Cardiomyopathy Dilated 2D

Mendelian MONDO:0030300 Pathograph 33 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

Cardiomyopathy, dilated, 2D (CMD2D; OMIM 619371) is an autosomal recessive, neonatal- to early-infantile-onset dilated cardiomyopathy caused by biallelic germline variants in RPL3L, the heart- and skeletal-muscle-specific paralog of the core 60S ribosomal protein RPL3. Affected infants present between the first day of life and about 2.5 months with left ventricular dilatation, severely reduced systolic function, atrioventricular-valve regurgitation and rapidly progressive heart failure or cardiogenic shock. Many die in infancy; survivors have mostly required ventricular assist and heart transplantation, and one infant recovered on drug therapy. No skeletal myopathy has been reported. The disorder is known from about 13 families and 16-17 published patients. Most carry one recurrent hotspot missense allele (Gly27Asp or Asp308Asn/Val) with a private second allele. ClinGen rates the recessive RPL3L relationship Moderate under the broader dilated cardiomyopathy term (MONDO:0005021); the 2026 expert panel's "high evidence" category includes Moderate. A 2026 study using one explanted patient heart and AC16 cardiomyocyte-like cells proposes combined mechanisms: non-hotspot alleles behave like loss of function and allow RPL3 compensation, while hotspot alleles aggregate in the nucleolus, disrupt rRNA processing and keep RPL3 repressed, producing cardiac ribosome deficiency. Rpl3l knockout mice and population RPL3L-null homozygotes lack this severe disease, so simple loss of function does not explain it.

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1
Inheritance
11
Pathophys.
21
Phenotypes
4
Gaps
33
Pathograph
1
Genes
4
Medical Actions
1
Differentials
3
Models
14
References
1
Deep Research
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Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic variants co-segregate with disease in each reported family, and heterozygous carrier parents are unaffected. Most patients are compound heterozygous; two homozygous cases are reported, one in a consanguineous population and one through segmental uniparental disomy.
Autosomal recessive inheritance
Show evidence (4 references)
PMID:32514796 SUPPORT DIRECT Human Clinical
"The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern."
Segregation in three families supports recessive inheritance.
PMID:35323613 SUPPORT DIRECT Human Clinical
"Pathogenic variants were segregated as autosomal recessive to two offspring born with compound heterozygous RPL3L variants and affected by neonatal DCM."
An independent family with two affected compound heterozygous siblings.
PMID:35323613 SUPPORT DIRECT Human Clinical
"Both carrier parents were unaffected and had normal echocardiograms."
Heterozygous carriers were clinically unaffected.
+ 1 more reference
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Discussions and Knowledge Gaps

4
Why do recessive human RPL3L genotypes cause fatal neonatal DCM when Rpl3l knockout mice, and humans homozygous for population RPL3L null alleles, lack severe cardiac disease?
HUMAN MODEL MISMATCH OPEN cmd2d_knockout_does_not_model_disease
Attached to
pathophysiology#Loss of RPL3L Function from Non-hotspot Alleles pathophysiology#Persistent RPL3 Repression
Knockout mice compensate with RPL3. In gnomAD, All of Us and UK Biobank, one person is homozygous for R226X and 17 are homozygous for the c.1167+1G>A splice-donor allele without reported severe early DCM. The proposed answer is that hotspot alleles block RPL3 compensation, but that rests on AC16 cells and one explanted heart. No hotspot knock-in animal or patient iPSC cardiomyocyte model has been reported.
Proposed experiments
Hotspot knock-in mouse or patient iPSC cardiomyocytes
exp_cmd2d_hotspot_knockin
Generate a mouse carrying Gly27Asp or Asp308Asn in trans with a null allele, or patient-derived iPSC cardiomyocytes with isogenic correction of each allele, and test whether RPL3 compensation fails, 28S rRNA falls and contractile failure appears in the neonatal period.
Show evidence (3 references)
PMID:41495453 SUPPORT DIRECT Human Clinical
"The lack of severe cardiac dysfunction in both putative RPL3L-knockout humans and Rpl3l-knockout mice strongly suggests that RPL3L-linked DCM is unlikely to be caused by simple RPL3L deficiency, despite the autosomal recessive inheritance pattern in affected families."
Population and mouse evidence against simple loss of function.
PMID:41495453 SUPPORT DIRECT Human Clinical
"In addition, 17 individuals are homozygous for the splice donor variant (c.1167+1G>A)."
Homozygous putative null humans in population databases.
PMID:41495453 SUPPORT DIRECT BACKGROUND Model Organism
"Despite the recessive inheritance pattern in humans, Rpl3l knockout mice show no overt cardiac phenotype, probably because of compensatory RPL3 upregulation through unknown mechanisms."
The mouse-human discrepancy, summarised from other groups' knockout studies.
Does loss of RPL3L-containing ribosomes alter translation elongation, mitochondrial coupling, or neither?
CONTROVERSY OPEN cmd2d_contested_knockout_mechanisms
Attached to
pathophysiology#Altered Translation Elongation Dynamics pathophysiology#Increased Ribosome-Mitochondria Association
Three knockout mouse lines disagree. One shows impaired contractility and altered elongation; one shows no translational-efficiency change but more ribosome-mitochondria contact; one shows neither and no mitochondrial change. None models the hotspot genotype, so the human relevance of all three is uncertain.
Show evidence (1 reference)
PMID:36733907 SUPPORT DIRECT Model Organism
"mRNA expression analysis and ribosome profiling failed to show differences between the hearts of Rpl3l null and wild type mice in adulthood."
A null ribosome-profiling result contrasting with the elongation study.
How representative are the roughly 13 published families, and what explains the milder course and synonymous allele in the one medically recovered infant?
KNOWLEDGE GAP OPEN cmd2d_small_evidence_base
Attached to
pathophysiology#Biallelic RPL3L Variants
Phenotype, prognosis and the allele-class model all rest on fewer than 20 patients. Most were ascertained through severe neonatal presentation and exome sequencing, which may bias toward severe disease. The synonymous c.501G>A allele has no splicing or expression study, and the gain-of-function model was tested only for G27D and D308N.
Show evidence (1 reference)
PMID:36291431 SUPPORT DIRECT Human Clinical
"Bi-allelic variants in RPL3L have been reported in only seven patients from four unrelated families in the literature."
The patient pool was very small as of 2022.
Does the perinatal switch from RPL3 to RPL3L explain why disease begins in the neonatal period?
EMERGING HYPOTHESIS OPEN cmd2d_neonatal_paralog_switch
Attached to
pathophysiology#Persistent RPL3 Repression
In mouse ventricle, RPL3 dominates at birth and RPL3L gradually replaces it. Onset might coincide with the switch, when hotspot RPL3L represses RPL3 before functional RPL3L-containing ribosomes are available. This timing link has not been tested in humans.
Show evidence (1 reference)
PMID:36733907 SUPPORT INDIRECT Model Organism
"Methods and Results: Here, we observed that mouse cardiac ventricles express RPL3 at birth, where it is gradually replaced by RPL3L in adulthood but re-expressed with induction of hypertrophy in adults."
Mouse developmental timing of the paralog switch.
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Pathophysiology

