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GeneDx
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 301-519-2100
Fax: 301-519-2892
E-mail: [email protected]
www.genedx.com
Test Information Sheet
Cardiology Genetics:
FBN1 Gene Analysis in Marfan Syndrome and Related Fibrillinopathies
OMIM Numbers:
154700 (Marfan syndrome); 129600 (ectopia lentis syndrome); 604308 (MASS syndrome); 134797 (FBN1 gene) 1
Clinical Features:
Marfan syndrome is a connective tissue disorder that can affect multiple organ systems including the skeletal, ocular,
and cardiovascular systems and is caused by pathogenic variants in the FBN1 gene. A diagnosis is based on the
presence of major and minor clinical criteria, as established by the Ghent nosology.2, 3 Skeletal features can include
chest malformations (pectus carinatum/excavatum), tall stature, increased joint mobility, and scoliosis. Eye findings
most commonly include lens dislocation (ectopia lentis) and myopia. The cardiovascular features are typically mitral
valve prolapse and/or aortic root dilatation, which can progress to aortic dissection. Patient management and treatment
is mainly focused on slowing the progression of aortic root dilation, the most common cause of morbidity and early
mortality. Therefore, genetic testing is important for identifying presymptomatic family members who carry a FBN1
pathogenic variant, and at risk for developing features of Marfan syndrome, who will benefit from appropriate
monitoring for aortic root dilatation.
Pathogenic variants in the FBN1 gene have also been observed in families with isolated ectopia lentis and MASS
syndrome (myopia, mitral valve prolapse, borderline/non-progressive aortic root dilation, skeletal and skin findings).
MASS is a connective tissue disorder related to Marfan syndrome but with milder cardiovascular findings.
Genetics:
The FBN1 gene is located on chromosome 15q21.1 and has 65 exons coding for the fibrillin-1 protein. Fibrillin 1,
with fibrillin 2 and fibrillin 3, forms microfibrils that are present in elastic and non-elastic fibers contributing to the
structure of multiple organ systems in the body. Fibrillin 1 also has been shown to aid in the regulation of growth
factors, such as TGFβ. Pathogenic variants in FBN1 result in decreased formation of microfibrils and increased
TGFβ signaling, ultimately resulting in the clinical features observed in Marfan syndrome. Marfan syndrome follows
autosomal dominant inheritance with variable expressivity; approximately 25% of cases result from de novo
pathogenic variants.
Missense, nonsense, splicing, and insertion/deletion pathogenic variants have been reported in the FBN1 gene.
Approximately 60% of pathogenic variants are missense changes and frequently affect cysteine residues involved
in disulfide bonding.4 Variants resulting in protein truncation (nonsense and frameshift variants) account for greater
than 30% of pathogenic variants identified.4, 5 In a minority of cases, large deletions of multiple exons have been
reported in the FBN1 gene.6 While the phenotypic spectrum associated with FBN1 pathogenic variants is broad,
some generalized gentotype-phenotype correlations have been observed. A clustering of pathogenic variants in
exons 24-32 has been reported in neonatal Marfan syndrome and atypically severe Marfan syndrome.7 Missense
variants involving a cysteine residue tend to occur more frequently in patients with ectopis lentis, while nonsense
variants have been reported to be more prevalent in patients with major skeletal criteria.5
Reasons for Referral:
1. Molecular confirmation of a clinical diagnosis in symptomatic individuals
2. Risk assessment of asymptomatic family members of a proband with Marfan syndrome
3. Differentiation of hereditary Marfan syndrome from other acquired (non-genetic) or genetic phenotypically similar
disorders
4. Genetic counseling and recurrence risk calculation
Information Sheet on FBN1 Testing
Page 1 of 2
© GeneDx
Revision Date: 09/2016
Test Methods:
Using genomic DNA from the submitted specimen, the coding regions and splice junctions of exons 1 to 65
are enriched using a proprietary targeted capture system developed by GeneDx. These targeted regions are
sequenced simultaneously by massively parallel (NextGen) sequencing on an Illumina platform with pairedend reads. Bi-directional sequence is assembled, aligned to reference gene sequences based on human
genome build GRCh37/UCSC hg19, and analyzed for sequence variants. Capillary sequencing is used to
confirm all potentially pathogenic variants and to obtain sequence for regions where fewer than 15 reads are
achieved by NextGen sequencing. Concurrent deletion/duplication testing is performed for this gene using
exon-level oligo array CGH (ExonArrayDx). Data analysis is performed using gene-specific filtering. Probe
sequences and locations are based on human genome build GRCh37/UCSC hg19. The array is designed to
detect most intragenic deletions and duplications. Confirmation of copy number changes is performed by
MLPA, qPCR, or repeat array CGH analysis. Sequence and array CGH alterations are reported according to
the Human Genome Variation Society (HGVS) or International System for Human Cytogenetic Nomenclature
(ISCN) guidelines, respectively. Benign and likely benign variants, if present, are not included in this report
but are available upon request.
