MYLK Variants of Uncertain Significance as Risk Factors for Aortic Dissection

Myosin light chain kinase (MYLK) variants of uncertain significance (VUS) are not considered actionable under current guidelines, yet MYLK encodes a kinase essential for vascular smooth muscle contractility, and pathogenic variants are associated with aortic dissection at modest diameters.

We report 8 patients carrying MYLK variants (7 VUS, 1 pathogenic) who developed aortic dissection requiring surgery. In our institutional registry of 1,048 patients undergoing aortic genetic panel testing, MYLK carriers had higher rates of acute aortic syndromes, namely Type A dissections.

Four phenotypic patterns emerged: dissection at aortic diameters of 40 mm (below guideline thresholds); reoperation at a median of 7 vs 24 months in non-MYLK dissection patients; co-occurring ACTA2 VUS suggesting oligogenic risk amplification; and intrapedigree VUS-to-pathogenic reclassification of the same MYLK V1522A variant across 2 timepoints and testing facilities.

The MYLK variant patient journeys support lower surveillance thresholds and cascade genetic screening.