*5.1. Candidate Gene Studies*

Literature on the genetics of FMD is scarce and, when available, studies are generally underpowered to assess the role of the tested genes. The main reason is the lack of large pedigrees to perform linkage analyses or large cohorts of well-characterized FMD patients for association studies. Variants in genes belonging to pathways related to the extracellular matrix of the arterial wall failed to show significant or even promising associations with FMD. Single Nucleotide Polymorphisms (SNPs) in the elastin gene (*ELN*), which harbours causative mutations for supravalvular aortic stenosis in Williams–Beuren syndrome (OMIM reference: #194050) (Perdu & Jeunemaitre, Unpublished data), as well as in the alpha1-antitrypsin gene (*AAT*) [42], were distributed evenly in patients with FMD and healthy controls or patients with essential hypertension. The modest sample size (*N* cases = 161) and lack of comprehensive coverage of the genes of interest, including regulatory regions, may partially explain these negative findings. Screening for causative mutations in the actin α-2 gene (*ACTA2*), involved in rare cases of aortic aneurysms was also negative [43]. Finally, as indicated above, screening for mutations involved in rare vascular syndromes such as Marfan, Loeys-Dietz and vascular Ehlers-Danlos Syndrome, in the TGFβ signalling pathway and/or extracellular matrix components (e.g., fibrillin and collagen genes) was disappointing [26,37]. Fortunately, the development of Next Generation Sequencing (NGS) opened the possibility to conduct hypothesis free experiments, such as exome sequencing, to explore families.
