How is Marfan syndrome inherited?
Marfan syndrome is inherited in an autosomal dominant manner. Marfan syndrome is caused by the presence of one genetic change (called a mutation) in the FBN1 gene. We all have two copies of the FBN1 gene, one from mom and one from dad. A person has Marfan syndrome when a mutation on one copy of the FBN1 gene prevents it from working, even though the second copy of the FBN1 gene is normal. A person with Marfan syndrome has a 50% chance of passing the copy of the FBN1 gene with the mutation to each of their children who would then also have Marfan syndrome, and 50% to pass down the normal copy of the FBN1 gene to each of their children who would not have Marfan syndrome.
75% of individuals with Marfan syndrome have a parent who also has Marfan syndrome, meaning it was inherited. However, the other 25% of individuals with Marfan syndrome do not inherit the genetic change from a parent. The genetic changes that cause Marfan syndrome in these individuals are de novo, meaning they happened spontaneously or randomly only in that individual, likely around the time they were conceived.
A genetic counselor can help individuals and families understand the way Marfan syndrome runs in families. In the US, genetic counselors can be located at the Find a Genetic Counselor website on the National Society of Genetic Counselor website.
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Is there variable expression or incomplete penetrance of Marfan syndrome?
There is both variable expression (different medical issues appearing in person to person) and incomplete penetrance (not everyone with the gene change in FBN1 has all the features of the condition) seen in Marfan syndrome. Not all people with Marfan syndrome will have every possible symptom, and some may never even know that they have Marfan syndrome. It can therefore be very difficult to predict what symptoms an individual with Marfan syndrome may develop during their lifetime.
A medical geneticist and/or genetic counselor can help individuals and families better understand the symptoms and impact of Marfan syndrome. In the US, genetic counselors can be located at the Find a Genetic Counselor website on the National Society of Genetic Counselor website.
What is a variant or VUS in the FBN1 gene?
A variants is just another word for a change or mutation in a gene. A pathogenic variant in the FBN1 gene would be one that causes Marfan syndrome. However, variants can be extra tricky if they are classified as variants of uncertain significance (VUS or VOUS for short). VUSs tend to be the most frustrating "answer" for people who have received genetic testing. If your genetic testing came back with a VUS in the FBN1 gene, this means that the laboratory has detected a change in the gene, but is unsure about what it means at the time. Laboratories will often ask for your permission to keep your sample and results, and can let you know once a more certain answer is found. Other times, your doctor must call the laboratory every few years to learn if the VUS has been reclassified as pathogenic (disease causing) or benign (non disease causing). This often happens after more people have genetic testing and can show that they have the same change as you, and then their symptoms are compared with your symptoms as well as other people with the same change. Then, science can make an interpretation to tell you that this change is causing a disorder or not.
Some changes don't mean anything, at all, though! Just because you have a change in your FBN1 gene doesn't mean that you have Marfan syndrome. Think of it like baking an apple pie: if you replace red apples with green apples, it's a change, but not quite enough to stop you from getting a delicious apple pie. However, if you replace sugar with salt, you'll get an awfully salty apple pie, creating something that doesn't taste quite right. This is how laboratories work to change a VUS into a positive or negative result- they do research to figure out if this change is causing a problem, or if it's no big deal at all.
A genetic counselor can help individuals and families navigate genetic testing and VUSs in Marfan syndrome. In the US, genetic counselors can be located at the Find a Genetic Counselor website on the National Society of Genetic Counselor website.
Can you have Marfan syndrome without having a FBN1 gene mutation?
Because there are so many different kinds of mutations possible, you can technically still have Marfan syndrome without having a mutation in the FBN1 gene. If you are concerned that you may have Marfan syndrome, you can have genetic testing done that can check all of the genes that can have an appearance similar to Marfan syndrome, which includes the FBN1 gene. Even with negative genetic testing, a clinical diagnosis of Marfan syndrome can be made if Ghent criteria is met.
A genetic counselor can help individuals and families navigate genetic testing for Marfan syndrome. In the US, genetic counselors can be located at the Find a Genetic Counselor website on the National Society of Genetic Counselor website.
- Dietz, H. (2017, October 12). Marfan Syndrome. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK1335/
- Understanding variants of uncertain significance in the era of multigene panels: Through the eyes of the patient. Reuter C, Chun N, Pariani M, Hanson-Kahn A. J Genet Couns. 2019 Aug;28(4):878-886. doi: 10.1002/jgc4.1130. Epub 2019 May 3. https://www.ncbi.nlm.nih.gov/pubmed/31050105?report=abstract
My child has Marfan syndrome. Will others in the family have it?
Because Marfan syndrome is inherited in an autosomal dominant inheritance pattern, it means that every first degree relative of an affected individual has a 50% chance of also having it. First degree relatives are siblings, children, and parents. Second degree relatives should have testing after first degree relatives are all tested. in a specific example, let's say 27-year-old Andrea has been diagnosed with Marfan. Andrea has 3 children. EACH of her children has an individual 50% chance to also have it. Andrea has 2 siblings: one brother and one sister. EACH of her siblings has an individual 50% chance to also have it. Andrea's mother has testing and is negative. This means that Andrea's mothers side of the family does NOT need to have any more testing. Andrea's father has testing and is positive. Each of Andrea's father's siblings should have testing as well, because they have an individual 50% chance of being positive as well.
A genetic counselor can help individuals and families navigate inheritance and genetic testing for Marfan syndrome. In the US, genetic counselors can be located at the Find a Genetic Counselor website on the National Society of Genetic Counselor website.