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Unit 2: Lesson 1

Foundation 1: Biomolecules

Inherited disorders: Marfan syndrome


Marfan syndrome is a fairly common (1 in 5,000) genetic disorder that is characterized by a myriad of symptoms affecting connective tissues. The predominant genetic defect is in the FBN1 gene, which codes for the glycoprotein fibrillin-1—and important component of the extracellular matrix (ECM). Fibrillin-1 is particularly important for the proper formation of elastic fibers, such as those which constitute the walls of large blood vessels, ligaments, and regions of the eye. In addition to providing structural integrity in connective tissue, the ECM also serves as a reservoir for growth factors. Marfan syndrome is interesting in that while all individuals with the mutated FBN1 genotype will demonstrate distinct symptoms, each individual may have a completely different phenotype. Figure 1 shows the frequency of common symptoms of Marfan syndrome among patients with the same mutation.
Figure 1: Relative incidences of common symptoms in Marfan syndrome.
The symptoms associated with Marfan syndrome are easily understood in terms of defects in the physiological roles of fibrillin-1. The most immediately recognizable of these is the characteristic body morphology that can arise in Marfan syndrome: disproportionately long, slender limbs and digits, above average height, stooped shoulders, scoliosis, and either a protruding or sunken appearing chest. In addition, many of these individuals have abnormally flexible joints and early onset arthritis. These individuals are also predisposed to a number of conditions involving the heart and major blood vessels including poor circulation and various heart murmurs. The most serious of these is a situation known as ‘aortic dissection,’ wherein blood under high pressure forces its way between layers of the wall of the aorta. This can lead to massive hemorrhage and death within minutes if it goes untreated.
A patient has come to see you complaining of arthritis. You find that he has a heart murmur and weak circulation to his extremities. You also notice that he is 6’7” tall with extremely long fingers. You suspect Marfan syndrome and record a thorough family history from the patient. Figure 2 shows the pedigree of this patient’s family with respect to symptoms of Marfan syndrome.
Figure 2: Patient’s family history and pedigree with respect to symptoms of Marfan syndrome.
\quad1 = Your patient
\quad1a = Son; 6’7” tall; treated for scoliosis from young age
\quad1b = Normal appearing daughter; average height
\quad2,3 = Normal appearing brother and sister; average heights
\quad4 = Tall sister; arthritis from age 26
\quad5 = Father; 6’7” tall; died of aortic dissection
\quad6 = Aunt; normal limb length; liked to show ‘how flexible’ she was; lost eyesight at age 40
\quad7 = Normal appearing uncle; average height
\quad8 = Uncle with long fingers; average height; circulation issues \quad* = Mother’s side of the family all appear normal; average heights
Data adapted from: Stheneur, C., Tubach, F., Jouneaux, M., Roy, C., Benoist, G., Chevallier, B., Boileau, C., Jondeau, G. (2014). Study of phenotype evolution during childhood in Marfan syndrome to improve clinical recognition. Genetics in Medicine, 16(3), 246-250.
Based on Figure 2, what is the most likely mode of inheritance for Marfan syndrome?
Choose 1 answer:
Choose 1 answer: