Congenital Heart Disease Program, Cincinnati, Ohio, 45229, USA; Gruschen.veldtman{at}cchmc.org

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Marfan syndrome (MFS) is an autosomal dominant connective-tissue disorder associated with abnormalities of the cardiovascular, ocular and musculoskeletal systems. Aortopathy, manifest as thoracic aortic aneurysm (TAA) and dissection, is the major cause of morbidity and mortality. Most individuals with MFS carry mutations in the gene FBN1. This gene encodes the extracellular matrix (ECM) protein fibrillin-1, which plays essential roles in the formation of microfibrils, organisation of ECM components and sequestration of growth factors such as transforming growth factor beta (TGFβ). Thus, mutations in FBN1 lead to deleterious biomechanical effects and aberrant signalling pathway activation within the aorta and other affected tissues.

Though autosomal dominant, MFS has wide phenotypic variability. For example, the age of onset, severity and rate of progression of TAA is currently unpredictable. These gaps in knowledge pose important limitations in clinical decision making with respect to timing of elective surgery, frequency of imaging follow-up, physical activity restriction and drug management. In their Heart paper, , Franken et al have undertaken the important task of investigating whether the specific subtype of FBN1 mutation could be used to predict the risk of TAA severity.1 The current study examined 290 patients with MFS and known FBN1 mutations followed at two specialist units, including Universitat Autonoma de Barcelona in Spain, and the Academic Medical Centre of Amsterdam, The Netherlands. The investigators tracked aortic diameter, aortic dilation rate and clinical endpoints of dissection and death from 2004 to 2015.

The pathogenesis of MFS

Mutations in FBN1 can cause (1) reduction in the fibrillin produced in the cell, that is, quantitative defects, (2) change the structure or stability of the protein, and/or (3) alter the ability of fibrillin to be exported to the ECM (figure 1) . Mutations in FBN1 that result in haploinsufficiency (HI) lead to reduced amounts of fibrillin, fewer microfibrils and increased activated TGFβ levels due …

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