11
Biallelic RPL3L Variants
Mechanism confidence: Established
Germline biallelic RPL3L variants, mostly missense in the conserved RPL3 domain, plus three frameshifts, the splice-donor allele c.1167+1G>A (exon 9 skipping) and one synonymous allele. In the 2026 meta-analysis of the 11 families known to that study, nine were compound heterozygous, and most patients combined a recurrent hotspot allele (Asp308Asn/Val in six families, Gly27Asp in three) with a private second allele. RPL3L is expressed only in cardiac and skeletal muscle and becomes the dominant RPL3-family protein in adult human left ventricular cardiomyocytes.
RPL3L hgnc:10351 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPL3L (hgnc:10351). hgnc:10351 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: missense, frameshift and synonymous variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS
Compound heterozygosity is the usual genotype; two homozygous cases (R116H in a consanguineous family; D308V through segmental uniparental disomy) are reported.
structural constituent of ribosome GO:0003735 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves structural constituent of ribosome (GO:0003735). GO:0003735 is a molecular function from the Gene Ontology.
Downstream
Loss of RPL3L Function from Non-hotspot Alleles
Hotspot RPL3L Toxic Gain of Function
Show evidence (6 references)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals."
Founding report of biallelic RPL3L variants in five affected individuals.
PMID:32514796 SUPPORT DIRECT BACKGROUND Human Clinical
"RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle."
Muscle-restricted expression of the 60S ribosomal paralog.
PMID:41495453 SUPPORT DIRECT Human Clinical
"Affected individuals typically carry one of two recurrent hotspot missense variants paired with a private allele."
The hotspot-plus-private-allele genotype structure across reported families.
+ 3 more references
Loss of RPL3L Function from Non-hotspot Alleles
Mechanism confidence: Provisional
Non-hotspot missense and truncating alleles appear to remove RPL3L function. In AC16 cells these alleles behave like knockout and allow compensatory RPL3 up-regulation; in mice, Rpl3l deletion likewise leads to retained RPL3 expression. Loss of function alone does not cause severe disease in mice or in humans homozygous for population null alleles.
RPL3L hgnc:10351 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPL3L (hgnc:10351). hgnc:10351 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
The non-hotspot (private) allele of a compound heterozygous genotype.
Animal models
Rpl3l knockout mouse (Grimes et al.) Mouse recapitulates Complete Rpl3l loss with compensatory RPL3 maintenance, matching the proposed behaviour of non-hotspot alleles.
Downstream
Cardiac Ribosome Deficiency
Altered Translation Elongation Dynamics
Show evidence (2 references)
PMID:41495453 SUPPORT DIRECT In Vitro
"Whereas non-hotspot variants phenocopy knockout and allow RPL3 compensation, hotspot variants induce nucleolar protein aggregation, disrupt rRNA processing and block compensation by preserving the role of RPL3L in repressing RPL3 via unproductive splicing."
Summary of the allele-class distinction measured in isogenic cells.
PMID:36733907 SUPPORT INDIRECT Model Organism
"Thus, deletion of Rpl3l forces maintenance of RPL3 expression within the heart that appears to fully compensate for the loss of RPL3L, although older Rpl3l -/- mice showed a mild but significant reduction in heart weight."
In mice, complete Rpl3l loss is compensated by RPL3.
Hotspot RPL3L Toxic Gain of Function
Mechanism confidence: Provisional
Recurrent hotspot proteins (G27D, D308N) are retained almost exclusively in the nucleus, aggregate with nucleolar proteins and bind the RPL3 chaperone GRWD1 and the biogenesis factor C7orf50 more strongly. They also keep RPL3L's ability to repress RPL3 through unproductive splicing. These data come from engineered AC16 cardiomyocyte-like cells, and only G27D and D308N were tested, so the same behaviour for D308V is inferred. The hotspot proteins have not been imaged in patient myocardium.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
RPL3L hgnc:10351 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPL3L (hgnc:10351). hgnc:10351 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
The recurrent hotspot allele (G27D or D308N/V) of a compound heterozygous genotype.
nucleolus GO:0005730 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nucleolus (GO:0005730). GO:0005730 is a cellular component from the Gene Ontology.
Downstream
Impaired 60S Ribosomal Subunit Biogenesis
Persistent RPL3 Repression
Show evidence (4 references)
PMID:41495453 SUPPORT DIRECT In Vitro
"Interestingly, GRWD1 (known as Rrb1 in yeast) and C7orf50 (Rbp95), the top two proteins driving the separation of hotspot variants from other variants, both exhibited increased affinity for the hotspot variants, supporting the concept of toxic GOF effects"
Interactome rewiring specific to the hotspot alleles.
PMID:41495453 SUPPORT DIRECT In Vitro
"These findings establish combined loss-of-function and gain-of-function mechanisms for RPL3L-associated cardiomyopathy and inform genetic screening, diagnosis and therapeutic development."
The authors' conclusion that the hotspot alleles act by gain of function.
PMID:41495453 SUPPORT DIRECT In Vitro
"hotspot variants induce nucleolar protein aggregation, disrupt rRNA processing and block compensation"
The three gain-of-function effects, measured for G27D and D308N only; D308V is inferred to behave the same way.
+ 1 more reference
Persistent RPL3 Repression
Mechanism confidence: Provisional
Wild-type RPL3L, and hotspot RPL3L, induce an RPL3 isoform targeted for nonsense-mediated decay, so RPL3 cannot rise to replace the missing functional RPL3L. The non-hotspot alleles lose this ability and permit compensation. Measured in AC16 cells; absent RPL3 compensation was inferred in one explanted patient heart.
regulation of alternative mRNA splicing, via spliceosome GO:0000381 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves regulation of alternative mRNA splicing, via spliceosome (GO:0000381). GO:0000381 is a biological process from the Gene Ontology. nuclear-transcribed mRNA catabolic process, nonsense-mediated decay GO:0000184 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184). GO:0000184 is a biological process from the Gene Ontology.
Downstream
Cardiac Ribosome Deficiency
Show evidence (2 references)
PMID:41495453 SUPPORT DIRECT In Vitro
"suggesting that both the SNP and hotspot variants largely retain the ability to induce RPL3 unproductive splicing, whereas non-hotspot variants have lost it."
Allele-specific retention of RPL3 unproductive splicing.
PMID:41495453 SUPPORT INDIRECT Human Clinical
"The lack of significant RPL3 compensation in patient hearts probably contributes to the several cardiac defects seen in human patients and may explain the phenotypic differences between humans and knockout mice."
Absent RPL3 compensation in patient myocardium, interpreted as contributing to disease.
Impaired 60S Ribosomal Subunit Biogenesis
Mechanism confidence: Provisional
Cells expressing hotspot alleles accumulate 45S and 32S pre-rRNA, lose cytoplasmic 28S rRNA and show reduced 60S subunits, monosomes and polysomes. Homology modelling of the founding variants also predicted weakened binding of RPL3L to 60S rRNA.
ribosomal large subunit biogenesis GO:0042273 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ribosomal large subunit biogenesis (GO:0042273). GO:0042273 is a biological process from the Gene Ontology. rRNA processing GO:0006364 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal rRNA processing (GO:0006364). GO:0006364 is a biological process from the Gene Ontology.
Downstream
Cardiac Ribosome Deficiency
Show evidence (3 references)
PMID:41495453 SUPPORT DIRECT In Vitro
"Consistent with a defect in ribosome biogenesis, sucrose gradient sedimentation revealed a dramatic reduction in 60S and monosomes and polysomes in cells expressing the hotspot variant D308N"
Direct measurement of the 60S defect in the cell model.
PMID:41495453 SUPPORT DIRECT In Vitro
"The increased pre-rRNA accumulation observed in hotspot variant cells relative to shRPL3 cells further supports the notion that expression of these recurrent variants contributes additional toxicity."
rRNA processing is disrupted beyond simple RPL3-family deficiency.
PMID:32514796 SUPPORT INDIRECT Computational
"Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit."
A structural prediction, not an experimental measurement.
Cardiac Ribosome Deficiency
Mechanism confidence: Provisional
Reduced functional cytoplasmic ribosomes in cardiomyocytes. Left ventricular tissue from one explanted heart (D308N/T189M) showed a marked loss of 28S rRNA, which the isogenic cell lines reproduced. This is the human-tissue anchor of the proposed mechanism, but it rests on a single patient.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cytoplasmic translation GO:0002181 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cytoplasmic translation (GO:0002181). GO:0002181 is a biological process from the Gene Ontology.
cytosolic large ribosomal subunit GO:0022625 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves cytosolic large ribosomal subunit (GO:0022625). GO:0022625 is a cellular component from the Gene Ontology.
Downstream
Cardiomyocyte Degeneration and Death
Show evidence (2 references)
PMID:41495453 SUPPORT DIRECT Human Clinical
"Bioanalyzer analysis of total RNA revealed a drastic reduction in the 28S rRNA peak compared to control CM heart ventricular tissues or human AC16 cardiomyocyte-like cells"
Loss of 28S rRNA in explanted patient left ventricle.
PMID:41495453 SUPPORT DIRECT Human Clinical
"To investigate the pathogenetic mechanisms of RPL3L mutations in DCM, we examined the explanted heart from a 5-month-old male patient carrying D308N/T189M9."
The human-tissue finding comes from one explanted heart.
Altered Translation Elongation Dynamics
Mechanism confidence: Hypothetical
In Rpl3l knockout mouse hearts, ribosome occupancy at codons changes, and translation of contraction- and DCM-related transcripts is most affected. RPL3L-containing ribosomes collide less than RPL3-containing ones. A second knockout study found no change in translational efficiency, so the finding is contested and has not been tested in patient tissue.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
translational elongation GO:0006414 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal translational elongation (GO:0006414). GO:0006414 is a biological process from the Gene Ontology.
Animal models
Rpl3l knockout mouse (Shiraishi et al.) Mouse recapitulates Ribosome profiling of knockout hearts shows altered codon occupancy.
Downstream
Impaired Left Ventricular Systolic Function and Dilatation
Show evidence (2 references)
PMID:37080962 SUPPORT DIRECT Model Organism
"RPL3L-containing ribosomes were less prone to collisions compared with RPL3-containing canonical ribosomes."
Mouse finding on how RPL3L ribosomes differ in elongation.
PMID:36882085 REFUTE DIRECT Model Organism
"Using both ribosome profiling (Ribo-seq) and a novel orthogonal approach consisting of ribosome pulldown coupled to nanopore sequencing (Nano-TRAP), we find that RPL3L modulates neither translational efficiency nor ribosome affinity towards a specific subset of transcripts."
An independent knockout found no translational-efficiency change.
Increased Ribosome-Mitochondria Association
Mechanism confidence: Hypothetical
In Rpl3l knockout mouse cardiomyocytes, RPL3-containing ribosomes associate more with mitochondria and ATP rises. This effect depends on RPL3 replacing RPL3L, the compensation that hotspot alleles are proposed to block in patients, so it is not linked to the patient genotype here and has no upstream or downstream edge. Explanted human myocardium showed disturbed mitochondrial structure, but no study links the two.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrion (GO:0005739). GO:0005739 is a cellular component from the Gene Ontology.
Animal models
Rpl3l knockout mouse (Milenkovic et al.) Mouse recapitulates The knockout shows the ribosome-mitochondria change that defines this node.
Show evidence (2 references)
PMID:36882085 SUPPORT DIRECT Model Organism
"Instead, we reveal a complex cellular scenario in which RPL3L modulates the expression of RPL3, which in turn affects ribosomal subcellular localization and, ultimately, mitochondrial activity."
Mouse knockout evidence for a ribosome-mitochondria effect.
PMID:36733907 REFUTE DIRECT Model Organism
"Moreover, ribosomes lacking RPL3L showed no differences in localization within cardiomyocytes compared to wild type controls, nor was there an alteration in cardiac tissue ultrastructure or mitochondrial function in adult Rpl3l -/- mice."
A second knockout found no change in ribosome localization or mitochondrial function.
Cardiomyocyte Degeneration and Death
Mechanism confidence: Provisional
Explanted and autopsy myocardium shows myocytolysis, degenerated myocytes with perinuclear vacuolization, cardiomyocyte death, disturbed mitochondrial structure and disordered sarcomeres, with myocyte hypertrophy and interstitial fibrosis.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Myocardial Fibrosis
Impaired Left Ventricular Systolic Function and Dilatation
Show evidence (2 references)
PMID:40820268 SUPPORT DIRECT Human Clinical
"Histopathological analysis revealed cardiomyocyte death, collagen deposition, disturbed mitochondrial structure, and deregulated sarcomeres."
Patient myocardial histopathology.
PMID:32514796 SUPPORT DIRECT Human Clinical
"Myocardial pathology assessment showed degenerated myocytes with perinuclear vacuolization, hypertrophic muscle fibers and diffuse interstitial fibrosis."
Myocyte degeneration in the founding family.
Impaired Left Ventricular Systolic Function and Dilatation
Mechanism confidence: Established
Left (and often right) ventricular dilatation with severely reduced ejection fraction, from 6% to about 36% at presentation in reported cases.
cardiac muscle contraction GO:0060048 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac muscle contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology.
heart left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Rpl3l knockout mouse (Grimes et al.) Mouse fails to recapitulate No cardiac structural or functional abnormality at baseline or after pressure overload.
Rpl3l knockout mouse (Shiraishi et al.) Mouse partially recapitulates Reduced contractility without the fulminant neonatal dilated cardiomyopathy of patients.
Downstream
Heart Failure
Dilated Cardiomyopathy
Left Ventricular Dilatation
Reduced Left Ventricular Ejection Fraction
Cardiomegaly
Mitral Regurgitation Functional regurgitation secondary to ventricular and annular dilatation; valve structure was not reported as abnormal.
Tricuspid Regurgitation Functional regurgitation secondary to right-sided dilatation.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Echocardiogram showed severely decreased biventricular systolic function (EF 6%), moderate LV dilation (LV end-diastolic diameter 3.7 cm; z-score 6.9) with mild LA dilation, and mild tricuspid and mitral valve regurgitation."
Ventricular dilatation with severe systolic failure in an affected infant.
Heart Failure
Mechanism confidence: Established
Rapidly progressive heart failure and cardiogenic shock in the neonatal and early infantile period, frequently fatal without mechanical support and transplantation.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cardiogenic Shock
Congestive Heart Failure
Dyspnea
Tachypnea
Lethargy
Fatigue
Feeding Difficulties
Hepatomegaly Congestive hepatomegaly from systemic venous congestion.
Show evidence (2 references)
PMID:35323613 SUPPORT DIRECT Human Clinical
"This is the second report in the literature to the best of our knowledge and our findings support the pathogenicity of biallelic RPL3L pathologic variants associated with rapidly progressive neonatal DCM and heart failure with a poor prognosis."
Rapidly progressive heart failure is the clinical outcome.
PMID:32514796 SUPPORT DIRECT Human Clinical
"He showed no signs of hypotonia and died on the 15th day of life due to acute cardiac decompensation."
Fatal neonatal cardiac decompensation.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cardiomyopathy Dilated 2D Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

21
Cardiovascular 14
Dilated Cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644), qualified as neonatal onset. HP:0001644 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (3 references)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period."
Neonatal DCM in all five founding patients.
PMID:32514796 SUPPORT DIRECT Human Clinical
"Perinatal monitoring revealed a DCM at the first day of life."
Earliest reported onset.
PMID:36291431 SUPPORT DIRECT Human Clinical
"Whole exome sequencing has identified an infant girl with fulminant dilated cardiomyopathy (DCM), leading to severe acute heart failure associated with ribosomal protein large 3-like (RPL3L) gene pathologic variants."
An independent case with fulminant DCM.
Left Ventricular Dilatation HP:4000141 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular dilatation (HP:4000141). HP:4000141 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42156347 SUPPORT DIRECT Human Clinical
"Cardiac ultrasound revealed an enlarged left ventricle, moderate mitral valve regurgitation, and an ejection fraction of 31%."
Enlarged left ventricle on echocardiography.
Reduced Left Ventricular Ejection Fraction HP:0012664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced left ventricular ejection fraction (HP:0012664). HP:0012664 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Echocardiogram showed severely decreased biventricular systolic function (EF 6%), moderate LV dilation (LV end-diastolic diameter 3.7 cm; z-score 6.9) with mild LA dilation, and mild tricuspid and mitral valve regurgitation."
Severely reduced ejection fraction.
PMID:35323613 SUPPORT DIRECT Human Clinical
"Echocardiography (ECHO) showed left ventricular (LV) dilatation and biventricular depressed function (moderately depressed LV function with ejection fraction (LV EF) of 36%) (Figure 1C)."
Reduced ejection fraction in an independent family.
Congestive Heart Failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35323613 SUPPORT DIRECT Human Clinical
"This is the second report in the literature to the best of our knowledge and our findings support the pathogenicity of biallelic RPL3L pathologic variants associated with rapidly progressive neonatal DCM and heart failure with a poor prognosis."
Heart failure accompanies the DCM.
PMID:42156347 SUPPORT DIRECT Human Clinical
"Her brother had succumbed to fulminant cardiomyopathy and heart failure at the same age."
Fatal heart failure in a sibling; the report does not state that the brother was genotyped.
Cardiogenic Shock HP:0030149 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiogenic shock (HP:0030149). HP:0030149 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"She was born after an uneventful pregnancy and was admitted due to cardiogenic shock on her 48th day of life."
Presentation with cardiogenic shock.
Mitral Regurgitation HP:0001653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitral regurgitation (HP:0001653). HP:0001653 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42156347 SUPPORT DIRECT Human Clinical
"Cardiac ultrasound revealed an enlarged left ventricle, moderate mitral valve regurgitation, and an ejection fraction of 31%."
Moderate mitral regurgitation.
PMID:32514796 SUPPORT DIRECT Human Clinical
"Echocardiogram showed severely decreased biventricular systolic function (EF 6%), moderate LV dilation (LV end-diastolic diameter 3.7 cm; z-score 6.9) with mild LA dilation, and mild tricuspid and mitral valve regurgitation."
Mild mitral regurgitation in a founding-family patient.
Tricuspid Regurgitation HP:0005180 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tricuspid regurgitation (HP:0005180). HP:0005180 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"He was diagnosed with DCM and tricuspid insufficiency on the sixth day of life."
Tricuspid insufficiency at diagnosis.
Pulmonary Arterial Hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Echocardiography showed dilated right ventricle (RV) and pulmonary arterial hypertension (Fig. 1b, upper panel)."
Pulmonary arterial hypertension on echocardiography.
Cardiomegaly HP:0001640 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomegaly (HP:0001640). HP:0001640 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Chest X-ray revealed cardiomegaly with diffusely increased vascularity and a small right pleural effusion."
Radiographic cardiomegaly.
Abnormal T-wave HP:0005135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal T-wave (HP:0005135). HP:0005135 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Electrocardiogram showed right axis deviation with RV conduction delay, prominent LV forces for age and nonspecific ST and T wave abnormalities."
ST and T-wave abnormalities on ECG.
Abnormal ST Segment HP:0012249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal ST segment (HP:0012249). HP:0012249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Electrocardiogram showed right axis deviation with RV conduction delay, prominent LV forces for age and nonspecific ST and T wave abnormalities."
Nonspecific ST abnormalities on ECG.
Premature Atrial Contractions HP:0006699 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature atrial contractions (HP:0006699). HP:0006699 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37308880 SUPPORT DIRECT Human Clinical
"In addition to previously reported clinical features, the patient showed the previously unreported complication of occasional premature atrial contractions and a first-degree atrioventricular block."
Single-case observation.
First Degree Atrioventricular Block HP:0011705 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is First degree atrioventricular block (HP:0011705). HP:0011705 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37308880 SUPPORT DIRECT Human Clinical
"In addition to previously reported clinical features, the patient showed the previously unreported complication of occasional premature atrial contractions and a first-degree atrioventricular block."
Single-case observation.
Myocardial Fibrosis HP:0001685 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocardial fibrosis (HP:0001685). HP:0001685 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Pathology evaluation of the explant heart showed moderate myocyte hypertrophy, interstitial fibrosis, and multi-focal subendocardial myocytolysis with evidence of chronic LV ischemia (Fig. 1c)."
Interstitial fibrosis in explanted heart.
PMID:40820268 SUPPORT DIRECT Human Clinical
"Histopathological analysis revealed cardiomyocyte death, collagen deposition, disturbed mitochondrial structure, and deregulated sarcomeres."
Collagen deposition in an independent case.
Digestive 3
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32514796 SUPPORT DIRECT Human Clinical
"At 2 months of age, she presented with fatigue, vomiting, and lethargy."
Vomiting at presentation.
PMID:32514796 SUPPORT DIRECT Human Clinical
"presented with non-bilious, non-bloody vomiting and tachypnea."
Vomiting at presentation in the affected brother.
Feeding Difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42156347 SUPPORT DIRECT Human Clinical
"A 2-month-old girl was admitted in June 2022 with poor appetite, breathlessness, and lethargy."
Poor appetite as a presenting symptom.
Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36291431 SUPPORT DIRECT Human Clinical
"She had hepatomegaly; the liver was 3 cm below the right subcostal margin but no splenomegaly or ascites was observed."
Single-case observation in decompensated heart failure.
Nervous System 1
Lethargy HP:0001254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lethargy (HP:0001254). HP:0001254 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32514796 SUPPORT DIRECT Human Clinical
"At 2 months of age, she presented with fatigue, vomiting, and lethargy."
Lethargy at presentation.
PMID:42156347 SUPPORT DIRECT Human Clinical
"A 2-month-old girl was admitted in June 2022 with poor appetite, breathlessness, and lethargy."
Lethargy at presentation in an independent family.
Respiratory 2
Tachypnea HP:0002789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tachypnea (HP:0002789). HP:0002789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"presented with non-bilious, non-bloody vomiting and tachypnea."
Tachypnea at presentation.
Dyspnea HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42156347 SUPPORT DIRECT Human Clinical
"A 2-month-old girl was admitted in June 2022 with poor appetite, breathlessness, and lethargy."
Breathlessness at presentation.
Constitutional 1
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"At 2 months of age, she presented with fatigue, vomiting, and lethargy."
Fatigue as a presenting symptom.
🧬

