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Test ID: FBN1B FBN1 Full Gene Sequence, Varies

Useful For

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

Method Name

Custom Sequence Capture and Targeted Next-Generation Sequencing

Reporting Name

FBN1 Full Gene Sequence

Specimen Type

Varies


Advisory Information


In cases where there are hallmark features of Marfan syndrome, in particular the combination of ectopia lentis and aortic aneurysm or dissection in a patient or their family, FBN1 analysis (this assay) may be an appropriate first step in testing. In cases with more nonspecific features, such as isolated ascending aortic aneurysm or isolated skeletal features of Marfan syndrome, MFRGP / Marfan Syndrome and Related Disorders Multi-Gene Panel, Varies may be the more appropriate test to choose. Professional clinical judgment should be used by the ordering clinician. A genetic consultation may be helpful in determining the appropriate testing strategy for your patient.

 

Targeted testing for familial variants (also called site-specific or known mutation testing) is available for this gene. See:

-KVAR1 / Known Variant Analysis-1 Variant, Varies

-KVAR2 / Known Variant Analysis-2 Variants, Varies

-KVAR3 / Known Variant Analysis-3+ Variants, Varies

 

Call 800-533-1710 to confirm the appropriate test for targeted testing.



Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.



Necessary Information


1. Marfan and Related Disorders Patient Information (T636) is required, see Special Instructions. Testing may proceed without the patient information however it aids in providing a more thorough interpretation. Ordering providers are strongly encouraged to complete the form and send it with the specimen.

2. Include physician name and phone number with specimen.

 



Specimen Required


Prior Authorization is available for this test. Submit the required form with the specimen.

 

Submit only 1 of the following specimens:

 

Specimen Type: Whole blood

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 14 days

 

Specimen Type: DNA

Container/Tube: 2 mL screw top tube

Specimen Volume: 100 mcL (microliters)

Collection Instructions:

1. The preferred volume is 100 mcL at a concentration of 250 ng/mcL.

2. Include concentration and volume on tube.

Specimen Stability Information: Frozen (preferred)/Ambient/Refrigerated


Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Clinical Information

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

An interpretive report will be provided.

Interpretation

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.

Clinical Reference

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

Day(s) and Time(s) Performed

Wednesday; Varies

Analytic Time

2 weeks (after prior authorization is granted)

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81408

LOINC Code Information

Test ID Test Order Name Order LOINC Value
FBN1B FBN1 Full Gene Sequence 77114-7

 

Result ID Test Result Name Result LOINC Value
37289 Result Summary 50397-9
37290 Result Details 82939-0
37291 Interpretation 69047-9
37292 Additional Information 48767-8
37293 Method 49549-9
37294 Disclaimer 62364-5
37295 Reviewed By 18771-6

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. FBN1, Full Gene Sequence Prior Authorization Ordering Instructions in Special Instructions.

3. If not ordering electronically, complete, print, and send a Cardiovascular Test Request Form (T724) with the specimen.

Mayo Clinic Laboratories | Cardiology Catalog Additional Information:

mml-lipids-lipoproteins