Thoracic aortic aneurysm and dissection (TAAD) is a major cause of cardiovascular morbidity and mortality. Loss-of-function variants in LOX, encoding the extracellular matrix crosslinking enzyme lysyl oxidase, have been reported to cause familial TAAD. Using a next-generation TAAD gene panel, we identified five additional probands carrying LOX variants, including two missense variants affecting highly conserved amino acids in the LOX catalytic domain and three truncating variants. Connective tissue manifestations are apparent in a substantial fraction of the variant carriers. Some LOX variant carriers presented with TAAD early in life, while others had normal aortic diameters at an advanced age. Finally, we identified the first patient with spontaneous coronary artery dissection carrying a LOX variant. In conclusion, our data demonstrate that loss-of-function LOX variants cause a spectrum of aortic and arterial aneurysmal disease, often combined with connective tissue findings.

Acute and interventional Cardiology University of Leicester Leicester LE3 9QP UK

Center of Medical Genetics Faculty of Medicine and Health Sciences University of Antwerp and Antwerp University Hospital 2650 Antwerp Belgium

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University and Motol University Hospital Praha 5 15006 Prague Czech Republic

Department of Cardiac Surgery University of Antwerp and Antwerp University Hospital 2650 Antwerp Belgium

Department of Cardiology IKEM Praha 4 14021 Prague Czech Republic

Department of Clinical Genetics Copenhagen University Hospital 2100 Copenhagen Denmark

Department of Human Genetics Radboud University Medical Center 6525 Nijmegen The Netherlands

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