Genetic Associations

1
RPL3L (Biallelic RPL3L variants are reported in CMD2D. The evidence rests on about 13 published families (16-17 patients), with segregation in several multiplex sibships, recurrent hotspot alleles across unrelated families, and functional data from one explanted heart and engineered AC16 cells. ClinGen rates the recessive pair Moderate under the broader dilated cardiomyopathy term (MONDO:0005021). The 2026 expert-panel "high evidence" category includes Moderate, so it does not imply Definitive or Strong.)
Gene: RPL3L hgnc:10351 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPL3L (hgnc:10351). hgnc:10351 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (9 references)
PMID:32514796 SUPPORT DIRECT Human Clinical
"In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies."
The founding gene-disease claim.
PMID:35323613 SUPPORT DIRECT Human Clinical
"In the present brief report, we identified two pathogenic RPL3L variants, each harbored in unaffected heterozygous parents: mother (RPL3L c.1076_1080delCCGTG (p.Ala359Glyfs*4)) and father (RPL3L c.80G > A (p.Gly27Asp))."
Independent family replicating the gene-disease link.
PMID:37308880 SUPPORT DIRECT Human Clinical
"Whole-exome sequencing (WES) revealed compound heterozygous variants (c.80G > A (p.Gly27Asp) and c.1074dupA (p.Ala359fs*6)) in RPL3L (NM_005061.3)."
A further family with the recurrent Gly27Asp allele.
+ 6 more references
💊

Medical Actions

4
Heart failure pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Cardiotonic Agent NCIT:C78322 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Cardiotonic Agent (NCIT:C78322). NCIT:C78322 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Supportive heart-failure drugs, including inotropes (milrinone, dobutamine), digoxin and ACE inhibition, as used in case reports. No RPL3L-specific efficacy data exist; one infant recovered on drug therapy, while most others progressed despite inotropic support.
Mechanism Target:
Heart Failure — Supports failing pump function; does not correct the ribosomal defect.
Show evidence (3 references)
PMID:35323613 SUPPORT DIRECT Human Clinical
"Inotropic support (milrinone) was started to improve cardiac output due to depressed LV function."
Inotropic support in a case report; the patient later died.
PMID:42156347 SUPPORT DIRECT Human Clinical
"On day 4 of treatment, oral digoxin was initiated using a rapid digitalization protocol, after which dobutamine was discontinued."
Inotrope and digoxin use in the infant who recovered.
PMID:42156347 SUPPORT DIRECT Human Clinical
"Drug therapy improved the patient's cardiac function, and she demonstrated normal cardiac function after 6 months."
A single uncontrolled case; recovery cannot be attributed to the drugs.
Ventricular assist device as bridge to transplant
Action: Left Ventricular Assist Device InsertionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Left Ventricular Assist Device Insertion (NCIT:C172327). NCIT:C172327 is a clinical intervention from the NCI Thesaurus. NCIT:C172327
Platform: Device
Mechanical circulatory support with a pediatric left ventricular assist device (Berlin Heart EXCOR) bridged one infant to heart transplantation.
Mechanism Target:
Heart Failure — Replaces failing left ventricular output until transplantation.
Show evidence (1 reference)
PMID:36291431 SUPPORT DIRECT Human Clinical
"She required a Berlin-Excor left ventricular assist device due to worsening of her heart failure as a bridge to orthotopic heart transplantation."
Single-case use as a bridge to transplant.
Heart transplantation
Action: Heart TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Heart Transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. NCIT:C15246
Platform: Surgery
The main life-saving intervention reported; transplanted patients survived to at least 9-10 years.
Mechanism Target:
Heart Failure — Replaces the affected heart.
Show evidence (3 references)
PMID:40820268 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"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."
Transplantation as the life-saving option.
PMID:36291431 SUPPORT DIRECT Human Clinical
"At three months follow-up after heart transplantation, she has been doing well."
Short-term post-transplant outcome.
PMID:35323613 SUPPORT DIRECT Human Clinical
"Early diagnosis of RPL3L variants can facilitate listing for a heart transplant."
Genetic diagnosis informs transplant listing.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Recessive recurrence risk counselling, carrier testing of relatives and reproductive options once both familial variants are known.
Show evidence (1 reference)
PMID:42156347 SUPPORT INDIRECT BACKGROUND Human Clinical
"Genetic testing now plays a central role in identifying the underlying etiology, guiding family screening, and informing genetic counseling, particularly in early-onset or familial cases."
General statement about early-onset DCM, not an RPL3L-specific study.
🔬

Diagnosis

2
Exome sequencing
Every reported case was identified by exome sequencing, after cardiomyopathy panels that did not include RPL3L. RPL3L should be considered in infantile DCM with negative panel testing.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals."
Exome sequencing identified the founding variants.
Myocardial histopathology
Explant or autopsy myocardium shows myocytolysis, degenerated myocytes and interstitial fibrosis. These findings are not specific to RPL3L disease.
Show evidence (1 reference)
PMID:32514796 SUPPORT DIRECT Human Clinical
"Pathology evaluation of the explant heart showed moderate myocyte hypertrophy, interstitial fibrosis, and multi-focal subendocardial myocytolysis with evidence of chronic LV ischemia (Fig. 1c)."
Explant histopathology in an affected infant.
📈

Progression

2
Neonatal or early infantile onset
Age: 0-2.5 months
Dilated cardiomyopathy is detected from the first day of life to about 2.5 months, with rapid decompensation.
Show evidence (1 reference)
PMID:37308880 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Dilated cardiomyopathy type-2D (CMD2D) is a rare heart disease causing a severe cardiomyopathy with neonatal onset and rapid progression to cardiac decompensation and death in untreated patients."
The typical onset and course.
Death in infancy or transplantation
Age: 2 weeks-10 years
Several infants died between about two weeks and four months; transplanted children were alive at 9-10 years. One infant recovered normal function on drug therapy, an exception whose basis is unknown.
Show evidence (4 references)
PMID:36291431 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"RPL3L is a newer and likely pathogenic gene associated with a severe form of early-onset dilated cardiomyopathy with poor prognosis necessitating heart transplantation."
Poor prognosis and reliance on transplantation.
PMID:35323613 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Two patients (Cases 3 and 4) underwent successful heart transplantations and were alive at age 9 and 10 years, respectively, at publication [11]."
Long-term survival after transplantation, as relayed from the founding report.
PMID:32514796 SUPPORT DIRECT Human Clinical
"He is currently 9 years of age, and his post-transplant course has been complicated by lymphoproliferative disorder confirmed on ileal biopsy, eosinophilic esophagitis, pancreatitis, left hydronephrosis, and a chronic anemia."
Survival to 9 years after transplantation, from the founding report.
+ 1 more reference
📊

Prevalence

1
Reported patients worldwide
Cases In Literature Ultra Rare
About 16-17 patients from about 13 families (Germany, Colombia, Spain, USA, China and other cases) have been published. This is a publication count, not a population prevalence estimate.
Show evidence (2 references)
PMID:40820268 SUPPORT DIRECT Human Clinical
"To date, only 13 patients with RPL3L-related CMD2D have been reported, with nearly all of whom are attributed to compound missense mutations."
Literature count before this case report.
PMID:41495453 SUPPORT DIRECT Human Clinical
"Meta-analyses of all 11 cases highlight two prominent features: compound heterozygosity and hotspot missense variants."
Eleven families known to the 2026 study; two later Chinese families bring the total to about 13.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Cardiomyopathy Dilated 2D:

Metabolic, infectious and mitochondrial causes of infantile DCM
Overlapping Features Secondary metabolic and infectious causes, and mitochondrial disease, were excluded in reported patients before RPL3L testing.
Show evidence (2 references)
PMID:36291431 SUPPORT DIRECT Human Clinical
"Secondary causes for DCM due to metabolic and infectious etiologies were ruled out."
Metabolic and infectious causes formed the clinical differential.
PMID:36291431 SUPPORT DIRECT Human Clinical
"Other genetic tests for mitochondrial disorders by sequence analysis and deletion testing of the mitochondrial genome were negative."
Mitochondrial disease was excluded.
🐁

Animal Models

3
Rpl3l knockout mouse (Grimes et al.)
Knockout mice show no change in cardiac structure or function at baseline or after pressure overload, because RPL3 stays up-regulated; by 18 months their hearts are smaller. The model does not reproduce dilated cardiomyopathy.
Species
Mouse
Genotype
Rpl3l -/- germline deletion
Publication
PMID:36733907
Pathograph links
Loss of RPL3L Function from Non-hotspot Alleles recapitulates fidelity: moderate observes: molecular Complete Rpl3l loss with compensatory RPL3 maintenance, matching the proposed behaviour of non-hotspot alleles.
Limitations: Models complete loss on both alleles, not the human hotspot-plus-private genotype.
Divergences from the human mechanism
cause unrepresented qualifying
No hotspot allele is present, so the gain-of-function arm that blocks RPL3 compensation is absent.
Show evidence (1 reference)
PMID:36733907 SUPPORT DIRECT Model Organism
"Thus, deletion of Rpl3l forces maintenance of RPL3 expression within the heart that appears to fully compensate for the loss of RPL3L, although older Rpl3l -/- mice showed a mild but significant reduction in heart weight."
Knockout with RPL3 compensation.
Impaired Left Ventricular Systolic Function and Dilatation fails to recapitulate fidelity: low observes: tissue No cardiac structural or functional abnormality at baseline or after pressure overload.
Limitations: Adult-focused phenotyping; neonatal cardiac function was not the main readout.
Divergences from the human mechanism
cause unrepresented invalidating
RPL3 compensation, which hotspot alleles block in humans, is intact in the knockout.
Show evidence (1 reference)
PMID:36733907 SUPPORT DIRECT Model Organism
"Rpl3l gene-deleted mice were generated to examine the role of this gene in the heart, although Rpl3l -/- mice showed no overt changes in cardiac structure or function at baseline or after pressure overload hypertrophy, likely because RPL3 expression was upregulated and maintained in adulthood."
No DCM phenotype in the knockout.
Rpl3l knockout mouse (Shiraishi et al.)
Male knockout mice have impaired cardiac contractility and altered ribosome elongation dynamics, most marked for contraction- and DCM-related transcripts.
Species
Mouse
Genotype
Rpl3l -/- (male mice studied)
Publication
PMID:37080962
Pathograph links
Altered Translation Elongation Dynamics recapitulates fidelity: unknown observes: cellular Ribosome profiling of knockout hearts shows altered codon occupancy.
Limitations: Not confirmed in patient tissue, and a second knockout study found no translational-efficiency change.
Divergences from the human mechanism
species mismatch qualifying
Measured in adult mouse heart, not in neonatal human myocardium with hotspot alleles.
Show evidence (1 reference)
PMID:37080962 SUPPORT DIRECT Model Organism
"Ribosome occupancy at mRNA codons was found to be altered in the RPL3L-deficient heart, and the changes were negatively correlated with those observed in myoblasts overexpressing RPL3L."
The elongation readout in knockout hearts.
Impaired Left Ventricular Systolic Function and Dilatation partially recapitulates fidelity: low observes: tissue Reduced contractility without the fulminant neonatal dilated cardiomyopathy of patients.
Limitations: A mild adult phenotype in contrast to fatal neonatal disease.
Divergences from the human mechanism
species mismatch qualifying
Mild contractile impairment in adult male mice, versus fulminant neonatal failure in humans.
Show evidence (1 reference)
PMID:37080962 SUPPORT DIRECT Model Organism
"Deficiency of RPL3L-containing ribosomes in RPL3L knockout male mice resulted in impaired cardiac contractility."
Contractile impairment in knockout mice.
Rpl3l knockout mouse (Milenkovic et al.)
Viable knockout in which RPL3 replaces RPL3L in cardiomyocyte ribosomes; ribosome-mitochondria contacts and ATP increase.
Species
Mouse
Genotype
Rpl3l -/- viable homozygous knockout
Publication
PMID:36882085
Pathograph links
Increased Ribosome-Mitochondria Association recapitulates fidelity: unknown observes: cellular The knockout shows the ribosome-mitochondria change that defines this node.
Limitations: Not observed in a second knockout line and not measured in patients.
Divergences from the human mechanism
species mismatch qualifying
Mouse cardiomyocytes lacking RPL3L entirely, not human hotspot-plus-private genotypes.
Show evidence (1 reference)
PMID:36882085 SUPPORT DIRECT Model Organism
"In contrast, we show that depletion of RPL3L leads to increased ribosome-mitochondria interactions in cardiomyocytes, which is accompanied by a significant increase in ATP levels, potentially as a result of fine-tuning of mitochondrial activity."
The defining measurement.
{ }

