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Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and systolic dysfunction leading to congestive heart failure. MYLK3 encodes cardiac myosin light chain kinase, a key regulator of sarcomeric contraction. Recent evidence links heterozygous loss-of-function variants in MYLK3 to autosomal dominant DCM, with clinical phenotypes mirroring reduced kinase activity and sarcomeric phosphorylation deficits. MYLK3 and dilated cardiomyopathy association is supported by both human genetics and model systems.
Whole-exome sequencing in a familial DCM pedigree identified a read-through variant, c.2459G>C (p.Ter820SerextTer19), segregating with disease, and screening of 15 additional DCM patients revealed a second LoF frameshift variant, c.1879_1885del (p.Leu627fsTer41) (PMID:29235529). Both variants were absent from population databases and predicted to disrupt protein expression.
Segregation analysis in the index pedigree demonstrated co-segregation of c.2459G>C with DCM across affected relatives, and targeted screening confirmed a second unrelated proband, supporting autosomal dominant inheritance with haploinsufficiency as the likely mechanism.
In vitro assays and immunohistochemistry of patient-derived cardiac tissue revealed markedly reduced cMLCK protein levels and decreased phosphorylation of myosin light chain 2, consistent with loss of kinase function (PMID:29235529). These findings align with cardiac enlargement and heart failure phenotypes in MYLK3-deficient zebrafish models.
Heterozygous Mylk3 knockout mice exhibit a ~25% reduction in fractional shortening by 4 months, ~75% decrease in cMLCK protein, and enlarged ventricular cardiomyocytes without overt fibrosis, recapitulating key features of human DCM due to MYLK3 haploinsufficiency (PMID:31244672).
Integration of genetic segregation, supportive functional assays, and concordant animal models yields a strong ClinGen gene–disease validity for MYLK3 in DCM. Inclusion of MYLK3 in clinical cardiomyopathy panels can facilitate diagnosis and management of affected families.
Gene–Disease AssociationStrong2 probands with segregation in one pedigree and concordant functional data Genetic EvidenceStrongTwo unrelated LoF variants identified with family co-segregation across a DCM pedigree and additional proband screening Functional EvidenceModerateIn vitro assays show reduced cMLCK expression and phosphorylation; heterozygous mouse model partially recapitulates human DCM |