Marfan Syndrome

Preferred test to confirm diagnosis when MFS is strongly suspected by consensus criteria

Acceptable test to confirm diagnosis for individuals with clinical phenotype of MFS

Related Tests

Preferred panel for individuals with clinical phenotype of aortic or vascular aneurysm, dissection, or rupture if no single specific diagnosis is strongly suspected

Useful when a pathogenic familial variant identifiable by sequencing is known

Marfan syndrome (MFS) is a connective tissue disorder that exhibits a high degree of clinical variability. Clinical symptoms typically involve the cardiovascular, ocular, and skeletal systems. Early diagnosis is crucial for treatment of skeletal, orthopedic, and cardiovascular abnormalities. The diagnosis of MFS can be made or suspected based on established clinical criteria (see below). MFS is caused by pathogenic variants in the FBN1 gene; however, there is significant overlap of the clinical features with syndromes caused by pathogenic variants in other genes.

Disease Overview

Prevalence

1/5,000-10,000

Symptoms

  • A clinical diagnosis of MFS in an individual without a family history of MFS (when Shprintzen-Goldberg syndrome [SGS], Loeys-Dietz syndrome [LDS], and Ehlers-Danlos syndrome type IV [EDS IV] have been excluded) is based on the presence of any of the following:
    • Aortic root dilatation or dissection and ectopia lentis
    • Aortic root dilatation or dissection and pathogenic FBN1 variant
    • Ectopia lentis and an FBN1 gene variant previously reported to be associated with cardiovascular disease
    • Aortic root dilatation or dissection and at least seven points from the table below
    • Revised Ghent Nosology Point Values for Specific Characteristics
      Characteristics Point Valuea

      Wrist AND thumb sign 

      3

      Wrist OR thumb sign 

      1

      Pectus carinatum

      2

      Pectus excavatum or chest asymmetry

      1

      Hindfoot deformity

      2

      Plain des planus

      1

      Pneumothorax

      2

      Dural ectasia

      2

      Acetabular protrusion

      2

      Reduced upper segment-to-lower segment (US/LS) ratio AND increased arm span-to-height ratio AND no severe scoliosis

      1

      Scoliosis or thoracolumbar kyphosis

      1

      Reduced elbow extension

      1

      Skin striae

      1

      Myopia >3 diopters

      1

      Mitral valve prolapse (all types)

      1

      Characteristic facial features

      1

      aScore ≥7 indicates systemic involvement

      Source: Loeys, 2010 

  • A clinical diagnosis of MFS in an individual with a family history of MFS (when SGS, LDS, and EDS IV have been excluded) is based on the presence of any of the following:
    • Ectopia lentis
    • Systemic findings scoring seven points or higher (refer to table of point values, above)
    • Aortic root dilation or dissection
  • Other disorders associated with FBN1 gene variants:
    • Neonatal MFS: atrioventricular valve dysfunction, pulmonary emphysema, joint contractures, crumpled ears, and loose skin
    • MFS phenotype with severe congenital lipodystrophy and progeroid-like appearance
    • Mitral valve prolapse syndrome: mitral valve prolapse, pectus excavatum, scoliosis, mild arachnodactyly
    • Familial ectopia lentis: bilateral ectopia lentis, sometimes scoliosis
    • MASS syndrome: mitral valve prolapse, aortic enlargement, skin, skeletal findings
    • Weill-Marchesani syndrome type 2: ectopia lentis, brachydactyly, joint stiffness, short stature
    • SGS: craniosynostosis, arachnodactyly, brachycephaly, pectus deformities, scoliosis, mental retardation, rarely aortic root dilatation
    • Aortic aneurysm, ascending and dissection
    • Acromicric dysplasia
    • Geleophysic dysplasia type 2
    • Stiff skin syndrome

Genetics

Gene

FBN1

Inheritance

Autosomal dominant

  • 25% of cases are de novo

Penetrance

High variability; age dependent

Variants

  • The revised Ghent nosology defines causal FBN1 variants
  • Variants segregate with disease in MFS families  
  • Few genotype/phenotype correlations
  • MFS with FBN1 variants identified in exons 24-32 generally have a severe prognosis
  • Exon 64 frameshift variants reported in individuals with Marfan phenotype, generalized lipodystrophy, and progeroid facial appearance
  • Large genomic deletions of regulatory elements have been reported in individuals with MFS or MFS spectrum disorders, including MASS phenotype

Test Interpretation

Sensitivity/Specificity

  • Clinical sensitivity
    • Sequencing: ranges from ~70-93%; dependent on accuracy of clinical diagnosis  
    • Deletion/duplication analysis: ~5% 
  • Analytical sensitivity/specificity: 99%

Results

  • Positive: pathogenic FBN1 variant detected
    • Consistent with diagnosis of MFS or FBN1-related disorder in a symptomatic individual
  • Negative: no known pathogenic FBN1 variant detected
    • Reduces risk, but does not exclude the diagnosis of MFS
  • Inconclusive: variant of uncertain clinical significance may be detected
    • Unclear is variant is diseas causing or benign

Limitations

  • Not determined or evaluated:
    • Deep intronic and regulatory region variants
    • Large deletions/duplications of exon 40 may or may not be detected, depending on the location of breakpoints
    • Breakpoints of large FBN1 deletions/duplications
  • Variants in genes other than FBN1
  • Diagnostic errors can occur due to:
    • Rare sequence variations or repeat element insertions
    • Primer- or probe-site variants
  • Do not use for prenatal testing for an unknown FBN1 variant
    References