SMAD3 and brain aneurysm: Severe cases of MFS were associated with co-occurrence of another TAAD-causing mutation, including additional variants of FBN1 or SMAD3. Interestingly, severe disease was also associated with mutations in COL4A1; variants of COL4A1 have been reported in stroke and cerebral aneurysms (Lanfranconi and Markus, 2010).