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FBN1

Alias

ACMICD; ECTOL1; FBN; GPHYSD2; MASS; MFLS; MFS1; OCTD; SGS; SSKS; WMS; WMS2

Associated disorders

The FBN1 gene is associated with autosomal dominant Marfan syndrome (MedGen UID: 44287), MASS syndrome (MedGen UID: 346932), thoracic aortic aneurysms and dissections (TAAD) (MedGen UID: 468423), isolated ectopia lentis (MedGen UID: 342716), and stiff skin syndrome (MedGen UID: 348877). Other FBN1-related conditions have been reported (OMIM: 134797).

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FBN1

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Pathogenic FBN1 variants are associated with 70%-93% of clinical cases of Marfan syndrome and are a rare cause of TAAD.

The FBN1 gene encodes fibrillin-1, a large, extracellular matrix glycoprotein, which is a major structural component of microfibrils. Microfibrils provide a scaffold for elastin deposition for the force-bearing structural support in connective tissue throughout the body.

OMIM: 134797

Clinical condition

The FBN1 gene is associated with autosomal dominant Marfan syndrome (MFS; MedGen UID: 44287), MASS syndrome (MedGen UID: 346932), thoracic aortic aneurysms and dissections (MedGen UID: 468423), isolated ectopia lentis (MedGen UID: 342716), and stiff skin syndrome (MedGen UID: 348877). Other FBN1-related conditions have been reported (OMIM: 134797).

FBN1-related conditions are a spectrum of connective tissue disorders primarily involving the cardiovascular, skeletal, pulmonary, and ocular systems.

  • Individuals meeting the revised Ghent criteria are clinically diagnosed with MFS and present with a combination of aortic root aneurysm, ectopia lentis, and systemic symptoms, including skeletal, dural, skin, and lung features (PMID: 20591885).
  • MASS syndrome refers to individuals with the clinical features of mitral valve prolapse, aortic root dilation, skeletal abnormalities (long limbs, pectus deformity), and skin conditions (striae atrophicae; PMID: 2739055).
  • Thoracic aortic aneurysms and dissections are clinically characterized by dilatation or dissection of the aortic root and ascending or descending thoracic aorta in the absence of major criteria for MFS (PMID: 22237449).
  • Isolated ectopia lentis is characterized by dislocation of the lens of the eye with or without skeletal features and without aortic dilation. Under the current Ghent nosology, ectopia lentis with an FBN1 pathogenic variant is considered MFS (PMID: 24635535, 20591885).
  • Stiff skin syndrome is characterized by congenitally hard, thick skin, usually covering the entire body, that limits joint mobility and causes flexion contractures. Individuals may also have focal lipodystrophy and muscle weakness (PMID: 20375004).

Gene information
The FBN1 gene encodes the fibrillin-1 protein, a large glycoprotein that is part of the extracellular matrix structures called microfibrils (PMID: 3536967, 1852207). Microfibrils are ubiquitous elements of connective tissue and perform tissue-specific functions, including elasticity in skin, ligaments, and blood vessels, and more rigid structural support in bones, nerves, muscles, and lenses. Microfibrils have also been shown to sequester the transforming growth factor beta and modulate its activity contributing to organ growth and repair (PMID: 27437668).

Inheritance
FBN1-related conditions exhibit autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing that variant on to their offspring. FBN1 pathogenic variants exhibit high penetrance but variable expression, meaning that almost all individuals who inherit a disease-causing variant will develop some feature of these disorders, but those features vary among individuals (PMID: 10774478, 17657824). Virtually every individual with a pathogenic variant in FBN1will develop aortic disease at some point in their lifetime (PMID: 18310266).

Approximately 25% of individuals with MFS have a de novo pathogenic variant, and gonadal mosaicism has also been reported (PMID: 27437668).

Management
Regardless of current clinical presentation, counseling regarding the risk for more severe features in individuals and their offspring is recommended (PMID: 20591885). The following surveillance and management options are also suggested.

Cardiovascular
  • Echocardiogram at the time of diagnosis is recommended to determine baseline aortic root and ascending aortic measurements, and six months later to determine the rate of enlargement (PMID: 20359588). Surveillance includes annual aortic imaging if the aorta is stable, and more frequently if the aorta is 4.5 cm or greater (in an adult), if aortic size is increasing rapidly (≥0.5 cm/year), or if concerns arise regarding heart or valve function (PMID: 20359588, 20591885).
  • Beta-blocking medication is recommended to reduce the hemodynamic stress on the aorta (PMID: 20591885).
  • Acute ascending aortic dissection is treated by emergency surgical repair (PMID: 20591885).
  • Prophylactic surgical repair of the aorta is considered when the aortic diameter approaches 5.0 cm, with consideration of family history of early dissection, rate of aortic growth, and valvular and cardiac health (PMID: 20359588, 20591885). It is reasonable to consider prophylactic ascending and aortic root replacement in women considering pregnancy with an aorta of 4.0 cm or greater. All women with MFS should have cardiovascular monitoring at increased frequency during and after pregnancy (PMID: 20359588, 20591885).
  • Regular imaging of the entire aorta after aortic root surgery is recommended in adulthood (PMID:20591885).
  • Mitral valve repair or replacement is advised for severe regurgitation with progressive left ventricular dilation or dysfunction, especially in patients undergoing aortic valve-sparing root replacement (PMID: 20591885).
Ophthalmologic

Annual ophthalmologic evaluation is recommended for the detection of ectopia lentis, cataracts, glaucoma, and retinal detachment with aggressive refraction (to prevent amblyopia; PMID: 20591885).

Orthopedic

Referral to orthopedist is recommended for standard management of skeletal manifestations, including scoliosis and pectus deformity (PMID: 20591885).

Activity modification

Contact sports, exercise exhaustion, and isometric activities involving a Valsalva maneuver should be avoided. Moderate exercise is appropriate and encouraged in most individuals with FBN1-related conditions (PMID: 20591885).

Genetic counseling and testing

Genetic counseling and testing are recommended for affected individuals and at-risk family members to explain testing, interpret genetic test results, and arrange familial testing (PMID: 20359588).

Review date: February 2018

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
FBN1 NM_000138.4