MYLK pathogenic variants aortic disease presentation, pregnancy risk, and characterization of pathogenic missense variants

Stephanie E Wallace, Ellen S Regalado, Limin Gong, Alexandra L Janda, Dong-Chuan Guo, Claudio F Russo, Richard J Kulmacz, Nadine Hanna, Guillaume Jondeau, Catherine Boileau, Pauline Arnaud, Kwanghyuk Lee, Suzanne M Leal, Matias Hannuksela, Bo Carlberg, Tami Johnston, Christian Antolik, Ellen M Hostetler, Roberto Colombo, Dianna M Milewicz

Research output: Contribution to journalArticlepeer-review


PURPOSE: Heritable thoracic aortic disease 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 60 cases with MYLK pathogenic variants were analyzed (five null and two 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 (87%) were aortic dissections. Aortic diameters were minimally enlarged at the time of dissection in many cases. Time-to-aortic-event curves showed that missense pathogenic variant (PV) carriers have earlier-onset aortic events than null PV carriers. An MYLK missense variant segregated with aortic disease over five generations but decreases MYLK kinase acitivity marginally. Functional Assays fail to identify all pathogenic variants in MYLK.

CONCLUSION: These data further define the aortic phenotype associated with MYLK pathogenic variants. Given minimal aortic enlargement before dissection, an alternative approach to guide the timing of aortic repair is proposed based on the probability of a dissection at a given age.

Original languageEnglish
Pages (from-to)144-151
Number of pages8
JournalGenetics in Medicine
Issue number1
Publication statusPublished - Jan 2019


  • Adult
  • Aged
  • Aneurysm, Dissecting
  • Aorta/pathology
  • Aortic Diseases/genetics
  • Calcium-Binding Proteins/genetics
  • Female
  • Genetic Testing
  • Heterozygote
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Myosin-Light-Chain Kinase/genetics
  • Pedigree
  • Pregnancy


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