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Test Catalog

Test ID: FBN1B    
FBN1 Full Gene Sequence, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Aiding in the diagnosis of:

-FBN1-associated Marfan syndrome

-Autosomal dominant ectopia lentis

-Isolated ascending aortic aneurysm and dissection

-Isolated skeletal features of Marfan syndrome

-MASS phenotype (mitral valve prolapse, aortic diameter increased, stretch marks, skeletal features of MFS)-Shprintzen-Goldberg syndrome

-Autosomal dominant Weill-Marchesani syndrome

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test uses next-generation sequencing (NGS) to evaluate for the presence of FBN1 variants associated with Marfan syndrome (MFS) or other FBN1-associated conditions. Additionally, NGS is used to test for the presence of large deletions and duplications.

 

Prior Authorization is available for this assay; see Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Fibrillin-1 is a 320-kD cysteine-rich glycoprotein found in the extracellular matrix. Monomers of fibrillin-1 associate to form microfibrils that provide mechanical stability and elastic properties to connective tissues. Fibrillin-1 is encoded by the FBN1 gene, which contains 65 exons and is located at chromosome 15q21.

 

Pathogenic FBN1 variants are most commonly associated with Marfan syndrome (MFS), an autosomal dominant connective tissue disorder involving the ocular, skeletal, and cardiovascular systems. Ocular MFS manifestations most commonly include myopia and lens displacement. Skeletal manifestations can include arachnodactyly (abnormally long and slender fingers and toes), dolichostenomelia (long limbs), pectus (chest wall) deformity, and scoliosis. Cardiovascular manifestations, which are the major cause of early morbidity and mortality in MFS, include aortic aneurysm and dissection, as well as mitral valve and tricuspid valve prolapse. There is significant inter- and intrafamilial variability in the MFS phenotype.

 

Pathogenic FBN1 variants have also been reported in several other rare phenotypes with variable overlap with classic MFS. In some cases, MFS may present in the neonatal period with severe, rapidly progressive disease (previously termed "neonatal Marfan syndrome"). Other FBN1-associated conditions include autosomal dominant ectopia lentis (displacement of the lens of the eye), familial thoracic aortic aneurysm and dissection, isolated skeletal features of MFS, MASS phenotype (mitral valve prolapse, aortic diameter increased, stretch marks, skeletal features of MFS), Shprintzen-Goldberg syndrome (Marfanoid-craniosynostosis; premature ossification and closure of sutures of the skull), and autosomal dominant Weill-Marchesani syndrome (short stature, short fingers, ectopia lentis).

 

Hundreds of pathogenic variants have been identified in FBN1, many of them unique to individual families. There is a wide range of variability, including intrafamilial variability, in expressivity among pathogenic FBN1 variants. Approximately two-thirds of pathogenic FBN1 variants are missense changes, with the majority of these being cysteine substitutions. Approximately 25% to 33% of pathogenic FBN1 variants are de novo, in which an individual has no family history of disease. Pathogenic FBN1 variants have been shown to occur across the gene. Some genotype-phenotype correlations have been observed, including the association with truncating and splicing variants with risk for aortic dissection, cysteine-based variants, and ectopia lentis, and severe, early onset MFS and variants in exons 24 through 32.

 

Marfan syndrome has significant clinical overlap with a condition called Loeys-Dietz syndrome (LDS); however, the vascular phenotype of LDS can be more severe, and LDS is caused by pathogenic variants in different genes (TGFBR1, TGFBR2, SMAD3, and TGFB2). When the diagnosis of MFS, LDS, or a related disorder is suspected, the use of genetic testing is important to verify the diagnosis and provide appropriate clinical management. Confirmation of the genetic diagnosis also allows for preconception, prenatal, and family counseling.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline.

 

Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

 

Unless reported or predicted to impact splicing, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Absence of a pathogenic variant does not preclude the diagnosis of Marfan syndrome or other FBN1-associated condition unless a specific pathogenic variant has already been identified in an affected family member.

 

Clinical Correlations:

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete. If testing was performed because of a family history of Marfan syndrome or a related disorder, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual would allow for more informative testing of at risk individuals.

 

Technical Limitations:  

Next-generation sequencing may not detect all types of genetic variants. Additionally, rare polymorphisms may be present that could lead to false-negative or false-positive results. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. Please contact a genetic counselor, call 800-533-1710 to discuss alternative testing methods. If the patient has had an allogeneic blood or marrow transplant or a recent (ie, <6 weeks from time of sample collection) heterologous blood transfusion these results may be inaccurate due to the presence of donor DNA.

 

Reclassification of variants policy:

At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

 

Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of the patient's results.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Baudhuin LM, Kotzer KE, Lagerstedt SA: Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events. Genet Med 2015 Mar;17(3):177-187, doi:10.1038/gim.2014.91

2. Baudhuin LM, Kotzer KE, Lagerstedt SA: Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants. J Hum Genet 2015 May;60(5):241-252, doi: 10.1038/jhg.2015.10

3. Faivre L, Collod-Beroud G, Loeys BL, et al: Effect of mutation type and location on clinical outcome of 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 2007;81(3):454-466

4. Loeys BL, Dietz HC, Braverman AC, et al: The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-485

5. Boileau C, Jondeau G, Mizuguchi T, Matsumoto N: Molecular genetics of Marfan syndrome. Curr Opin Cardiol 2005 May;20(3):194-200

6. Faivre L, Gorlin RJ, Wirtz MK, et al: In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet 2003 Jan;40(1):34-36

Special Instructions Library of PDFs including pertinent information and forms related to the test