MYL3 – Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by ventricular dilatation and systolic dysfunction leading to heart failure and transplantation. The essential light chain gene MYL3 is well known in hypertrophic cardiomyopathy, and recent reports implicate biallelic MYL3 variants in autosomal recessive Dilated Cardiomyopathy.

In a pediatric case, a 2-year-old girl presented with edema, muscle weakness (HP:0001324), lethargy (HP:0001254), vomiting (HP:0002013), and cardiogenic shock (HP:0030149), along with first-degree atrioventricular block (HP:0011705). Echocardiography revealed severe biventricular systolic and diastolic dysfunction, and she harbored a homozygous splice-acceptor variant c.560-2A>G ([PMID:38561731]). This single instance extends the MYL3-related DCM phenotype into infancy.

Exome sequencing in three unrelated consanguineous families identified homozygous variants c.106G>T (p.Glu36Ter), c.170C>A (p.Ala57Asp), and c.482-1G>A, each segregating with early-onset cardiomyopathy in affected relatives, while heterozygous carriers remained unaffected ([PMID:33288880]). These findings account for four probands across four families, demonstrating complete recessive segregation.

The allelic spectrum includes two loss-of-function mutations (one nonsense, one splice) and one hypomorphic missense. All variants are absent from population controls and occur at conserved residues in the EF-hand Ca²⁺-binding domains of the essential light chain.

Functional studies in zebrafish show that morpholino knockdown of the MYL3 orthologue cmlc1 causes cardiomyopathy phenotypes that are rescued by wild-type but not mutant (c.106G>T or c.170C>A) transcripts. A minigene assay confirmed aberrant splicing due to c.482-1G>A ([PMID:33288880]), consistent with a loss-of-function mechanism.

In contrast, human iPSC-derived cardiomyocytes carrying heterozygous or homozygous c.170C>A exhibited normal gene expression, morphology, contractility, and calcium handling, supporting a benign classification for p.Ala57Asp in isolation ([PMID:29914921]). This points to possible variant-specific or dosage-dependent effects.

Overall, four probands in four families with biallelic MYL3 variants, robust segregation, and concordant in vivo and in vitro functional data support a moderate level of clinical validity for autosomal recessive MYL3 in DCM. Additional large-scale and longitudinal studies are needed to clarify penetrance and phenotype variability. Key Take-home: Biallelic loss-of-function MYL3 alleles are a clinically actionable cause of early-onset DCM in children.

References

• BMC Pediatrics | 2024 | Familial dilated cardiomyopathy in a child: a case report. PMID:38561731
• Genetics in Medicine | 2021 | Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3. PMID:33288880
• Circulation | 2018 | Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells. PMID:29914921

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