Thoracic aortic aneurysms (TAAs) result from progressive dilatation of the aorta and entail a high risk for aortic dissection and rupture. The latter events associate with a mortality rate of 50%, representing a prominent cause of morbidity and sudden death in the Western population. Over the past 25 years, extensive gene identification efforts have pinpointed more than 25 genes associated with familial TAA risk, explaining about 30% of all familial TAA cases. Functional characterization of these genes has revealed perturbed extracellular matrix homeostasis, transforming growth factor‑β signaling, and vascular smooth muscle cell contractility as important TAA processes. To expedite the development of novel therapeutic strategies, acquisition of even more extensive insights into the genetic and mechanistic TAA picture is mandatory. Owing to the recent advent and fast evolution of next-generation sequencing technologies, we anticipate that the identification of additional genetic TAA causes will remain quite straightforward in the upcoming years. Given that TAA is characterized by greatly reduced penetrance and variable expressivity, modifier studies now represent a challenging, yet important, new avenue in the field of TAA genetics. In this project, we pursue the genetic modifiers that determine phenotypical variability in selected families with an autosomal dominantly inherited syndromic TAA form, namely Loeys-Dietz syndrome. State-of-the-art technologies, such as genome sequencing and creation of induced pluripotent stem cells, will be used. The anticipated outcomes will advance TAA knowledge significantly beyond the current understanding, aid genetic counseling, and offer unprecedented opportunities to find leads to novel therapeutic strategies.