Novel LOX Variants in Five Families with Aortic/Arterial Aneurysm and Dissection with Variable Connective Tissue Findings

Abstract

Thoracic aortic aneurysm and dissection (TAAD) is a major cause of cardiovascular morbidity and mortality. Loss-of-function variants in <i>LOX</i>, 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 <i>LOX</i> variants, including two missense variants affecting highly conserved amino acids in the <i>LOX</i> catalytic domain and three truncating variants. Connective tissue manifestations are apparent in a substantial fraction of the variant carriers. Some <i>LOX</i> 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 <i>LOX</i> variant. In conclusion, our data demonstrate that loss-of-function <i>LOX</i> variants cause a spectrum of aortic and arterial aneurysmal disease, often combined with connective tissue findings.