MYLK3 was evaluated for autosomal dominant dilated cardiomyopathy (DCM) using SOP v10 on 26/06/2025.
Human genetic evidence supporting this gene-disease relation includes case-level data and segregation data. At least three variants, all proven loss of function (haploinsufficiency), have been reported in humans with DCM, and two were shown to segregate with DCM in affected family members (Tobita et al 2017 PMID: 29235529, Hodatsu et al 2019 PMID: 30690923). There is also evidence of recessive DCM caused by bi-allelic loss-of-function and missense variants, although this evidence was not scored (Al-Hassnan et al 2020 PMID: 32870709 ).
This gene-disease relationship is also supported by experimental evidence, including expression data and animal models. MYLK3 is exclusively expressed in the mammalian heart (Seguchi et al 2007 PMID: 17885681, Chan et al 2008 PMID: 18202317), where its major function is to phosphorylate MCL2 (encoded by MYL2) (Seguchi et al 2007 PMID: 17885681). MYLK3 has been shown to be essential for normal sarcomere assembly (Chan et al 2008 PMID: 18202317, Seguchi et al 2007 PMID: 17885681).
There are multiple animal models including heterozygous knock-out mice and zebrafish and transgenic mouse models for MYLK3 loss-of-function variants previously reported in affected individuals. Zebrafish knock-down studies showed DCM-like phenotypes, with abnormal histology, enlarged cardiac dimensions and thinned ventricular walls in knock-downs vs wild-type (Seguchi et al 2007 PMID: 17885681). Heterozygous knock-out mice showed significant reduction in contractility and increase in left ventricular chamber dimensions both at systole and diastole in vs wild-type. Hemodynamic measurements also showed decrease in end-systolic pressure, LV dilatation and decrease in LV contractility (Tougas et al 2019 PMID: 31244672). A mouse knock-in model of a human splice variant (confirmed to cause haploinsufficiency) showed obvious LV dilatation with reduced LV contraction in homozygous mice, and LV dilatation with mildly reduced LV contraction in heterozygote mice vs wild-type (Hitsumoto et al 2023 PMID: 37128901). While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 07/11/2025 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.