Marfan Syndrome (FBN1) Sequencing and Deletion/Duplication

Use to confirm diagnosis of Marfan syndrome in individuals meeting consensus criteria

  • Testing for a known familial sequence variant by sequencing gene of interest. A copy of the family member’s test result documenting the familial gene variant is REQUIRED.
  • To determine if the variant(s) of interest are detectable by this assay, contact an ARUP genetic counselor at 800-242-2787.

See Related Tests

Marfan syndrome (MFS) is a connective tissue disorder that exhibits a high degree of clinical variability. Symptoms typically involve the cardiovascular, ocular, and skeletal systems. Early diagnosis is crucial for treatment of skeletal, orthopedic, and cardiovascular abnormalities to enable affected individuals to approach a normal lifespan. The diagnosis of MFS can be made based on established clinical criteria (see below). It 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

Diagnostic Criteria

A clinical diagnosis of MFS can be made in an individual without a family history based on the presence of either:

  • An FBN1 gene known pathogenic variant and either
    • Aortic root dilatation (z-score of ≥2.0)
      or
    • Ectopia lentis
  • Aortic root dilatation (z-score of ≥2.0) and either

A clinical diagnosis of MFS can be made in an individual with a family history based on the presence of any of the following:

  • Ectopia lentis
  • ≥7 points on the revised Ghent nosology scale
  • Aortic root dissection or dilatation (z-score ≥3.0 for those <20 years of age or ≥2.0 for those ≥20 years of age)
Revised Ghent Nosology Point Values for Specific Characteristics
Characteristics Point Value

Wrist AND thumb sign

3

Wrist OR thumb sign

1

Pectus carinatum

2

Pectus excavatum or chest asymmetry

1

Hindfoot deformity

2

Pes 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

3 of 5 characteristic facial features

1

Source: Loeys, 2010 

Genetics

Gene

FBN1

See the Phenotypes Associated With FBN1 Gene table.

Inheritance

Autosomal dominant; 25% of cases are de novo

Penetrance

High

Variants

Large gene deletions are causative for 5% of MFS, and large genomic deletions of regulatory elements have been reported in individuals with MFS or MFS spectrum disorders, including the MASS (mitral valve prolapse, aortic root dilation, skin striae, and skeletal features) phenotype. The following variants have associations with a particular syndrome or phenotype:

  • Pathogenic FBN1 variants in exons 24-32 generally cause a severe phenotype.
  • Pathogenic missense variants in fourth 8-cysteine domain (exon 38 of FBN1) cause stiff skin syndrome.
  • Heterozygous pathogenic variants in fifth 8-cysteine domain of FBN1 cause geleophysic dysplasia 2 and acromicric dysplasia.
  • Frameshift variants in exon 64 reported may cause lipodystrophy and progeroid facial appearance.

Test Interpretation

Methodology

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Sensitivity/Specificity

Clinical Sensitivity

Approximately 95-98% depending on accuracy of clinical diagnosis 

Analytic Sensitivity/Specificity

For massively parallel sequencing:

Variant Class Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region Analytic Specificity (NPA)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc Deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [Single exon]

>99.9

Exon-levelc Duplications

83.3 (56.4-96.4) [3 exons or larger]

>99.9

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA).

bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Results

Result Variant(s) Detected Clinical Significance

Positive

Pathogenic FBN1 variant detected

Confirms diagnosis of MFS or FBN1-related disorder in a symptomatic individual

Negative

No known pathogenic FBN1 variant detected

Reduces possibility of, but does not exclude, a diagnosis of MFS

Inconclusive

Variant of uncertain clinical significance detected

Unclear if variant is disease causing or benign

Limitations

  • A negative result does not exclude a diagnosis of MFS or other FBN1-related disorders.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the FBN1 gene
    • Regulatory region and deep intronic variants
    • Breakpoints of large deletions/duplications
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by MPS
    • Large duplications less than 3 exons in size
    • Noncoding transcripts
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
Phenotypes Associated With FBN1 Gene
OMIM Number Phenotype Inheritance

102370

Acromicric dysplasia

AD

129600

Ectopia lentis, familial

AD

614185

Geleophysic dysplasia

AD

616914

Marfan lipodystrophy syndrome

AD

154700

Marfan syndrome

AD

604308

MASS syndrome

AD

184900

Stiff skin syndrome

AD

608328

Weill-Marchesani syndrome 2

AD

References

Additional Resources