MYLK Variants of Uncertain Significance as Risk Factors for Aortic Dissection

BACKGROUND: 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. CASE SUMMARY: 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. DISCUSSION: 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. CONCLUSIONS: The MYLK variant patient journeys support lower surveillance thresholds and cascade genetic screening.