Source YAML

click to show 
name: Cardiomyopathy Dilated 2D
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: cardiomyopathy, dilated, 2D
  term:
    id: MONDO:0030300
    label: cardiomyopathy, dilated, 2D
synonyms:
- CMD2D
- dilated cardiomyopathy type 2D
- RPL3L-related dilated cardiomyopathy
- RPL3L-related neonatal dilated cardiomyopathy
description: >-
  Cardiomyopathy, dilated, 2D (CMD2D; OMIM 619371) is an autosomal recessive,
  neonatal- to early-infantile-onset dilated cardiomyopathy caused by biallelic
  germline variants in RPL3L, the heart- and skeletal-muscle-specific paralog of
  the core 60S ribosomal protein RPL3. Affected infants present between the first
  day of life and about 2.5 months with left ventricular dilatation, severely
  reduced systolic function, atrioventricular-valve regurgitation and rapidly
  progressive heart failure or cardiogenic shock. Many die in infancy; survivors
  have mostly required ventricular assist and heart transplantation, and one
  infant recovered on drug therapy. No skeletal myopathy has been reported. The
  disorder is known from about 13 families and 16-17 published patients. Most
  carry one recurrent hotspot missense allele (Gly27Asp or Asp308Asn/Val) with a
  private second allele. ClinGen rates the recessive RPL3L relationship Moderate
  under the broader dilated cardiomyopathy term (MONDO:0005021); the 2026 expert
  panel's "high evidence" category includes Moderate. A 2026 study using one explanted patient heart and AC16
  cardiomyocyte-like cells proposes combined mechanisms: non-hotspot alleles
  behave like loss of function and allow RPL3 compensation, while hotspot alleles
  aggregate in the nucleolus, disrupt rRNA processing and keep RPL3 repressed,
  producing cardiac ribosome deficiency. Rpl3l knockout mice and population
  RPL3L-null homozygotes lack this severe disease, so simple loss of function does
  not explain it.
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
  Evidence base: three families (five patients) in the founding 2020 report, a
  further US sibship of two, single Chinese and US cases (2022-2023), four
  additional cases in the 2026 mechanistic study (which counted 11 families
  known to it), and two further Chinese families (R116C/E202G and E108K/Q167=)
  not included in that count, giving about 13 families and 16-17 patients.
  Counts across reports overlap and are not independent cohorts. RPL3L also
  appeared as one of seven homozygous novel candidate genes in a Saudi
  consanguineous childhood cardiomyopathy cohort, without functional follow-up.
  ClinGen has a cached gene-validity record for RPL3L with the broader term
  dilated cardiomyopathy (MONDO:0005021, autosomal recessive, Moderate,
  2025-05-30), which is not this entry's MONDO term, so no
  gene_disease_validity tier is recorded and no relationship_type is asserted;
  the 2026 ClinGen DCM expert-panel reassessment (Jordan et al.) lists RPL3L
  among genes newly classified as high evidence, a category that includes
  Moderate. In a genome-wide study (PMID:30271950), heterozygous RPL3L missense
  and splice-donor variants were associated with atrial fibrillation; that is a
  separate susceptibility phenotype, not CMD2D. The same splice-donor allele
  (c.1167+1G>A, exon 9 skipping) has also been reported among CMD2D patient
  alleles (PMID:41495453). Some reports cite the
  general dilated cardiomyopathy OMIM series (115200) rather than 619371.
  RPL3L must not be confused with its ubiquitous paralog RPL3. GeneReviews check
  (just check-genereviews --online, 2026-10-08) found no CMD2D- or
  RPL3L-specific GeneReviews chapter.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic variants co-segregate with disease in each reported family, and
    heterozygous carrier parents are unaffected. Most patients are compound
    heterozygous; two homozygous cases are reported, one in a consanguineous
    population and one through segmental uniparental disomy.
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern.
    explanation: Segregation in three families supports recessive inheritance.
  - reference: PMID:35323613
    reference_title: Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Pathogenic variants were segregated as autosomal recessive to two offspring born with compound heterozygous RPL3L variants and affected by neonatal DCM.
    explanation: An independent family with two affected compound heterozygous siblings.
  - reference: PMID:35323613
    reference_title: Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Both carrier parents were unaffected and had normal echocardiograms.
    explanation: Heterozygous carriers were clinically unaffected.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The two exceptions are a homozygous R116H case identified in a consanguineous population12 and a homozygous D308V case reported in this study (because of segmental uniparental disomy; Supplementary Note).
    explanation: Homozygous cases exist alongside the compound heterozygous majority.
pathophysiology:
- name: Biallelic RPL3L Variants
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Germline biallelic RPL3L variants, mostly missense in the conserved RPL3
    domain, plus three frameshifts, the splice-donor allele c.1167+1G>A (exon 9
    skipping) and one synonymous allele. In the 2026 meta-analysis of the 11
    families known to that study, nine were compound heterozygous, and most
    patients combined a recurrent hotspot allele (Asp308Asn/Val in six families,
    Gly27Asp in three) with a private second allele. RPL3L is expressed only in
    cardiac and skeletal muscle and becomes the dominant RPL3-family protein in
    adult human left ventricular cardiomyocytes.
  genes:
  - preferred_term: RPL3L
    term:
      id: hgnc:10351
      label: RPL3L
  molecular_functions:
  - preferred_term: structural constituent of ribosome
    term:
      id: GO:0003735
      label: structural constituent of ribosome
  genetic_context:
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    allele_type: missense, frameshift and synonymous
    description: Compound heterozygosity is the usual genotype; two homozygous cases (R116H in a consanguineous family; D308V through segmental uniparental disomy) are reported.
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals.
    explanation: Founding report of biallelic RPL3L variants in five affected individuals.
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle.
    explanation: Muscle-restricted expression of the 60S ribosomal paralog.
    quote_role: BACKGROUND
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Affected individuals typically carry one of two recurrent hotspot missense variants paired with a private allele.
    explanation: The hotspot-plus-private-allele genotype structure across reported families.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The four remaining variants are putative LOF, including three truncating frameshift variants (T340Nfs*25 previously unreported, threonine to asparagine followed by 25 amino acids) and a splice donor variant (c.1167+1G>A) that causes exon 9 skipping
    explanation: Truncating and splice alleles in patients, including the splice-donor allele also associated with atrial fibrillation.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Meta-analyses of all 11 cases highlight two prominent features: compound heterozygosity and hotspot missense variants."
    explanation: Pooled analysis of the 11 families known to that study; two later Chinese families (PMID:40820268, PMID:42156347) are not included.
  - reference: PMID:37308880
    reference_title: "Novel compound heterozygous variants in the RPL3L gene causing dilated cardiomyopathy type-2D: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The latter novel variant may result in the absence of protein production with a significant decrease in mRNA level, suggesting it is a loss-of-function mutation.
    explanation: A frameshift allele with reduced mRNA, consistent with a null second allele.
  downstream:
  - target: Loss of RPL3L Function from Non-hotspot Alleles
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41495453
      reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: The difference in RPL3 compensation again suggests that the non-hotspot variants R161W and T189M, but not hotspot variants G27D and D308N, are functionally equivalent to RPL3L knockout.
      explanation: In isogenic AC16 cells, the non-hotspot alleles behave as loss of function.
  - target: Hotspot RPL3L Toxic Gain of Function
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41495453
      reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: Taken together, we found that the hotspot variants G27D and D308N, but not their coinherited non-hotspot variants T189M and R161W, are responsible for ribosome biogenesis defects and cellular toxicity.
      explanation: Hotspot alleles, specifically, confer the toxic cellular effect in the isogenic cell model.
- name: Loss of RPL3L Function from Non-hotspot Alleles
  biological_scale: MOLECULAR
  role: mechanism
  mechanism_confidence: PROVISIONAL
  description: >-
    Non-hotspot missense and truncating alleles appear to remove RPL3L function.
    In AC16 cells these alleles behave like knockout and allow compensatory RPL3
    up-regulation; in mice, Rpl3l deletion likewise leads to retained RPL3
    expression. Loss of function alone does not cause severe disease in mice or
    in humans homozygous for population null alleles.
  genes:
  - preferred_term: RPL3L
    term:
      id: hgnc:10351
      label: RPL3L
  genetic_context:
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: The non-hotspot (private) allele of a compound heterozygous genotype.
  evidence:
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: Whereas non-hotspot variants phenocopy knockout and allow RPL3 compensation, hotspot variants induce nucleolar protein aggregation, disrupt rRNA processing and block compensation by preserving the role of RPL3L in repressing RPL3 via unproductive splicing.
    explanation: Summary of the allele-class distinction measured in isogenic cells.
  - reference: PMID:36733907
    reference_title: Rpl3l gene deletion in mice reduces heart weight over time.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: Thus, deletion of Rpl3l forces maintenance of RPL3 expression within the heart that appears to fully compensate for the loss of RPL3L, although older Rpl3l -/- mice showed a mild but significant reduction in heart weight.
    explanation: In mice, complete Rpl3l loss is compensated by RPL3.
  downstream:
  - target: Cardiac Ribosome Deficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41495453
      reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: This combination—loss of ribosomal function coupled with blockade of RPL3 compensation—results in ribosome deficiency, as observed in patient hearts
      explanation: Loss of RPL3L function causes ribosome deficiency only when RPL3 compensation is blocked by the hotspot allele.
  - target: Altered Translation Elongation Dynamics
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37080962
      reference_title: RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Although the loss of RPL3L-containing ribosomes altered translation elongation dynamics for the entire transcriptome, its effects were most pronounced for transcripts related to cardiac muscle contraction and dilated cardiomyopathy, with the abundance of the encoded proteins being correspondingly decreased.
      explanation: Rpl3l knockout mouse hearts show altered elongation; not measured in patient tissue.
- name: Hotspot RPL3L Toxic Gain of Function
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Recurrent hotspot proteins (G27D, D308N) are retained almost exclusively in
    the nucleus, aggregate with nucleolar proteins and bind the RPL3 chaperone
    GRWD1 and the biogenesis factor C7orf50 more strongly. They also keep
    RPL3L's ability to repress RPL3 through unproductive splicing. These data
    come from engineered AC16 cardiomyocyte-like cells, and only G27D and D308N
    were tested, so the same behaviour for D308V is inferred. The hotspot
    proteins have not been imaged in patient myocardium.
  genes:
  - preferred_term: RPL3L
    term:
      id: hgnc:10351
      label: RPL3L
  genetic_context:
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: The recurrent hotspot allele (G27D or D308N/V) of a compound heterozygous genotype.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: nucleolus
    term:
      id: GO:0005730
      label: nucleolus
  evidence:
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: Interestingly, GRWD1 (known as Rrb1 in yeast) and C7orf50 (Rbp95), the top two proteins driving the separation of hotspot variants from other variants, both exhibited increased affinity for the hotspot variants, supporting the concept of toxic GOF effects
    explanation: Interactome rewiring specific to the hotspot alleles.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: These findings establish combined loss-of-function and gain-of-function mechanisms for RPL3L-associated cardiomyopathy and inform genetic screening, diagnosis and therapeutic development.
    explanation: The authors' conclusion that the hotspot alleles act by gain of function.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: hotspot variants induce nucleolar protein aggregation, disrupt rRNA processing and block compensation
    explanation: The three gain-of-function effects, measured for G27D and D308N only; D308V is inferred to behave the same way.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: The rarity of these hotspot variants in the general population and their repeated occurrence in a substantial proportion of affected families strongly challenges an LOF mechanism for these variants.
    explanation: Population-genetic argument against a simple loss-of-function mechanism for the hotspot alleles.
  downstream:
  - target: Impaired 60S Ribosomal Subunit Biogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41495453
      reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: The sequestration of these essential 60S ribosome biogenesis factors by hotspot variants probably contributes to the 60S biogenesis defect and the toxic GOF associated with these variants.
      explanation: Sequestration of biogenesis factors links hotspot proteins to the 60S defect; the authors hedge with "probably".
  - target: Persistent RPL3 Repression
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41495453
      reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: By contrast, in cells expressing hotspot variants, RPL3 remains repressed while mutant RPL3L is retained in the nucleus, resulting in ribosome deficiency.
      explanation: Hotspot proteins keep RPL3 repressed in the cell model.
- name: Persistent RPL3 Repression
  biological_scale: MOLECULAR
  role: mediator
  mechanism_confidence: PROVISIONAL
  description: >-
    Wild-type RPL3L, and hotspot RPL3L, induce an RPL3 isoform targeted for
    nonsense-mediated decay, so RPL3 cannot rise to replace the missing
    functional RPL3L. The non-hotspot alleles lose this ability and permit
    compensation. Measured in AC16 cells; absent RPL3 compensation was inferred
    in one explanted patient heart.
  biological_processes:
  - preferred_term: regulation of alternative mRNA splicing, via spliceosome
    term:
      id: GO:0000381
      label: regulation of alternative mRNA splicing, via spliceosome
  - preferred_term: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence:
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: suggesting that both the SNP and hotspot variants largely retain the ability to induce RPL3 unproductive splicing, whereas non-hotspot variants have lost it.
    explanation: Allele-specific retention of RPL3 unproductive splicing.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: The lack of significant RPL3 compensation in patient hearts probably contributes to the several cardiac defects seen in human patients and may explain the phenotypic differences between humans and knockout mice.
    explanation: Absent RPL3 compensation in patient myocardium, interpreted as contributing to disease.
  downstream:
  - target: Cardiac Ribosome Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41495453
      reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: This combination—loss of ribosomal function coupled with blockade of RPL3 compensation—results in ribosome deficiency, as observed in patient hearts
      explanation: Blocking RPL3 compensation is one of the two inputs to ribosome deficiency.
- name: Impaired 60S Ribosomal Subunit Biogenesis
  biological_scale: CELLULAR
  role: mechanism
  mechanism_confidence: PROVISIONAL
  description: >-
    Cells expressing hotspot alleles accumulate 45S and 32S pre-rRNA, lose
    cytoplasmic 28S rRNA and show reduced 60S subunits, monosomes and polysomes.
    Homology modelling of the founding variants also predicted weakened binding
    of RPL3L to 60S rRNA.
  biological_processes:
  - preferred_term: ribosomal large subunit biogenesis
    modifier: DECREASED
    term:
      id: GO:0042273
      label: ribosomal large subunit biogenesis
  - preferred_term: rRNA processing
    modifier: ABNORMAL
    term:
      id: GO:0006364
      label: rRNA processing
  evidence:
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: Consistent with a defect in ribosome biogenesis, sucrose gradient sedimentation revealed a dramatic reduction in 60S and monosomes and polysomes in cells expressing the hotspot variant D308N
    explanation: Direct measurement of the 60S defect in the cell model.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: The increased pre-rRNA accumulation observed in hotspot variant cells relative to shRPL3 cells further supports the notion that expression of these recurrent variants contributes additional toxicity.
    explanation: rRNA processing is disrupted beyond simple RPL3-family deficiency.
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    snippet: Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit.
    explanation: A structural prediction, not an experimental measurement.
  downstream:
  - target: Cardiac Ribosome Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41495453
      reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: Hotspot variants further promote nucleolar protein aggregation and rRNA processing defects, driving additional ribosome deficiency and cellular toxicity.
      explanation: The biogenesis defect adds to ribosome deficiency.
- name: Cardiac Ribosome Deficiency
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Reduced functional cytoplasmic ribosomes in cardiomyocytes. Left ventricular
    tissue from one explanted heart (D308N/T189M) showed a marked loss of 28S
    rRNA, which the isogenic cell lines reproduced. This is the human-tissue
    anchor of the proposed mechanism, but it rests on a single patient.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: cytosolic large ribosomal subunit
    term:
      id: GO:0022625
      label: cytosolic large ribosomal subunit
  biological_processes:
  - preferred_term: cytoplasmic translation
    modifier: DECREASED
    term:
      id: GO:0002181
      label: cytoplasmic translation
  evidence:
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Bioanalyzer analysis of total RNA revealed a drastic reduction in the 28S rRNA peak compared to control CM heart ventricular tissues or human AC16 cardiomyocyte-like cells
    explanation: Loss of 28S rRNA in explanted patient left ventricle.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: To investigate the pathogenetic mechanisms of RPL3L mutations in DCM, we examined the explanted heart from a 5-month-old male patient carrying D308N/T189M9.
    explanation: The human-tissue finding comes from one explanted heart.
  downstream:
  - target: Cardiomyocyte Degeneration and Death
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41495453
      reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: confirmed a global downregulation of the ribosome
      explanation: In the explanted D308N/T189M heart, gene-set analysis showed ribosome downregulation together with an upregulated apoptosis signature; that ribosome deficiency drives cardiomyocyte death is an inference from co-occurrence in one heart.
    - reference: PMID:41495453
      reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: Hotspot variants disrupt ribosome biogenesis and impair cell viability.
      explanation: In AC16 cells, hotspot-driven ribosome defects reduce cell viability; the cell model stands in for cardiomyocytes.
- name: Altered Translation Elongation Dynamics
  biological_scale: CELLULAR
  role: mechanism
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In Rpl3l knockout mouse hearts, ribosome occupancy at codons changes, and
    translation of contraction- and DCM-related transcripts is most affected.
    RPL3L-containing ribosomes collide less than RPL3-containing ones. A second
    knockout study found no change in translational efficiency, so the finding
    is contested and has not been tested in patient tissue.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: translational elongation
    modifier: ABNORMAL
    term:
      id: GO:0006414
      label: translational elongation
  evidence:
  - reference: PMID:37080962
    reference_title: RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: RPL3L-containing ribosomes were less prone to collisions compared with RPL3-containing canonical ribosomes.
    explanation: Mouse finding on how RPL3L ribosomes differ in elongation.
  - reference: PMID:36882085
    reference_title: Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Using both ribosome profiling (Ribo-seq) and a novel orthogonal approach consisting of ribosome pulldown coupled to nanopore sequencing (Nano-TRAP), we find that RPL3L modulates neither translational efficiency nor ribosome affinity towards a specific subset of transcripts.
    explanation: An independent knockout found no translational-efficiency change.
  downstream:
  - target: Impaired Left Ventricular Systolic Function and Dilatation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37080962
      reference_title: RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: Deficiency of RPL3L-containing ribosomes in RPL3L knockout male mice resulted in impaired cardiac contractility.
      explanation: Mouse knockout contractile impairment; a link from altered elongation to contractility is inferred.
- name: Increased Ribosome-Mitochondria Association
  biological_scale: CELLULAR
  role: mechanism
