Exploring the Genetic Architecture of Spontaneous Coronary Artery Dissection Using Whole-Genome Sequencing.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome that predominantly affects women. Its pathophysiology remains unclear but connective tissue disorders (CTD) and other vasculopathies have been observed in many SCAD patients. A genetic component for SCAD is increasingly appreciated, although few genes have been robustly implicated. We sought to clarify the genetic cause of SCAD using targeted and genome-wide methods in a cohort of sporadic cases to identify both common and rare disease-associated variants. METHODS: A cohort of 91 unrelated sporadic SCAD cases was investigated for rare, deleterious variants in genes associated with either SCAD or CTD, while new candidate genes were sought using rare variant collapsing analysis and identification of novel loss-of-function variants in genes intolerant to such variation. Finally, 2 SCAD polygenic risk scores were applied to assess the contribution of common variants. RESULTS: We identified 10 cases with at least one rare, likely disease-causing variant in CTD-associated genes, although only one had a CTD phenotype. No genes were significantly associated with SCAD from genome-wide collapsing analysis, however, enrichment for TGF (transforming growth factor)-ß signaling pathway genes was found with analysis of 24 genes harboring novel loss-of-function variants. Both polygenic risk scores demonstrated that sporadic SCAD cases have a significantly elevated genetic SCAD risk compared with controls. CONCLUSIONS: SCAD shares some genetic overlap with CTD, even in the absence of any major CTD phenotype. Consistent with a complex genetic architecture, SCAD patients also have a higher burden of common variants than controls.

Generation of VCCRIi001-A, a human induced pluripotent stem cell line, from a patient with spontaneous coronary artery dissection.

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic form of coronary artery disease of unknown cause that predominantly affects women (>90%; mean age 44-55 years) and can be fatal. The finding of familial clustering, including the concordant involvement of monozygotic twins, and its association with the PHACTR1/EDN1 genetic locus, indicate a genetic predisposition to its pathophysiology. A human induced pluripotent stem cell line (hiPSC) was generated from a patient who had survived an episode of SCAD. This disease-specific hiPSC line will be useful for the study of SCAD after differentiation into blood vessel-forming cells.

Idiopathic sclerochoroidal calcification.

PURPOSE: Sclerochoroidal calcification is a rare ocular condition characterized by multifocal, yellow-white elevated fundus lesions typically located in the superotemporal quadrant along the superior arcades. The pathology of calcification can be classified as dystrophic, metastatic, or idiopathic. Vision-threatening complications may arise, such as choroidal neovascular membrane and serous retinal detachment. The pathogenesis of sclerochoroidal calcification remains unclear. CASE REPORT: A 72-year-old Caucasian male patient presented to the clinic for routine examination. Fundus evaluation revealed bilateral, multifocal, pale yellow elevated lesions in the superotemporal fundus. Ultrasonography showed a focal area of hyper-reflectivity located in the posterior retina of both eyes, and optical coherence tomography showed an intact retina overlying the elevated lesions in the choroid. Systemic evaluation for dystrophic and metastatic calcification was negative, and the patient was diagnosed with idiopathic sclerochoroidal calcification. CONCLUSIONS: It is important to distinguish sclerochoroidal calcification from other conditions to prevent unnecessary intervention. Calcification of body tissues warrants a systemic evaluation, including screening for calcium and phosphorous levels, to rule out underlying systemic disease. If a biochemical abnormality is discovered, it can be appropriately treated with supplements. If calcification is deemed idiopathic, then annual dilated examinations are recommended to monitor the fundus lesions. Visual prognosis for sclerochoroidal classification is good, as the lesions are typically located away from the macula and foveal encroachment is rare.