COL3A1 mutations in spontaneous coronary artery dissection

Abstract Background Spontaneous coronary artery dissection (SCAD) affects mainly women with a mean age of 51 years.(1) Predicted damaging variants in connective tissue disease (CTD) genes have been found in a subset of patients with SCAD, however in some cases the typical phenotype associated with these conditions is lacking. Variants in the COL3A1 gene, on chromosome 2 encoding type III collagen, appear to be one of the most frequently reported in SCAD. Mutations in COL3A1 alter the production and structure of type III procollagen and weaken connective tissues, including blood vessel walls and cause vascular Ehlers-Danlos Syndrome (vEDS).(2) Purpose Systematically determine the known cases of SCAD with COL3A1 likely pathogenic/pathogenic (LP/P) variants to highlight COL3A1 as a SCAD-causative gene, in a subset of SCAD cases. Methods We searched PubMed using search terms "spontaneous coronary artery dissection" AND COL3A1, "spontaneous coronary artery dissection" AND "vascular Ehlers-Danlos syndrome", "spontaneous coronary artery dissection" AND genetics. We also searched the ClinVar database using COL3A1 [gene] and the following stipulations: clinical significance limited to pathogenic or likely Pathogenic; molecular consequence limited to frameshift, missense or nonsense, and review status limited to multiple submitters or at least one star. The COL3A1 variants identified were reclassified using American College of Medical Genetics (ACMG) criteria. Fisher's exact test was used for statistical comparisons. Results There were 42 published cases of SCAD with a LP/P mutation in COL3A1. Of the 42 published cases, there were two cases published twice. Using updated ACMG criteria, three cases were reclassified to variant of uncertain significance (VUS), from LP/P. This resulted in 37 unique cases of SCAD with LP/P variants using ACMG criteria. Of the cases with LP/P mutations where sex was known, 11/33 cases (35%) were male, higher than that reported in a large, published cohort where 86/750 SCAD cases (11.5%) were male (1) (p = 0.001129, 95% CI 0.115876 0.614725). Most SCAD cases with a COL3A1 LP/P mutation in whom age was reported, were under age 40 years (23/31, 74%), proportionally more cases when compared to a cohort of SCAD cases where 82/460 SCAD cases were under age 40 years (18%) (p value = 8.782e-11, 95% CI 0.02837315 0.18361793). Of the variant types reported (16/37), the majority were single nucleotide variants with one copy number variation (duplication). Conclusion While no one gene carries damaging variants in a large proportion of SCAD cases, COL3A1 variants have been found in a number of people with SCAD. Patients presenting with SCAD under 40 years and particularly males should be screened for pathogenic variants in aortopathy and connective tissue genes, such as COL3A1.Table:SCAD with COL3A1 LP/P variants 1TableSCAD with COL3A1 LP/P variants 2