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In Rpl3l knockout mouse cardiomyocytes, RPL3-containing ribosomes associate
    more with mitochondria and ATP rises. This effect depends on RPL3 replacing
    RPL3L, the compensation that hotspot alleles are proposed to block in
    patients, so it is not linked to the patient genotype here and has no
    upstream or downstream edge. Explanted human myocardium showed disturbed
    mitochondrial structure, but no study links the two.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:36882085
    reference_title: Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Instead, we reveal a complex cellular scenario in which RPL3L modulates the expression of RPL3, which in turn affects ribosomal subcellular localization and, ultimately, mitochondrial activity.
    explanation: Mouse knockout evidence for a ribosome-mitochondria effect.
  - reference: PMID:36733907
    reference_title: Rpl3l gene deletion in mice reduces heart weight over time.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Moreover, ribosomes lacking RPL3L showed no differences in localization within cardiomyocytes compared to wild type controls, nor was there an alteration in cardiac tissue ultrastructure or mitochondrial function in adult Rpl3l -/- mice.
    explanation: A second knockout found no change in ribosome localization or mitochondrial function.
- name: Cardiomyocyte Degeneration and Death
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Explanted and autopsy myocardium shows myocytolysis, degenerated myocytes with
    perinuclear vacuolization, cardiomyocyte death, disturbed mitochondrial
    structure and disordered sarcomeres, with myocyte hypertrophy and interstitial
    fibrosis.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:40820268
    reference_title: Novel Compound Heterozygous Missense Variants in RPL3L Gene Associated With Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Histopathological analysis revealed cardiomyocyte death, collagen deposition, disturbed mitochondrial structure, and deregulated sarcomeres.
    explanation: Patient myocardial histopathology.
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Myocardial pathology assessment showed degenerated myocytes with perinuclear vacuolization, hypertrophic muscle fibers and diffuse interstitial fibrosis.
    explanation: Myocyte degeneration in the founding family.
  downstream:
  - target: Myocardial Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32514796
      reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: Pathology evaluation of the explant heart showed moderate myocyte hypertrophy, interstitial fibrosis, and multi-focal subendocardial myocytolysis with evidence of chronic LV ischemia (Fig. 1c).
      explanation: Myocytolysis and fibrosis co-occur in the same explant; replacement fibrosis after myocyte loss is inferred, not shown.
  - target: Impaired Left Ventricular Systolic Function and Dilatation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Left Ventricular Systolic Function and Dilatation
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    Left (and often right) ventricular dilatation with severely reduced
    ejection fraction, from 6% to about 36% at presentation in reported cases.
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: cardiac muscle contraction
    modifier: DECREASED
    term:
      id: GO:0060048
      label: cardiac muscle contraction
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Echocardiogram showed severely decreased biventricular systolic function (EF 6%), moderate LV dilation (LV end-diastolic diameter 3.7 cm; z-score 6.9) with mild LA dilation, and mild tricuspid and mitral valve regurgitation.
    explanation: Ventricular dilatation with severe systolic failure in an affected infant.
  downstream:
  - target: Heart Failure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32514796
      reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: DCM progressed rapidly after birth leading to dilated left ventricle (LV), an ejection fraction (EF) of 28–32% and cardiac decompensation at the age of 12 days (Fig. 1b, upper panel).
      explanation: Progressive dilatation and systolic failure led to decompensation.
  - target: Dilated Cardiomyopathy
    causal_link_type: DIRECT
  - target: Left Ventricular Dilatation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42156347
      reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: Cardiac ultrasound revealed an enlarged left ventricle, moderate mitral valve regurgitation, and an ejection fraction of 31%.
      explanation: Left ventricular enlargement on echocardiography.
  - target: Reduced Left Ventricular Ejection Fraction
    causal_link_type: DIRECT
  - target: Cardiomegaly
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32514796
      reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: Chest X-ray revealed cardiomegaly with diffusely increased vascularity and a small right pleural effusion.
      explanation: Radiographic cardiomegaly accompanying ventricular dilatation.
  - target: Mitral Regurgitation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Functional regurgitation secondary to ventricular and annular dilatation; valve structure was not reported as abnormal.
    evidence:
    - reference: PMID:32514796
      reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: Echocardiogram showed severely decreased biventricular systolic function (EF 6%), moderate LV dilation (LV end-diastolic diameter 3.7 cm; z-score 6.9) with mild LA dilation, and mild tricuspid and mitral valve regurgitation.
      explanation: Atrioventricular-valve regurgitation co-occurs with ventricular dilatation; the functional mechanism is inferred.
  - target: Tricuspid Regurgitation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Functional regurgitation secondary to right-sided dilatation.
    evidence:
    - reference: PMID:32514796
      reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: Echocardiogram showed severely decreased biventricular systolic function (EF 6%), moderate LV dilation (LV end-diastolic diameter 3.7 cm; z-score 6.9) with mild LA dilation, and mild tricuspid and mitral valve regurgitation.
      explanation: Tricuspid regurgitation co-occurs with biventricular dysfunction; the functional mechanism is inferred.
- name: Heart Failure
  biological_scale: ORGANISM
  role: outcome
  mechanism_confidence: ESTABLISHED
  description: >-
    Rapidly progressive heart failure and cardiogenic shock in the neonatal and
    early infantile period, frequently fatal without mechanical support and
    transplantation.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:35323613
    reference_title: Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: This is the second report in the literature to the best of our knowledge and our findings support the pathogenicity of biallelic RPL3L pathologic variants associated with rapidly progressive neonatal DCM and heart failure with a poor prognosis.
    explanation: Rapidly progressive heart failure is the clinical outcome.
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: He showed no signs of hypotonia and died on the 15th day of life due to acute cardiac decompensation.
    explanation: Fatal neonatal cardiac decompensation.
  downstream:
  - target: Cardiogenic Shock
    causal_link_type: DIRECT
  - target: Congestive Heart Failure
    causal_link_type: DIRECT
  - target: Dyspnea
    causal_link_type: DIRECT
  - target: Tachypnea
    causal_link_type: DIRECT
  - target: Lethargy
    causal_link_type: DIRECT
  - target: Fatigue
    causal_link_type: DIRECT
  - target: Feeding Difficulties
    causal_link_type: DIRECT
  - target: Hepatomegaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Congestive hepatomegaly from systemic venous congestion.
    evidence:
    - reference: PMID:36291431
      reference_title: "Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: She had hepatomegaly; the liver was 3 cm below the right subcostal margin but no splenomegaly or ascites was observed.
      explanation: Hepatomegaly at presentation with acute heart failure; venous congestion as the intermediate is inferred.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: The defining feature, present in every reported patient, with onset from the first day of life to about 2.5 months.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    onset:
      onset_category: NEONATAL
      notes: Diagnosis ranged from the first day of life to 2.5 months; several cases fall in the infantile window after 28 days.
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period.
    explanation: Neonatal DCM in all five founding patients.
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Perinatal monitoring revealed a DCM at the first day of life.
    explanation: Earliest reported onset.
  - reference: PMID:36291431
    reference_title: "Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Whole exome sequencing has identified an infant girl with fulminant dilated cardiomyopathy (DCM), leading to severe acute heart failure associated with ribosomal protein large 3-like (RPL3L) gene pathologic variants.
    explanation: An independent case with fulminant DCM.
- name: Left Ventricular Dilatation
  category: Cardiovascular
  phenotype_term:
    preferred_term: Left ventricular dilatation
    term:
      id: HP:4000141
      label: Left ventricular dilatation
  evidence:
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Cardiac ultrasound revealed an enlarged left ventricle, moderate mitral valve regurgitation, and an ejection fraction of 31%.
    explanation: Enlarged left ventricle on echocardiography.
- name: Reduced Left Ventricular Ejection Fraction
  category: Cardiovascular
  description: Reported ejection fractions at presentation range from 6% to about 36%.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Echocardiogram showed severely decreased biventricular systolic function (EF 6%), moderate LV dilation (LV end-diastolic diameter 3.7 cm; z-score 6.9) with mild LA dilation, and mild tricuspid and mitral valve regurgitation.
    explanation: Severely reduced ejection fraction.
  - reference: PMID:35323613
    reference_title: Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Echocardiography (ECHO) showed left ventricular (LV) dilatation and biventricular depressed function (moderately depressed LV function with ejection fraction (LV EF) of 36%) (Figure 1C).
    explanation: Reduced ejection fraction in an independent family.
- name: Congestive Heart Failure
  category: Cardiovascular
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:35323613
    reference_title: Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: This is the second report in the literature to the best of our knowledge and our findings support the pathogenicity of biallelic RPL3L pathologic variants associated with rapidly progressive neonatal DCM and heart failure with a poor prognosis.
    explanation: Heart failure accompanies the DCM.
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Her brother had succumbed to fulminant cardiomyopathy and heart failure at the same age.
    explanation: Fatal heart failure in a sibling; the report does not state that the brother was genotyped.
- name: Cardiogenic Shock
  category: Cardiovascular
  phenotype_term:
    preferred_term: Cardiogenic shock
    term:
      id: HP:0030149
      label: Cardiogenic shock
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: She was born after an uneventful pregnancy and was admitted due to cardiogenic shock on her 48th day of life.
    explanation: Presentation with cardiogenic shock.
- name: Mitral Regurgitation
  category: Cardiovascular
  description: Secondary, functional atrioventricular-valve regurgitation accompanying ventricular dilatation.
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
  evidence:
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Cardiac ultrasound revealed an enlarged left ventricle, moderate mitral valve regurgitation, and an ejection fraction of 31%.
    explanation: Moderate mitral regurgitation.
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Echocardiogram showed severely decreased biventricular systolic function (EF 6%), moderate LV dilation (LV end-diastolic diameter 3.7 cm; z-score 6.9) with mild LA dilation, and mild tricuspid and mitral valve regurgitation.
    explanation: Mild mitral regurgitation in a founding-family patient.
- name: Tricuspid Regurgitation
  category: Cardiovascular
  phenotype_term:
    preferred_term: Tricuspid regurgitation
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: He was diagnosed with DCM and tricuspid insufficiency on the sixth day of life.
    explanation: Tricuspid insufficiency at diagnosis.
- name: Pulmonary Arterial Hypertension
  category: Cardiovascular
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Echocardiography showed dilated right ventricle (RV) and pulmonary arterial hypertension (Fig. 1b, upper panel).
    explanation: Pulmonary arterial hypertension on echocardiography.
- name: Cardiomegaly
  category: Cardiovascular
  phenotype_term:
    preferred_term: Cardiomegaly
    term:
      id: HP:0001640
      label: Cardiomegaly
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Chest X-ray revealed cardiomegaly with diffusely increased vascularity and a small right pleural effusion.
    explanation: Radiographic cardiomegaly.
- name: Abnormal T-wave
  category: Cardiovascular
  description: Nonspecific ST-segment and T-wave abnormalities on ECG.
  phenotype_term:
    preferred_term: Abnormal T-wave
    term:
      id: HP:0005135
      label: Abnormal T-wave
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Electrocardiogram showed right axis deviation with RV conduction delay, prominent LV forces for age and nonspecific ST and T wave abnormalities.
    explanation: ST and T-wave abnormalities on ECG.
- name: Abnormal ST Segment
  category: Cardiovascular
  phenotype_term:
    preferred_term: Abnormal ST segment
    term:
      id: HP:0012249
      label: Abnormal ST segment
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Electrocardiogram showed right axis deviation with RV conduction delay, prominent LV forces for age and nonspecific ST and T wave abnormalities.
    explanation: Nonspecific ST abnormalities on ECG.
- name: Premature Atrial Contractions
  category: Cardiovascular
  description: Reported in a single patient.
  phenotype_term:
    preferred_term: Premature atrial contractions
    term:
      id: HP:0006699
      label: Premature atrial contractions
  evidence:
  - reference: PMID:37308880
    reference_title: "Novel compound heterozygous variants in the RPL3L gene causing dilated cardiomyopathy type-2D: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: In addition to previously reported clinical features, the patient showed the previously unreported complication of occasional premature atrial contractions and a first-degree atrioventricular block.
    explanation: Single-case observation.
- name: First Degree Atrioventricular Block
  category: Cardiovascular
  description: Reported in a single patient.
  phenotype_term:
    preferred_term: First degree atrioventricular block
    term:
      id: HP:0011705
      label: First degree atrioventricular block
  evidence:
  - reference: PMID:37308880
    reference_title: "Novel compound heterozygous variants in the RPL3L gene causing dilated cardiomyopathy type-2D: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: In addition to previously reported clinical features, the patient showed the previously unreported complication of occasional premature atrial contractions and a first-degree atrioventricular block.
    explanation: Single-case observation.
- name: Myocardial Fibrosis
  category: Cardiovascular
  description: Interstitial fibrosis and collagen deposition in explanted or autopsy myocardium.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Pathology evaluation of the explant heart showed moderate myocyte hypertrophy, interstitial fibrosis, and multi-focal subendocardial myocytolysis with evidence of chronic LV ischemia (Fig. 1c).
    explanation: Interstitial fibrosis in explanted heart.
  - reference: PMID:40820268
    reference_title: Novel Compound Heterozygous Missense Variants in RPL3L Gene Associated With Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Histopathological analysis revealed cardiomyocyte death, collagen deposition, disturbed mitochondrial structure, and deregulated sarcomeres.
    explanation: Collagen deposition in an independent case.
- name: Lethargy
  category: Neurological
  description: A presenting symptom of decompensated heart failure.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: At 2 months of age, she presented with fatigue, vomiting, and lethargy.
    explanation: Lethargy at presentation.
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: A 2-month-old girl was admitted in June 2022 with poor appetite, breathlessness, and lethargy.
    explanation: Lethargy at presentation in an independent family.
- name: Fatigue
  category: Constitutional
  description: Reported at presentation in one infant who died of heart failure.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: At 2 months of age, she presented with fatigue, vomiting, and lethargy.
    explanation: Fatigue as a presenting symptom.
- name: Vomiting
  category: Digestive
  description: A presenting symptom in two siblings of one family; its relation to heart failure is not established.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: At 2 months of age, she presented with fatigue, vomiting, and lethargy.
    explanation: Vomiting at presentation.
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: presented with non-bilious, non-bloody vomiting and tachypnea.
    explanation: Vomiting at presentation in the affected brother.
- name: Feeding Difficulties
  category: Digestive
  description: Poor appetite at presentation in one infant.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: A 2-month-old girl was admitted in June 2022 with poor appetite, breathlessness, and lethargy.
    explanation: Poor appetite as a presenting symptom.
- name: Tachypnea
  category: Respiratory
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: presented with non-bilious, non-bloody vomiting and tachypnea.
    explanation: Tachypnea at presentation.
- name: Dyspnea
  category: Respiratory
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: A 2-month-old girl was admitted in June 2022 with poor appetite, breathlessness, and lethargy.
    explanation: Breathlessness at presentation.
- name: Hepatomegaly
  category: Digestive
  description: Congestive hepatomegaly reported in one infant with heart failure.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:36291431
    reference_title: "Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: She had hepatomegaly; the liver was 3 cm below the right subcostal margin but no splenomegaly or ascites was observed.
    explanation: Single-case observation in decompensated heart failure.
genetic:
- name: RPL3L
  gene_term:
    preferred_term: RPL3L
    term:
      id: hgnc:10351
      label: RPL3L
  variant_origin: GERMLINE
  presence: PRESENT
  association: >-
    Biallelic RPL3L variants are reported in CMD2D. The evidence rests on about
    13 published families (16-17 patients), with segregation in several
    multiplex sibships, recurrent hotspot alleles across unrelated families,
    and functional data from one explanted heart and engineered AC16 cells.
    ClinGen rates the recessive pair Moderate under the broader dilated
    cardiomyopathy term (MONDO:0005021). The 2026 expert-panel "high evidence"
    category includes Moderate, so it does not imply Definitive or Strong.
  notes: >-
    Reported alleles (NM_005061.3) include p.Gly27Asp (recurrent), p.Asp308Asn
    and p.Asp308Val (recurrent codon), p.Thr189Met, p.Arg161Trp, p.Arg343Trp,
    p.Ala51Thr, p.Val231Phe, p.Arg116Cys, p.Arg116His (homozygous, consanguineous
    family), p.Arg58Gln, p.Glu202Gly, p.Glu108Lys, homozygous p.Asp308Val
    (segmental uniparental disomy), frameshifts p.Ala359Glyfs*4, p.Ala359fs*6
    and p.Thr340Asnfs*25, the splice-donor c.1167+1G>A (exon 9 skipping), and
    the synonymous c.501G>A (p.Gln167=), whose pathogenic mechanism is
    unexplained. ClinGen's cached gene-validity
    record (CGGV, 2025-05-30) classifies RPL3L with the broader dilated
    cardiomyopathy term (MONDO:0005021), autosomal recessive, as Moderate; that
    is not this entry's MONDO term, so no gene_disease_validity tier is copied.
    No relationship_type is asserted, because CAUSATIVE corresponds to ClinGen
    Definitive or Strong and the only ClinGen rating is Moderate.
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.
    explanation: The founding gene-disease claim.
  - reference: PMID:35323613
    reference_title: Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "In the present brief report, we identified two pathogenic RPL3L variants, each harbored in unaffected heterozygous parents: mother (RPL3L c.1076_1080delCCGTG (p.Ala359Glyfs*4)) and father (RPL3L c.80G > A (p.Gly27Asp))."
    explanation: Independent family replicating the gene-disease link.
  - reference: PMID:37308880
    reference_title: "Novel compound heterozygous variants in the RPL3L gene causing dilated cardiomyopathy type-2D: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Whole-exome sequencing (WES) revealed compound heterozygous variants (c.80G > A (p.Gly27Asp) and c.1074dupA (p.Ala359fs*6)) in RPL3L (NM_005061.3).
    explanation: A further family with the recurrent Gly27Asp allele.
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Whole-exome sequencing identified two RPL3L mutations: c.501G>A (p.Q167=) inherited from the father and c.322G>A (p.E108K) from the mother."
    explanation: A case carrying a synonymous allele, whose effect was not functionally tested.
  - reference: PMID:40820268
    reference_title: Novel Compound Heterozygous Missense Variants in RPL3L Gene Associated With Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: To date, only 13 patients with RPL3L-related CMD2D have been reported, with nearly all of whom are attributed to compound missense mutations.
    explanation: The small size of the published patient pool.
  - reference: PMID:42708185
    reference_title: An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: "Nine newly assessed genes were classified as high evidence: BAG5, FLII, LMOD2, MYLK3, MYZAP, NRAP, PPA2, PPP1R13L, and RPL3L."
    explanation: The panel lists RPL3L as high evidence; this category is not a Definitive or Strong rating (see the next item).
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:42708185
