Am J Med Genet A. 2025 Aug 17:e64225. doi: 10.1002/ajmg.a.64225. Online ahead of print.
ABSTRACT
Dilated cardiomyopathy type 2D (CMD2D) is a rare autosomal recessive disorder characterized by neonatal-onset severe cardiomyopathy, rapid progression to cardiac decompensation, and high mortality, with heart transplantation being the only life-saving intervention. Although mutations in RPL3L, a muscle-specific ribosomal protein gene critical for cardiac and skeletal muscle function, are known to cause CMD2D, this disorder remains genetically and clinically undercharacterized. To date, only 13 patients with RPL3L-related CMD2D have been reported, with nearly all of whom are attributed to compound missense mutations. Using whole exome sequencing, we identified an infant with fulminant DCM and severe acute heart failure who carried compound heterozygous RPL3L variants: c.346C>T (p.R116C) and c.605A>G (p.E202G). Histopathological analysis revealed cardiomyocyte death, collagen deposition, disturbed mitochondrial structure, and deregulated sarcomeres. Computational protein modeling demonstrated these mutations induce conformational changes in RPL3L, suggesting potential functional relevance. This case expands the mutational spectrum of CMD2D and emphasizes the need for further genotype-phenotype correlations to elucidate the pathogenesis of this lethal disorder.
PMID:40820268 | DOI:10.1002/ajmg.a.64225
