**4. Challenges of the Genetic Investigation of FMD**

Several reasons make genetic investigation of FMD challenging and limit access to multi-generational families or large cohorts of patients: (i) as most patients are no longer operated nowadays, histopathologic confirmation of the diagnosis is lacking; (ii) the surrogate "gold standard", catheter-based angiography, which was at the basis of the current angiographic diagnostic criteria and classification cannot be proposed as a first-line screening test, in view of its invasiveness and potential risks [1]; (iii) while the string of beads is almost pathognomonic for multifocal FMD, the diagnosis of focal FMD requires exclusion of a number of FMD mimics, such as localized atherosclerosis, and inflammatory or inherited arteriopathies (Table 1), which implies a risk of misclassification and subsequent decrease in statistical power in case-control studies; (iv) in the absence of systematic exploration of controls and relatives of FMD patients, study results may be unreliable, as it has been estimated that 3–6% of subjects from the general population may harbour silent FMD lesion [6,7]; and (v) few large, multigenerational families are currently available for analysis. These hurdles may be partly overcome by the development of large national and international registries [3,4,39] including well characterized patients, with image archiving and biobanking, and the use of standardized, state-of-art imaging, as well as identification and validation of specific biomarkers, such as subtle changes in the arterial wall detected by high resolution echography [23,35,40,41].
