Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Aneurysms-osteoarthritis syndrome (AOS) [I71.1] [I71.2]

OMIM numbers: 613795, 603109 (SMAD3)

Dr. rer. nat. Karin Mayer

Scientific Background

In 2011 a further gene locus for familial thoracic aortic aneurysms and aortic dissections (TAAD) was mapped on chromosome 15q22.2–24.2 and missense mutations were identified in the SMAD3 gene which is located in this chromosomal region. Based on the analysis of three multigenerational families a dominantly inherited form of syndromic aortic aneurysms and dissections associated with osteoarthritis (aneurysms osteoarthritis syndrome (AOS)) was described. Besides TAAD, patients with AOS present with arterial tortuosity and craniofacial, skeletal and dermal abnormalities. Causal are mutations in the gene for SMAD3 (SMA and MAD-related protein 3), a further molecule of the transforming growth factor-β signaling pathway in the arterial wall. SMAD3 mutations were identified in 2% of patients with TAAD, after a negative mutation analyses in FBN1, TGFBR1 and TGFBR2. AOS is also called Loeys-Dietz syndrome with osteoarthritis, Loeys-Dietz syndrome 1C (LDS1C) or Loeys-Dietz syndrome type 4 (LDS4).