Marfan syndrome (MFS) is a rare genetic disease, with an estimated prevalence of 1:5,000 – 1:10,000, caused by mutations in FBN1, the gene coding for fibrillin-11. MFS is a connective tissue disorder with a spectrum of symptoms involving the ocular, skeletal, and cardiovascular system. The latter is the major source of morbidity and mortality associated with MFS, due to progressive aortic dilation leading to potential aneurysm, dissection, and rupture, as well as cardiac valvular dysfunction. There is also evidence of decreased myocardial function as well as an increased risk for arrhythmia potentially leading to sudden cardiac death2. Since no definitive cure exists, current treatment of MFS patients is limited to supportive care to minimize cardiovascular complications (mainly by the administration of β-adrenergic receptor blockers to slow down aortic root growth), and, when indicated, surgical aortic root replacement. Improving the outcome will require better targeted, disease- and patient-specific treatment as well as improved risk estimation at the time of diagnosis, underscoring the need for a more personalized approach to the management of the disease. It is important to correctly diagnose MFS at the earliest stage possible, in order to benefit from optimal treatment to prevent the development of potentially life-threatening complications. However, the diagnosis of MFS can be very challenging, especially at these early stages, since the syndrome encompasses a wide spectrum of potential presentations, some of which can be caused by related disorders which require a different clinical course of action. FBN1 genetic testing has become much more widely available recently due to improved technological capabilities associated with decreased costs, lowering the threshold for clinical genetic evaluation of potential MFS patients. This has led to an increased frequency of detection of novel FBN1 variants with unknown significance (VUS), which can neither be classified as benign or pathogenic according to the new guidelines from the American College of Medical Genetics and Genomics3. The current classification of new FBN1 variants is based on a case-by-case review of available background information combined with predictions derived from existing databases. Insufficient data as well as the lack of a suitable biological model for functional validation often leads to VUS classification (up to 30% of the variants analyzed in Prof. De Backer’s clinical lab).