    reference_title: An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: Thirty-five curations were classified as high evidence (16 Definitive, 10 Strong, 9 Moderate), increasing by 16 from the prior assessment.
    explanation: Defines "high evidence" as including Moderate, consistent with ClinGen's Moderate rating for RPL3L.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:32870709
    reference_title: Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: Homozygous variants were also detected in 7 novel candidates (ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1).
    explanation: A candidate-gene listing in a consanguineous cohort, without functional validation.
  - reference: CGGV:assertion_1dae12df-f703-4e4d-99b6-b38f6ed65fa0-2025-05-30T160000.000Z
    reference_title: RPL3L / dilated cardiomyopathy (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: RPL3L | HGNC:10351 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate
    explanation: ClinGen rates RPL3L Moderate for autosomal recessive dilated cardiomyopathy under the broader MONDO term, not this entry's term.
prevalence:
- population: Reported patients worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    About 16-17 patients from about 13 families (Germany, Colombia, Spain,
    USA, China and other cases) have been published. This is a publication
    count, not a population prevalence estimate.
  evidence:
  - reference: PMID:40820268
    reference_title: Novel Compound Heterozygous Missense Variants in RPL3L Gene Associated With Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: To date, only 13 patients with RPL3L-related CMD2D have been reported, with nearly all of whom are attributed to compound missense mutations.
    explanation: Literature count before this case report.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Meta-analyses of all 11 cases highlight two prominent features: compound heterozygosity and hotspot missense variants."
    explanation: Eleven families known to the 2026 study; two later Chinese families bring the total to about 13.
progression:
- phase: Neonatal or early infantile onset
  age_range: 0-2.5 months
  notes: Dilated cardiomyopathy is detected from the first day of life to about 2.5 months, with rapid decompensation.
  evidence:
  - reference: PMID:37308880
    reference_title: "Novel compound heterozygous variants in the RPL3L gene causing dilated cardiomyopathy type-2D: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Dilated cardiomyopathy type-2D (CMD2D) is a rare heart disease causing a severe cardiomyopathy with neonatal onset and rapid progression to cardiac decompensation and death in untreated patients.
    explanation: The typical onset and course.
    quote_role: REVIEW_SYNTHESIS
- phase: Death in infancy or transplantation
  age_range: 2 weeks-10 years
  notes: Several infants died between about two weeks and four months; transplanted children were alive at 9-10 years. One infant recovered normal function on drug therapy, an exception whose basis is unknown.
  evidence:
  - reference: PMID:36291431
    reference_title: "Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: RPL3L is a newer and likely pathogenic gene associated with a severe form of early-onset dilated cardiomyopathy with poor prognosis necessitating heart transplantation.
    explanation: Poor prognosis and reliance on transplantation.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:35323613
    reference_title: Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Two patients (Cases 3 and 4) underwent successful heart transplantations and were alive at age 9 and 10 years, respectively, at publication [11].
    explanation: Long-term survival after transplantation, as relayed from the founding report.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: He is currently 9 years of age, and his post-transplant course has been complicated by lymphoproliferative disorder confirmed on ileal biopsy, eosinophilic esophagitis, pancreatitis, left hydronephrosis, and a chronic anemia.
    explanation: Survival to 9 years after transplantation, from the founding report.
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Drug therapy improved the patient's cardiac function, and she demonstrated normal cardiac function after 6 months.
    explanation: The one reported medical recovery.
treatments:
- name: Heart failure pharmacotherapy
  description: >-
    Supportive heart-failure drugs, including inotropes (milrinone, dobutamine),
    digoxin and ACE inhibition, as used in case reports. No RPL3L-specific
    efficacy data exist; one infant recovered on drug therapy, while most
    others progressed despite inotropic support.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Heart Failure
    description: Supports failing pump function; does not correct the ribosomal defect.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Cardiotonic Agent
      term:
        id: NCIT:C78322
        label: Cardiotonic Agent
  evidence:
  - reference: PMID:35323613
    reference_title: Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Inotropic support (milrinone) was started to improve cardiac output due to depressed LV function.
    explanation: Inotropic support in a case report; the patient later died.
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: On day 4 of treatment, oral digoxin was initiated using a rapid digitalization protocol, after which dobutamine was discontinued.
    explanation: Inotrope and digoxin use in the infant who recovered.
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Drug therapy improved the patient's cardiac function, and she demonstrated normal cardiac function after 6 months.
    explanation: A single uncontrolled case; recovery cannot be attributed to the drugs.
- name: Ventricular assist device as bridge to transplant
  description: Mechanical circulatory support with a pediatric left ventricular assist device (Berlin Heart EXCOR) bridged one infant to heart transplantation.
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Heart Failure
    description: Replaces failing left ventricular output until transplantation.
  treatment_term:
    preferred_term: Left Ventricular Assist Device Insertion
    term:
      id: NCIT:C172327
      label: Left Ventricular Assist Device Insertion
  evidence:
  - reference: PMID:36291431
    reference_title: "Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: She required a Berlin-Excor left ventricular assist device due to worsening of her heart failure as a bridge to orthotopic heart transplantation.
    explanation: Single-case use as a bridge to transplant.
- name: Heart transplantation
  description: The main life-saving intervention reported; transplanted patients survived to at least 9-10 years.
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Heart Failure
    description: Replaces the affected heart.
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  evidence:
  - reference: PMID:40820268
    reference_title: Novel Compound Heterozygous Missense Variants in RPL3L Gene Associated With Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: 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.
    explanation: Transplantation as the life-saving option.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:36291431
    reference_title: "Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: At three months follow-up after heart transplantation, she has been doing well.
    explanation: Short-term post-transplant outcome.
  - reference: PMID:35323613
    reference_title: Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Early diagnosis of RPL3L variants can facilitate listing for a heart transplant.
    explanation: Genetic diagnosis informs transplant listing.
- name: Genetic counseling
  description: >-
    Recessive recurrence risk counselling, carrier testing of relatives and
    reproductive options once both familial variants are known.
  notes: >-
    No RPL3L-specific study evaluates counselling or cascade testing; this
    recommendation follows from the recessive inheritance and general
    guidance in a case report.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42156347
    reference_title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: Genetic testing now plays a central role in identifying the underlying etiology, guiding family screening, and informing genetic counseling, particularly in early-onset or familial cases.
    explanation: General statement about early-onset DCM, not an RPL3L-specific study.
    quote_role: BACKGROUND
animal_models:
- name: Rpl3l knockout mouse (Grimes et al.)
  species: Mouse
  genotype: Rpl3l -/- germline deletion
  publication: PMID:36733907
  description: >-
    Knockout mice show no change in cardiac structure or function at baseline
    or after pressure overload, because RPL3 stays up-regulated; by 18 months
    their hearts are smaller. The model does not reproduce dilated
    cardiomyopathy.
  modeled_mechanisms:
  - target: Loss of RPL3L Function from Non-hotspot Alleles
    model_scale: MOLECULAR
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Complete Rpl3l loss with compensatory RPL3 maintenance, matching the proposed behaviour of non-hotspot alleles.
    limitations: Models complete loss on both alleles, not the human hotspot-plus-private genotype.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: No hotspot allele is present, so the gain-of-function arm that blocks RPL3 compensation is absent.
    evidence:
    - reference: PMID:36733907
      reference_title: Rpl3l gene deletion in mice reduces heart weight over time.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Thus, deletion of Rpl3l forces maintenance of RPL3 expression within the heart that appears to fully compensate for the loss of RPL3L, although older Rpl3l -/- mice showed a mild but significant reduction in heart weight.
      explanation: Knockout with RPL3 compensation.
  - target: Impaired Left Ventricular Systolic Function and Dilatation
    model_scale: TISSUE
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: No cardiac structural or functional abnormality at baseline or after pressure overload.
    limitations: Adult-focused phenotyping; neonatal cardiac function was not the main readout.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: INVALIDATING
      description: RPL3 compensation, which hotspot alleles block in humans, is intact in the knockout.
    evidence:
    - reference: PMID:36733907
      reference_title: Rpl3l gene deletion in mice reduces heart weight over time.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Rpl3l gene-deleted mice were generated to examine the role of this gene in the heart, although Rpl3l -/- mice showed no overt changes in cardiac structure or function at baseline or after pressure overload hypertrophy, likely because RPL3 expression was upregulated and maintained in adulthood.
      explanation: No DCM phenotype in the knockout.
- name: Rpl3l knockout mouse (Shiraishi et al.)
  species: Mouse
  genotype: Rpl3l -/- (male mice studied)
  publication: PMID:37080962
  description: Male knockout mice have impaired cardiac contractility and altered ribosome elongation dynamics, most marked for contraction- and DCM-related transcripts.
  modeled_mechanisms:
  - target: Altered Translation Elongation Dynamics
    model_scale: CELLULAR
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    description: Ribosome profiling of knockout hearts shows altered codon occupancy.
    limitations: Not confirmed in patient tissue, and a second knockout study found no translational-efficiency change.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Measured in adult mouse heart, not in neonatal human myocardium with hotspot alleles.
    evidence:
    - reference: PMID:37080962
      reference_title: RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Ribosome occupancy at mRNA codons was found to be altered in the RPL3L-deficient heart, and the changes were negatively correlated with those observed in myoblasts overexpressing RPL3L.
      explanation: The elongation readout in knockout hearts.
  - target: Impaired Left Ventricular Systolic Function and Dilatation
    model_scale: TISSUE
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Reduced contractility without the fulminant neonatal dilated cardiomyopathy of patients.
    limitations: A mild adult phenotype in contrast to fatal neonatal disease.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Mild contractile impairment in adult male mice, versus fulminant neonatal failure in humans.
    evidence:
    - reference: PMID:37080962
      reference_title: RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Deficiency of RPL3L-containing ribosomes in RPL3L knockout male mice resulted in impaired cardiac contractility.
      explanation: Contractile impairment in knockout mice.
- name: Rpl3l knockout mouse (Milenkovic et al.)
  species: Mouse
  genotype: Rpl3l -/- viable homozygous knockout
  publication: PMID:36882085
  description: Viable knockout in which RPL3 replaces RPL3L in cardiomyocyte ribosomes; ribosome-mitochondria contacts and ATP increase.
  modeled_mechanisms:
  - target: Increased Ribosome-Mitochondria Association
    model_scale: CELLULAR
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    description: The knockout shows the ribosome-mitochondria change that defines this node.
    limitations: Not observed in a second knockout line and not measured in patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Mouse cardiomyocytes lacking RPL3L entirely, not human hotspot-plus-private genotypes.
    evidence:
    - reference: PMID:36882085
      reference_title: Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: In contrast, we show that depletion of RPL3L leads to increased ribosome-mitochondria interactions in cardiomyocytes, which is accompanied by a significant increase in ATP levels, potentially as a result of fine-tuning of mitochondrial activity.
      explanation: The defining measurement.
diagnosis:
- name: Exome sequencing
  description: Every reported case was identified by exome sequencing, after cardiomyopathy panels that did not include RPL3L. RPL3L should be considered in infantile DCM with negative panel testing.
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals.
    explanation: Exome sequencing identified the founding variants.
- name: Myocardial histopathology
  description: Explant or autopsy myocardium shows myocytolysis, degenerated myocytes and interstitial fibrosis. These findings are not specific to RPL3L disease.
  evidence:
  - reference: PMID:32514796
    reference_title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Pathology evaluation of the explant heart showed moderate myocyte hypertrophy, interstitial fibrosis, and multi-focal subendocardial myocytolysis with evidence of chronic LV ischemia (Fig. 1c).
    explanation: Explant histopathology in an affected infant.
differential_diagnoses:
- name: Metabolic, infectious and mitochondrial causes of infantile DCM
  description: Secondary metabolic and infectious causes, and mitochondrial disease, were excluded in reported patients before RPL3L testing.
  evidence:
  - reference: PMID:36291431
    reference_title: "Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Secondary causes for DCM due to metabolic and infectious etiologies were ruled out.
    explanation: Metabolic and infectious causes formed the clinical differential.
  - reference: PMID:36291431
    reference_title: "Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Other genetic tests for mitochondrial disorders by sequence analysis and deletion testing of the mitochondrial genome were negative.
    explanation: Mitochondrial disease was excluded.
discussions:
- discussion_id: cmd2d_knockout_does_not_model_disease
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Why do recessive human RPL3L genotypes cause fatal neonatal DCM when Rpl3l knockout mice, and humans homozygous for population RPL3L null alleles, lack severe cardiac disease?
  attaches_to:
  - pathophysiology#Loss of RPL3L Function from Non-hotspot Alleles
  - pathophysiology#Persistent RPL3 Repression
  rationale: >-
    Knockout mice compensate with RPL3. In gnomAD, All of Us and UK Biobank, one
    person is homozygous for R226X and 17 are homozygous for the c.1167+1G>A
    splice-donor allele without reported severe early DCM. The proposed answer
    is that hotspot alleles block RPL3 compensation, but that rests on AC16
    cells and one explanted heart. No hotspot knock-in animal or patient iPSC
    cardiomyocyte model has been reported.
  evidence:
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The lack of severe cardiac dysfunction in both putative RPL3L-knockout humans and Rpl3l-knockout mice strongly suggests that RPL3L-linked DCM is unlikely to be caused by simple RPL3L deficiency, despite the autosomal recessive inheritance pattern in affected families.
    explanation: Population and mouse evidence against simple loss of function.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: In addition, 17 individuals are homozygous for the splice donor variant (c.1167+1G>A).
    explanation: Homozygous putative null humans in population databases.
  - reference: PMID:41495453
    reference_title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Despite the recessive inheritance pattern in humans, Rpl3l knockout mice show no overt cardiac phenotype, probably because of compensatory RPL3 upregulation through unknown mechanisms.
    explanation: The mouse-human discrepancy, summarised from other groups' knockout studies.
    quote_role: BACKGROUND
  proposed_experiments:
  - experiment_id: exp_cmd2d_hotspot_knockin
    name: Hotspot knock-in mouse or patient iPSC cardiomyocytes
    description: Generate a mouse carrying Gly27Asp or Asp308Asn in trans with a null allele, or patient-derived iPSC cardiomyocytes with isogenic correction of each allele, and test whether RPL3 compensation fails, 28S rRNA falls and contractile failure appears in the neonatal period.
- discussion_id: cmd2d_contested_knockout_mechanisms
  kind: CONTROVERSY
  status: OPEN
  prompt: Does loss of RPL3L-containing ribosomes alter translation elongation, mitochondrial coupling, or neither?
  attaches_to:
  - pathophysiology#Altered Translation Elongation Dynamics
  - pathophysiology#Increased Ribosome-Mitochondria Association
  rationale: >-
    Three knockout mouse lines disagree. One shows impaired contractility and
    altered elongation; one shows no translational-efficiency change but more
    ribosome-mitochondria contact; one shows neither and no mitochondrial
    change. None models the hotspot genotype, so the human relevance of all
    three is uncertain.
  evidence:
  - reference: PMID:36733907
    reference_title: Rpl3l gene deletion in mice reduces heart weight over time.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: mRNA expression analysis and ribosome profiling failed to show differences between the hearts of Rpl3l null and wild type mice in adulthood.
    explanation: A null ribosome-profiling result contrasting with the elongation study.
- discussion_id: cmd2d_small_evidence_base
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How representative are the roughly 13 published families, and what explains the milder course and synonymous allele in the one medically recovered infant?
  attaches_to:
  - pathophysiology#Biallelic RPL3L Variants
  rationale: >-
    Phenotype, prognosis and the allele-class model all rest on fewer than 20
    patients. Most were ascertained through severe neonatal presentation and
    exome sequencing, which may bias toward severe disease. The synonymous
    c.501G>A allele has no splicing or expression study, and the
    gain-of-function model was tested only for G27D and D308N.
  evidence:
  - reference: PMID:36291431
    reference_title: "Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Bi-allelic variants in RPL3L have been reported in only seven patients from four unrelated families in the literature.
    explanation: The patient pool was very small as of 2022.
- discussion_id: cmd2d_neonatal_paralog_switch
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: Does the perinatal switch from RPL3 to RPL3L explain why disease begins in the neonatal period?
  attaches_to:
  - pathophysiology#Persistent RPL3 Repression
  rationale: >-
    In mouse ventricle, RPL3 dominates at birth and RPL3L gradually replaces it.
    Onset might coincide with the switch, when hotspot RPL3L represses RPL3
    before functional RPL3L-containing ribosomes are available. This timing
    link has not been tested in humans.
  evidence:
  - reference: PMID:36733907
    reference_title: Rpl3l gene deletion in mice reduces heart weight over time.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Methods and Results: Here, we observed that mouse cardiac ventricles express RPL3 at birth, where it is gradually replaced by RPL3L in adulthood but re-expressed with induction of hypertrophy in adults."
    explanation: Mouse developmental timing of the paralog switch.
references:
- reference: PMID:32514796
  title: Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
- reference: PMID:35323613
  title: Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
- reference: PMID:36291431
  title: "Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review."
- reference: PMID:37308880
  title: "Novel compound heterozygous variants in the RPL3L gene causing dilated cardiomyopathy type-2D: a case report and literature review."
- reference: PMID:40820268
  title: Novel Compound Heterozygous Missense Variants in RPL3L Gene Associated With Neonatal Dilated Cardiomyopathy.
- reference: PMID:42156347
  title: "Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report."
- reference: PMID:41495453
  title: Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
- reference: PMID:37080962
  title: RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function.
- reference: PMID:36733907
  title: Rpl3l gene deletion in mice reduces heart weight over time.
- reference: PMID:36882085
  title: Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart.
- reference: PMID:42708185
  title: An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.
- reference: PMID:32870709
  title: Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.
- reference: PMID:30271950
  title: Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation.
  findings:
  - statement: Heterozygous RPL3L missense and splice-donor variants are associated with atrial fibrillation; cited in the entry notes as a separate susceptibility phenotype, not CMD2D.
- reference: CGGV:assertion_1dae12df-f703-4e4d-99b6-b38f6ed65fa0-2025-05-30T160000.000Z
  title: RPL3L / dilated cardiomyopathy (Moderate)
📚

