Download A new genetic screening test for Marfan syndrome

A new genetic screening test for Marfan syndrome
A genetic analysis of the FBN1 gene in which mutations have been found to cause Marfan
Syndrome, type 1 (MFS1), is now available at SSI.
Background
Marfan syndrome (MFS) is an autosomal dominant condition with an incidence of 1:5000.
Mutations in the FBN1 gene are the major cause of MFS; more than 1000 MFS1-causing mutations
have been identified. The FBN1 gene encodes fibrillin-1 which is the major constitutive element of
extracellular microfibrils and has widespread distribution in both elastic and non-elastic
connective tissue throughout the body. FBN1 mutations result in connective tissue abnormalities
which lead to heart and eye problems in people with MFS1. Most MFS1-causing mutations are
missense mutations which lead to a reduction in the amount of fibrillin-1 produced by the cell,
alter the structure or stability of fibrillin-1, or impair the transport of fibrillin-1 out of the cell
resulting in a severe reduction in the amount of fibrillin-1 available to form microfibrils. Without
enough microfibrils, excess TGF-β growth factors are activated and elasticity in many tissues is
decreased, leading to overgrowth and instability of tissues and the signs and symptoms of MFS.
Individuals with MFS have a 50% chance of transmitting the mutation to their offspring.
Approximately 75% of MFS cases inherit their disease-causing mutation from a parent. The
remaining 25% have a spontaneous, de novo mutation, meaning their mutation arose as the
consequence of a new mutation in a germ cell or the fertilized egg itself.
Diagnosis and Indication
Individuals affected with MFS are usually tall and slender with elongated fingers and toes and
other skeletal abnormalities. The most common cardiovascular complication in MFS patients is
progressive aortic root dilatation. Ascending aortic aneurysm can precipitate acute type A aortic
dissection, aortic rupture, aortic regurgitation (AR), or all three. Other cardiovascular
manifestations include valvular disease involving the mitral valve, aortic valve, or both. Mitral
valve prolapse is the most prevalent valvular abnormality. The major ocular abnormality in MFS is
ectopia lentis (lens subluxation or dislocation). MFS features can appear at any age and may
worsen over time.
The diagnosis of MFS relies on defined clinical criteria (The revised Ghent nosology - J Med Genet
2010; 47:476-485); in which aortic root aneurysm (evaluated by echocardiography) and ectopia
lentis (evaluated by a slit lamp eye exam) are strongly weighted. In the absence of any family
history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of
MFS. In absence of either of these two, the presence of an FBN1 mutation or a combination of
systemic manifestations is required.
Results and interpretation
Whenever a causal-mutation is identified by genetic testing of FBN1, this information can be used
to support an MFS diagnosis and family specific genetic testing, cascade screening, can be used to
differentiate between relatives who are at-risk for the disease and those who are not.
Sampling
While the laboratory would prefer to receive blood sample, genomic DNA samples (>35
microgram) are also acceptable.
2-5 ml EDTA/Heparin blood samples (EDTA is preferred) should be sent in clearly labelled, tightly
capped tubes (incl. patient info), wrapped in a protective material, placed in a sealed plastic bag
and shipped by a carrier service in a styrofoam shipping box with a cool pack. Please do not freeze
of heat the sample.
If sending genomic DNA please send in clearly labelled, tightly capped tubes (caps wrapped in
parafilm) at room temperature (or with a cool pack) preferably by a carrier service
Further information
Information and advice can also be obtained from the Section of Molecular Medicine Clinical
Biochemistry, Immunology & Genetics on tel: 3268 3262 or e-mail: [email protected]
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