Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3

Daniel Peter Sayer Osborn, Leila Emrahi, Joshua Clayton, Mehrnoush Toufan Tabrizi, Alex Yui Bong Wan, Reza Maroofian, Mohammad Yazdchi, Michael Leon Enrique Garcia, Hamid Galehdari, Camila Hesse, Gholamreza Shariati, Neda Mazaheri, Alireza Sedaghat, Hayley Goullée, Nigel Laing, Yalda Jamshidi, Homa Tajsharghi

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


Purpose: Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. Methods: Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. Results: Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood–onset and sudden cardiac death. We identified a homozygous missense substitution (c.170C>A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G>T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G>A, predicted to result in skipping of exon 5). Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G>T or the missense c.170C>A variants. Minigene assay of the c.482-1G>A variant indicated a splicing defect likely resulting in disruption of the EF-hand Ca2+ binding domains. Conclusions: Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function.

Original languageEnglish
Pages (from-to)787-792
Number of pages6
JournalGenetics in Medicine
Issue number4
Publication statusPublished - Apr 2021


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