References & Deep Research

References

14
PMID:32514796
Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.
No top-level findings curated for this source.
PMID:35323613
Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.
No top-level findings curated for this source.
PMID:36291431
Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review.
No top-level findings curated for this source.
PMID:37308880
Novel compound heterozygous variants in the RPL3L gene causing dilated cardiomyopathy type-2D: a case report and literature review.
No top-level findings curated for this source.
PMID:40820268
Novel Compound Heterozygous Missense Variants in RPL3L Gene Associated With Neonatal Dilated Cardiomyopathy.
No top-level findings curated for this source.
PMID:42156347
Infantile dilated cardiomyopathy caused by RPL3L gene mutation: A case report.
No top-level findings curated for this source.
PMID:41495453
Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
No top-level findings curated for this source.
PMID:37080962
RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function.
No top-level findings curated for this source.
PMID:36733907
Rpl3l gene deletion in mice reduces heart weight over time.
No top-level findings curated for this source.
PMID:36882085
Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart.
No top-level findings curated for this source.
PMID:42708185
An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.
No top-level findings curated for this source.
PMID:32870709
Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.
No top-level findings curated for this source.
PMID:30271950
Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation.
1 finding
Heterozygous RPL3L missense and splice-donor variants are associated with atrial fibrillation; cited in the entry notes as a separate susceptibility phenotype, not CMD2D.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Cardiomyopathy_Dilated_2D · 2026-10-08T19:06:19Z · View source

