Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Osborn DPS

PROVIDER: S-EPMC8026398 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Osborn Daniel Peter Sayer DPS Emrahi Leila L Clayton Joshua J Tabrizi Mehrnoush Toufan MT Wan Alex Yui Bong AYB Maroofian Reza R Yazdchi Mohammad M Garcia Michael Leon Enrique MLE Galehdari Hamid H Hesse Camila C Shariati Gholamreza G Mazaheri Neda N Sedaghat Alireza A Goullée Hayley H Laing Nigel N Jamshidi Yalda Y Tajsharghi Homa H

Genetics in medicine : official journal of the American College of Medical Genetics 20201208 4

<h4>Purpose</h4>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.<h4>Methods</h4>Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed.<h4>Results</h4>Affected individuals presented with hypertrophic or d ...[more]

PMID: 33288880

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Project description:BACKGROUND:Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. OBJECTIVES:This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. METHODS:The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. RESULTS:Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). CONCLUSIONS:Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults.

Dataset Information

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

Purpose

Methods

Results

Conclusions

Publications

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

Similar Datasets

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