Marfan syndrome is inherited as an autosomal dominant condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. In approximately 25-30 percent of Marfan syndrome cases, this mutation occurs as the result of a new mutation. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

Marfan syndrome has been linked to defects or disruptions (mutations) of the fibrillin-1 (FBN1) gene. Not everyone who has a mutation of this gene develops the symptoms of Marfan syndrome.

Investigators have determined that most cases (> 95%) of Marfan syndrome occur due to defined mutation of the FBN1 gene located on the long arm (q) of chromosome 15 (15q21.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many segments (called bands) that are numbered. For example, "chromosome 15q21.1" refers to band 21.1 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The FBN1 gene contains instructions for producing (encoding) a protein known as fibrillin-1. Fibrillin-1 is a component of structures called microfibrils, which are fiber-like structures that are part of the extracellular matrix, a complex material that surrounds and connects cells throughout the body. Researchers believe fibrillin-1 plays an essential role in maintaining the strength and structural integrity of the connective tissue. Without fibrillin, connective tissue may be weak. Fibrillin-1 also influences the activity of a molecule that instructs cells how to behave (growth factor) called transforming growth factor-β (TGF-β).

A disorder that includes many features of Marfan syndrome (MFS) called Loeys-Dietz syndrome (LDS) can be caused by mutations in at least 5 different genes that influence the activity of TGF-β (TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3). Another condition called Shprintzen-Goldberg syndrome or SGS includes many features of MFS and most features of LDS, but also the added feature of problems with learning (intellectual disability). SGS is caused by mutations in another gene that regulates TGF-β activity called SKI.