Test Sensitivity:
Sequence analysis of all exons in the FBN1 gene is expected to identify a pathogenic variant in 72-93% of
individuals with a clinical suspicion of Marfan syndrome, with the pathogenic detection rate approaching 93% in
individuals fulfilling a clinical diagnosis of Marfan syndrome based on the Ghent nosology.4, 5, 8, 9 The test sensitivity
significantly decreases for individuals who do not meet Ghent criteria for Marfan syndrome.8 Large deletions have
been detected in approximately 2% of individuals who did not have a pathogenic variant identified by sequencing. 6
The technical sensitivity of the sequencing test is estimated to be 98%. Sequencing will not reliably detect deletions,
insertions, or rearrangements greater than or equal to five base pairs (bp). Deletions or duplications of less than
500 bp are not reliably detected by array CGH.
Sequence and deletion/duplication analysis of 15 other genes associated with related disorders is also
available. Please see the Marfan syndrome / Thoracic Aortic Aneurysm and Dissection (TAAD) and Related
Disorders panel at www.genedx.com.
Specimen Requirements and Shipping/Handling:
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Blood in EDTA (Preferred): A single tube with 2-5 mL whole sterile blood is sufficient. Specimens may be
refrigerated for up to 7 days prior to shipping*.
Oral Rinse (Alternative): At least 30mL of rinse in a 50mL centrifuge tube. Use a GeneDx oral rinse kit (others not
accepted). Specimens may be refrigerated for up to 10 days prior to shipping*.
Extracted DNA (Alternative): High quality extracted DNA can be accepted*. At least 20μg is requested (with a
minimum concentration of 50ng/μl).
Other Specimens & Additional Details: Other alternative specimens may also be accepted. Please visit our
specimen requirements page online and/or contact us for additional details.
*Ideal handling for blood, oral rinse, and extracted DNA is to ship immediately at ambient temperature for overnight delivery with arrival MondaySaturday, using a cool pack in hot weather.
To request a GeneDx specimen kit, contact your GeneDx sales representative or send your request to [email protected].
Required Forms:
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Cardiology Sample Submission (Requisition) Form – complete all pages
Payment Options Form or Institutional Billing Instructions
Consent Form
We highly recommend submitting relevant clinical information with each sample.
For test codes, prices, CPT codes, and turn-around-times, please refer to the “Cardiology Genetic Testing
Services” page on our website: www.genedx.com
References:
1.
Online Mendelian Inheritance in Man. www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM
2.
de Paepe A et al. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 62:417-426, 1996.
3.
Loeys BL The revised Ghent Nosology for the Marfan syndrome. J Med Genet 47:476-485, 2010.
4.
Boileau C et al. olecular genetics of Marfan syndrome. Curr Opin Cardiol. 20:194-200, 2005.
5.
Arbustini E et al. Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other
fibrillinopathies. Hum Mut. 26:494-509, 2005.
6.
Matyas G et al. Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome. Hum Genet. 122:23-32, 2007.
7.
Faivre L et al. Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation. Eur J Hum Genet.
17:491-501, 2009.
8.
Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet.
17:1121-1128, 2009.
9.
Akutsu K et al. Genetic analysis of young adult patients with aortic disease not fulfilling the diagnostic criteria for Marfan syndrome. Circulation 74:990-997, 2010.
Information Sheet FBN1 Testing
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© GeneDx
Revision Date: 9/2016