Fatal Infantile Cardiomyopathy Associated with a Homozygous MYL2 c.413T>A (p.Met138Lys) Variant: A Case Expanding the Recessive MYL2 Phenotypic Spectrum

Figures

• 

  Figure 1. Clinical course, pedigree, and conceptual disease framework of the homozygous MYL2 p.Met138Lys variant. (A) Clinical timeline of the proband from birth to death. Hypotonia and motor delay were recognized at approximately 6 months of age. Initial diagnostic evaluation, including metabolic screening, testing for spinal muscular atrophy (SMA) and Prader–Willi syndrome (PWS), and brain magnetic resonance imaging (MRI), was unrevealing. At approximately 10 months, the patient developed severe heart failure. Trio-based whole-exome sequencing subsequently identified a homozygous MYL2 p.Met138Lys variant. The patient died at 12 months despite maximal supportive care. (B) Pedigree demonstrating segregation of the MYL2 variant consistent with autosomal recessive inheritance. Both parents are heterozygous carriers, the affected child is homozygous, and the siblings are unaffected. (C) Conceptual schematic of the proposed disease mechanism. The MYL2 p.Met138Lys variant may impair sarcomeric structure and contractile function, thereby contributing to cardiomyopathy. This model is hypothesis-generating and does not represent direct functional validation.

• 

  Figure 2. MYL2 gene, protein structure, and evolutionary conservation of the p.Met138Lys variant. (A) Gene structure of MYL2 showing the seven-exon organization. The identified variant c.413T>A is located in exon 6 and results in the missense substitution p.Met138Lys. (B) Schematic representation of the MYL2 protein structure indicating the N-terminal and C-terminal regions and the EF-hand domains. The p.Met138Lys variant is positioned within the distal C-terminal region, corresponding to EF-hand domain 2. This localization supports potential disruption of calcium-binding or sarcomeric regulatory function. (C) Evolutionary conservation of residue 138 across species. A multiple-sequence alignment of representative orthologs demonstrates that residue 138 shows strong evolutionary conservation, with conservative substitutions observed in some taxa. The highlighted residues indicate the corresponding position across species, supporting the functional importance of this site.

• 

  Figure 3. Variant prioritization, segregation, in silico prediction, and ACMG/AMP classification of MYL2 p.Met138Lys. (A) Trio-based whole-exome sequencing workflow showing stepwise filtering from all variants to rare coding/splice-site variants and phenotype-relevant genes, identifying MYL2 c.413T>A (p.Met138Lys). (B) Pedigree consistent with autosomal recessive inheritance: both parents are heterozygous carriers (+/m), and the proband is homozygous (m/m). (C) In silico prediction and conservation summary. The variant is absent or ultra-rare in population databases (gnomAD) and is predicted to be deleterious by SIFT, probably damaging by PolyPhen-2, to have a high CADD score, to support pathogenicity by REVEL, and to be likely pathogenic by AlphaMissense. Met138 is conserved across species (see Figure 2). (D) ACMG/AMP-oriented evidence summary. PM2, PP3, and PP4 support classification, while PM1 was considered cautiously based on localization within a functionally relevant EF-hand-like region and residue conservation. Overall, the findings support a likely pathogenic classification.

• 

  Figure 4. Conceptual structural context of the MYL2 p.Met138Lys variant. (A) Schematic representation of the approximate location of Met138 within the C-terminal region of MYL2, shown in relation to EF-hand-like domain architecture. (B) Conceptual depiction of the wild-type methionine residue, highlighting its thioether-containing hydrophobic side chain and its possible contribution to local packing within the protein environment. (C) Conceptual depiction of the p.Met138Lys substitution, in which lysine introduces a positively charged terminal ammonium group that may plausibly influence local physicochemical properties or nearby intermolecular interactions. This schematic is conceptual and intended solely for illustrative purposes. It does not represent structural modeling, biophysical simulation, or experimental validation of pathogenicity.