5.2.1. Genetic Investigation of FMD Using Exome Sequencing in Families

The first exome sequencing study published on FMD was conducted in 16 related patients from 7 families including at least two first-degree relatives with confirmed FMD recruited in the French database of the Rare Vascular Diseases Referral Centre of the European Hospital Georges Pompidou (HEGP), Paris, France [31]. Under the hypothesis of implication of rare variants, the authors applied a filter on minor allele frequency <0.01, and only analysed coding variants that changed amino acids. Affected siblings share 50% of their genetic variants by chance. However, if several genetic variants located in the same gene are shared by siblings from several families, one can argue for genetic causality for this gene. A threshold of three families sharing variants in the same gene was arbitrary chosen in order to consider a gene as a putative candidate for FMD. Unfortunately, this condition has not be satisfied by any of the 3971 genes analysed [31], suggesting the lack of major common genetic determinant for FMD, at least under the assumption of classical Mendelian inheritance.

In the same study, the authors selected some genes harbouring rare coding variants without intra-familial segregation, and looked for the frequency of variants in these genes in 249 unrelated FMD patients, also ascertained from the Rare Vascular Diseases Referral Centre, HEGP and 689 controls from the SUpplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) study, a national sample of healthy volunteers. They applied a gene-based collapsing analysis named Optimal Sequence Kernel Association Test (SKAT-O), which is recommended for measuring association of multiple rare variants in a given gene instead of testing each individual variant separately, thereby providing more power [43]. Despite overall negative findings, this study unravelled nominally significant association between multifocal FMD and myosin light chain kinase (*MYLK*; previously involved in thoracic aortic aneurysms), dynein cytoplasmic heavy chain 1 gene (*DYNC2H1*), obscurin (*OBSCN*; a sarcomeric protein) and *RNF213*, previously associated with Moyamoya disease (*p* = 0.01) [43]. While these findings need replication, they highlight the importance of accurate phenotyping and classification, to distinguish multifocal FMD from focal FMD, which may have different pathophysiologies, and/or to avoid including phenocopies/FMD mimics.
