Spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD) are rapidly evolving in terms of their medical and scientific research. Since our publication titled Spontaneous Coronary Artery Dissection and Fibromuscular Dysplasia: Vasculopathies With a Predilection for Women  was first published online in July 2020, there has been increasing interest in SCAD and FMD, particularly focused on the genetics of these conditions. SCAD has historically been underdiagnosed and only in recent years widely acknowledged and diagnosed by specialist cardiologists. It is now being increasingly recognized by general medical physicians as exemplified by the recent review article in The New England Journal of Medicine . This is important, given its systemic vascular associations and the need for all physicians to recognize these and manage accordingly.
Coronary Artery Dissection, Fibromuscular Dysplasia
SCAD is unlikely to be a monogenic disease because most cases of SCAD are sporadic and standard aortopathy and dissection panels have a low detection rate for pathogenic mutations . Also, where familial clustering of SCAD has been seen different modes of inheritance have been implicated. The genetics of SCAD is an active field of research and in the last year, there have been several new publications in the area. Extreme care must be taken in interpreting reports of genes associated with SCAD and in their broader clinical application. Isolated potential pathogenic variants, which have been reported in cases and family clusters, may not be reproducible in a broader population of SCAD patients .
In a recent report that looked at rare genetic variants in 25 thoracic aortic aneurysm and dissection genes in 179 sporadic cases of SCAD +/- FMD and 102 cases of severe FMD only, a higher frequency of variants (pathogenic, likely pathogenic, and variants of unknown significance) was found in six Loeys-Dietz syndromes (LDS) genes (TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, TGFB3) . Although clinical features of LDS were lacking, all genes identified encode proteins in the transforming growth factor-b pathway, which implicates this pathway in the pathophysiology of SCAD . Seven likely pathogenic variants were identified in SMAD2, SMAD3, TGFB3, TGFBR2, FLNA, COL3A1, and two pathogenic variants in COL3A1 and LOX. The group also identified COL3A1, FLNA, and LOX pathogenic variants in patients with SCAD +/- FMD with a familial arteriopathy history .
In collaboration with David Adlam and colleagues, we analyzed whole-genome sequencing data from SCAD patients to identify pathogenic variants or likely pathogenic variants . Seven genes (PKD1, COL3A1, SMAD3, TGFB2, LOX, MYLK, and YY1AP1) were implicated in 3.6% of cases, with PKD1 being the highest-ranked gene in a rare variant collapsing analysis . All cases were heterozygous for the variants and did not manifest connective tissue disease phenotypes.
Genome-wide association studies have recently identified single nucleotide variant (SNV) risk loci associated with SCAD [6,7]. Each of these SNVs associated with genes involved in SCAD (PHACTR1) or other vascular disorders (LRP1, LINC00310, FBN1, ADAMTSL4). SCAD patients have been reported to score lowly on genome-wide or polygenic risk score (PRS; numerical estimates of the summed effects of many genetic variants) for atherosclerosis  and, consistent with this finding, a high PRS for SCAD was recently found to be associated with decreased atherosclerotic coronary disease risk . Together these findings add further support to the notion that different pathological mechanisms underlie SCAD and atherosclerotic coronary disease.
In the past year, there have been several notable publications in FMD genetics. Rare loss of function and missense mutations in the prostaglandin I2 receptor gene (PTGIR) have recently been described in a small percentage of FMD and SCAD patients, 0.5% and 0.3% respectively, in a large multicenter study . With the involvement of prostacyclin in the arterial system and its association with dissection, it is biologically feasible that this gene and related pathways may be involved in some patients with FMD and SCAD, although more work will be required to confirm this association .
A novel COL5A1 variant (c. 1540G>A, G514S) has been found to associate with multifocal FMD . The variant was found in four non-familial cases with multifocal FMD. The probands were of central European ancestry and shared a common haplotype (frequency of 0.4% in 1000 Genomes data), suggesting a founder effect. Histopathologic analysis of arterial and skin samples from these probands showed extensive fibrosis within the media of the aneurysmal segments with no medial necrosis. Although COL5A1 has previously been shown to be associated with classical Ehlers-Danlos Syndrome (cEDS), the COL5A1 G514S variant in patients with multifocal FMD was associated with arterial dissections and is, thus, the first reported COL5A1 variant that presents with a vascular Ehlers-Danlos syndrome (vEDS) phenotype. The authors thus raised the question of whether patients with multifocal FMD or arterial aneurysms and dissections, should be tested for COL5A1 G514S and undergo similar monitoring and management as patients with vEDS .