MYLK Mutations: Aortic Disease Presentation, Pregnancy Risk, and Characterization of Pathogenic Missense Variants

PURPOSE: Heritable thoracic aortic disease (HTAD) can result from null variants in MYLK, which encodes myosin light chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited. METHODS: Clinical data from 33 cases with MYLK pathogenic variants were analyzed (5 null and 2 missense variants) and the effect of missense variants on kinase activity was assessed. RESULTS: Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm repair or dissection); the majority of these events were aortic dissections (87%). Aortic diameters were minimally enlarged at the time of dissection in many cases. Time to aortic event curves showed missense mutation carriers have earlier onset aortic events than null mutation carriers. A MYLK missense variant segregated with aortic disease over five generations but only marginally decreases MLCK kinase activity, and functional assays fail to identify all pathogenic variants in MYLK. CONCLUSIONS: These data further define aortic phenotype associated with MYLK pathogenic variants. Given minimal aortic enlargement prior to dissection, an alternative approach to guide the timing of aortic repair is proposed based the probability of a dissection at a given age.