RPL3L – Dilated Cardiomyopathy

Neonatal dilated cardiomyopathy (DCM) represents a severe form of cardiomyopathy presenting with ventricular dilatation and reduced systolic function in the first weeks of life. Approximately 20–30% of DCM cases demonstrate familial aggregation, yet many cases lack a defined genetic etiology. A recent study reports bi-allelic missense variants in RPL3L as the underlying cause of neonatal-onset DCM ([PMID:32514796]).

Using whole-exome sequencing in five affected individuals from three independent families, causative compound heterozygous missense variants in RPL3L were identified. Each variant co-segregated with disease status in each kindred and was absent or extremely rare in control databases. This evidence supports an autosomal recessive inheritance pattern for RPL3L-associated DCM. Total number of probands: five ([PMID:32514796]); families: three ([PMID:32514796]).

The study described seven distinct missense variants: c.722C>T (p.Pro241Leu), c.481C>T (p.Arg161Trp), c.80G>A (p.Gly27Asp), c.922G>A (p.Asp308Asn), c.1027C>T (p.Arg343Trp), c.923A>T (p.Asp308Val), and c.566C>T (p.Thr189Met). All variants localize to the highly conserved RPL3 domain of the muscle-specific 60S ribosomal protein L3-like. No loss-of-function, splice-site, structural, or deep-intronic variants were reported. Recurrent or founder alleles were not observed across the cohorts ([PMID:32514796]).

Functional analyses relied on in silico three-dimensional homology modeling, which predicted that each missense change destabilizes RPL3L binding to the 60S ribosomal RNA component. Disruption of ribosome–RNA interaction likely impairs ribosome biogenesis specifically in cardiac muscle, providing a plausible disease mechanism. Although in vitro or in vivo models remain to be developed, the modeling data are concordant with the human phenotype. The mechanism suggests loss of ribosomal stability rather than dominant-negative effects, consistent with recessive inheritance ([PMID:32514796]).

No studies to date have reported conflicting or refuting evidence for the association between RPL3L variants and neonatal DCM. Alternative genetic causes were excluded through comprehensive filtering and segregation. There is no evidence of variant pathogenicity in heterozygous carriers.

In summary, multiple families with bi-allelic RPL3L missense variants present with an early-onset, severe form of DCM, supported by robust genetic and modeling data. This association reaches a ClinGen classification of Strong based on five probands, segregation in three families, and concordant in silico functional evidence. RPL3L should be considered in genetic testing panels for neonatal DCM. Key Take-home: Biallelic RPL3L missense variants cause neonatal dilated cardiomyopathy and warrant inclusion in diagnostic evaluation.

References

• Human genetics | 2020 | Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis. PMID:32514796

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