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

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. Exome sequencing wa...

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Bibliographic Details
Published in:	Genetics in medicine Vol. 23; no. 4; pp. 787 - 792
Main Authors:	Osborn, Daniel Peter Sayer, Emrahi, Leila, Clayton, Joshua, Tabrizi, Mehrnoush Toufan, Wan, Alex Yui Bong, Maroofian, Reza, Yazdchi, Mohammad, Garcia, Michael Leon Enrique, Galehdari, Hamid, Hesse, Camila, Shariati, Gholamreza, Mazaheri, Neda, Sedaghat, Alireza, Goullée, Hayley, Laing, Nigel, Jamshidi, Yalda, Tajsharghi, Homa
Format:	Journal Article
Language:	English
Published:	New York Elsevier Inc 01-04-2021 Nature Publishing Group US Elsevier Limited
Subjects:	Animals Biomedical and Life Sciences Biomedicine Brief Communication Cardiomyopathies - genetics Cardiomyopathy Cardiomyopathy, Dilated - genetics Clinical Medicine Consanguinity Death, Sudden, Cardiac - etiology Defibrillators diagnosis essential light-chain genes genetics Genetics & Heredity Human Genetics Humans hypertrophic cardiomyopathy Klinisk medicin Laboratory Medicine mutations myosin Myosin Light Chains - genetics Pedigree spectrum Translational Medicine TRIM Translationell medicin TRIM Zebrafish - genetics
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Summary:	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. Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1098-3600 1530-0366 1530-0366
DOI:	10.1038/s41436-020-01028-2