Full entry for CMD2D (MONDO:0030300, RPL3L, OMIM 619371), claim issue #13718. Deep research: claude_code provider (falcon not configured, fallback); report references 26/26 resolved. Curated an 11-node pathophysiology chain (biallelic RPL3L variants -> non-hotspot loss of function / hotspot toxic gain of function -> persistent RPL3 repression and impaired 60S biogenesis -> cardiac ribosome deficiency -> cardiomyocyte degeneration -> LV systolic failure -> heart failure), 19 HP phenotypes, inheritance, genetic (no gene_disease_validity tier because the cached ClinGen record CGGV assertion_1dae12df is for MONDO:0005021 dilated cardiomyopathy, AR, Moderate), prevalence, progression, 4 supportive treatments, 3 Rpl3l knockout mouse models with modeled_mechanisms, and 4 discussions (HUMAN_MODEL_MISMATCH, CONTROVERSY, KNOWLEDGE_GAP, EMERGING_HYPOTHESIS). Key PMIDs: 32514796, 35323613, 36291431, 37308880, 40820268, 42156347, 41495453, 37080962, 36733907, 36882085, 42708185, 32870709. Death in infancy (HP:0001522) was dropped as a phenotype because it is outside the PhenotypeTerm enum. Validation: just validate passed (101 snippets, 0 issues); count-verified-snippets 101/101; check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-snippet-length, check-snippet-grading, check-title-snippets, check-coarse-phenotypes all OK; model-scale-audit 5/5 links aligned; check-genereviews --online NO_CHAPTER. Review fixes (same session): removed relationship_type CAUSATIVE because the only ClinGen rating is Moderate (MONDO:0005021, AR) and the 2026 panel's "high evidence" category includes Moderate (definition sentence from PMID:42708185 now quoted); corrected family counts to about 13 families and 16-17 patients (the 2026 study's 11 exclude the PMID:40820268 and PMID:42156347 families); added the missing patient alleles (R58Q, T340Nfs*25, R116H, homozygous D308V, c.1167+1G>A exon 9 skipping); removed the ribosome-mitochondria edge, because it depends on RPL3 compensation that hotspot alleles block, and downgraded the elongation edge to INDIRECT_UNKNOWN_INTERMEDIATES; replaced the ribosome-deficiency to degeneration edge evidence with the patient-heart ribosome-downregulation sentence plus an AC16 viability sentence; added two gain-of-function supports; marked the knockout-mouse summary as BACKGROUND; wired 13 phenotypes to the LV-failure and heart-failure nodes (15/21 connected); added Fatigue and Vomiting phenotypes, diagnosis and differential_diagnoses blocks, a direct founding-paper citation for post-transplant survival, and PMID:30271950 as the reference for the atrial-fibrillation note. Re-validation: just validate 118 snippets, 0 issues; count-verified-snippets 118/118; validate-disorders passed; entity-refs, causal-targets, enum-values, duplicate-keys, snippet-length, snippet-grading, title-snippets, coarse-phenotypes and gene-activity grounding all OK.

Claude Code ▸
Cardiomyopathy, Dilated, 2D (CMD2D; RPL3L-related neonatal dilated cardiomyopathy): research report
claude-haiku-5-5, claude-opus-5-5 10 citations 2026-10-08T14:34:25.797388

RPL3L confirmed. Let me search the literature.

I'm pulling exact abstract quotes for the RPL3L/CMD2D papers. Next I'll check the variants in the original Ganapathi 2020 paper and the mechanism papers, then write the report.

I have enough sourced material and am writing the report now.

Cardiomyopathy, Dilated, 2D (CMD2D; RPL3L-related neonatal dilated cardiomyopathy): research report

Prepared: 2026-10-08 · Target: MONDO:0030300 · Category: Mendelian (autosomal recessive)

How this was made. The PubMed records were pulled through NCBI E-utilities. Quoted sentences come from an extraction tool and are labelled as abstract quotes. They have not been checked against references_cache/, so run just fetch-reference PMID:… and confirm each snippet before using it as KB evidence.

The only identifiers I confirmed directly are: - MONDO:0030300, from cache/mondo/terms.csv - HP:0001644 (Dilated cardiomyopathy), already in the draft entry - HGNC:10351 for RPL3L, which appears in the GenCC submission URL

All other ontology suggestions below are labels to look up, not CURIEs. That follows the repository rule against writing identifiers from memory.

1. Disease information

Overview. CMD2D is a rare, autosomal recessive, early-onset and usually fulminant dilated cardiomyopathy. It is caused by biallelic variants in RPL3L, a ribosomal protein made only in heart and skeletal muscle. Ganapathi et al. (2020) first described it: "bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy" (PMID:32514796, abstract).

Identifiers

System ID Status
MONDO MONDO:0030300 "cardiomyopathy, dilated, 2D" Verified (local cache)
OMIM phenotype 619371 Secondary sources only (search snippets, NORD/MONDO page). Confirm on omim.org. One 2026 case report uses OMIM #115200 (the general CMD1A series), so numbering varies between sources.
OMIM gene (RPL3L) 617416 Per Genomics England PanelApp. Confirm.
HGNC HGNC:10351 (repo form hgnc:10351) From the GenCC submission URL. Confirm with just validate-terms.
DOID DOID:0081160 Search hit only. Confirm.
Orphanet / ICD-10 / ICD-11 / MeSH No CMD2D-specific code found Falls under general DCM codes (ICD-10 I42.0).

Synonyms: CMD2D; RPL3L-related dilated cardiomyopathy; neonatal dilated cardiomyopathy due to RPL3L deficiency.

Data provenance: Aggregated from case reports and small family series. There are no registries or EHR cohorts.

2. Etiology

  • Cause: Biallelic (mostly compound heterozygous, occasionally homozygous) germline RPL3L variants. These are mostly missense in the conserved RPL3 domain, plus a few frameshift and synonymous/splice-region alleles (PMID:32514796, 35323613, 37308880, 42156347).
  • Carrier parents are unaffected. Each allele was "harbored in unaffected heterozygous parents" (PMID:35323613), which supports recessive inheritance.
  • Consanguinity: Present in some families, such as the Colombian family (PMID:32514796; Das review PMC9600237). A Saudi consanguineous cohort of 205 childhood-cardiomyopathy probands reported RPL3L among "7 novel candidates" with homozygous variants (PMID:32870709).
  • Environmental risk or protective factors: None reported. This is a monogenic disorder.
  • Related heterozygous signal (a separate phenotype, not CMD2D). Common and low-frequency RPL3L variants are linked to atrial fibrillation: "one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L" (Thorolfsdottir 2018, PMID:30271950). The variants are p.Ala75Val and c.1167+1G>A, and "the splice-donor variant in RPL3L results in exon skipping." Rare-variant collapsing in UK Biobank also tied RPL3L to AF (PMID:38390584), and the gene is an AF / P-wave-duration locus (PMID:32822252).
  • For the KB, this is a separate susceptibility claim. If included, use relationship_type: SUSCEPTIBILITY or a note, not a CMD2D phenotype.
  • Gene–environment interactions: None described.

3. Phenotypes

Fewer than 20 published patients exist. Zhang et al. counted "only 13 patients with RPL3L-related CMD2D" before their case (PMID:40820268), and a 2026 summary cites about 14 individuals from 11 families. Frequencies are therefore approximate counts, not prevalence estimates.

Phenotype HPO label to look up Onset / course Frequency (n ≈ 15–17) Source
Dilated cardiomyopathy Dilated cardiomyopathy (HP:0001644, verified) Neonatal to early infancy (day 1 to about 2.5 months); fulminant All cases PMID:32514796, 36291431
Congestive / acute heart failure Congestive heart failure Rapid decompensation Almost all "rapidly progressive neonatal DCM and heart failure with a poor prognosis" (PMID:35323613)
Reduced LV systolic function Reduced left ventricular ejection fraction / Decreased fractional shortening e.g. EF 31% (PMID:42156347); FS 13% (Das index case) All with echo data PMID:42156347, PMC9600237
Mitral regurgitation Mitral regurgitation Secondary 6/7 in Das review table PMC9600237
Tricuspid regurgitation Tricuspid regurgitation Secondary 3/7 PMC9600237
ST-T abnormalities Abnormal T-wave / ST segment (look up) — 5/7 PMC9600237
Right bundle branch block Right bundle branch block — 1/7 PMC9600237
Pulmonary hypertension Pulmonary arterial hypertension — 1/7 PMC9600237
Poor feeding, breathlessness, lethargy Feeding difficulties; Dyspnea; Lethargy Presenting symptoms Case-level PMID:42156347
Myocardial fibrosis and cardiomyocyte death (histology) Myocardial fibrosis Explant / biopsy 1 detailed case "Histopathological analysis revealed cardiomyocyte death, collagen deposition…" (PMID:40820268)
Sarcomere and mitochondrial ultrastructural abnormalities Look up (cellular) — 1 case PMID:40820268
Death in infancy Death in infancy Day 15 to day 124 5/7 in Das table PMC9600237
  • Incidental findings: Patent foramen ovale and ventricular septal defect each appear in one patient.
  • Skeletal muscle: No clinical myopathy has been reported, even though RPL3L is expressed in skeletal muscle.
  • Quality of life: No formal QoL data. Surviving patients are transplant recipients and carry the lifelong burden of transplant care.

4. Genetics and molecular information

  • Gene: RPL3L (ribosomal protein L3-like), chromosome 16p13.3. It is a muscle-restricted paralog of the core 60S protein RPL3. Das et al. describe it as "exclusively expressed in cardiac and skeletal muscles" (PMC9600237). "RPL3L is highly expressed in the heart tissue of humans and mice" (PMID:38254943).
  • Gene-disease validity:
  • The 2026 ClinGen-based DCM reassessment classified RPL3L as high evidence: "classified as high evidence: BAG5, FLII, LMOD2, MYLK3, MYZAP, NRAP, PPA2, PPP1R13L, and RPL3L" (Jordan 2026, PMID:42708185).
  • A GenCC submission for RPL3L–DCM (AR) exists.
  • Per the repository rule, record a tier only if a CGGV: record for this disease is cached (just clingen-list).

Reported variants (transcript NM_005061.3 where stated)

Variant Partner Ancestry / origin Outcome Ref
c.923A>T p.(Asp308Val) c.1027C>T p.(Arg343Trp) Germany, 2 sibs Both died (days 15 and 21) PMID:32514796
c.922G>A p.(Asp308Asn) c.566C>T p.(Thr189Met) Colombia, consanguineous Transplant at 6 mo; alive at 9 y PMID:32514796
c.80G>A p.(Gly27Asp) c.481C>T p.(Arg161Trp) Spain, 2 sibs One transplanted (alive at 10 y); one died (day 30) PMID:32514796
c.80G>A p.(Gly27Asp) c.1076_1080delCCGTG p.(Ala359Glyfs*4) USA, 2 sibs Both died (days 68 and 124) PMID:35323613
c.151G>A p.(Ala51Thr) c.691G>T p.(Val231Phe) USA LVAD (Berlin Heart EXCOR), then transplant; well at 3 mo PMID:36291431
c.80G>A p.(Gly27Asp) c.1074dupA p.(Ala359fs*6) China Severe DCM at 31 days PMID:37308880
c.346C>T p.(Arg116Cys) c.605A>G p.(Glu202Gly) China Fulminant DCM PMID:40820268
c.322G>A p.(Glu108Lys) c.501G>A p.(Gln167=) (paternal) China Brother died; proband recovered on drug therapy PMID:42156347
p.Glu108Lys (VUS in a trio-WES cohort) China — PMID:41270882
  • Recurrent alleles: p.Gly27Asp appears in at least 4 families, and codon Asp308 is hit twice (Asn and Val). Murphy et al. report that "Affected individuals typically carry one of two recurrent hotspot missense variants paired with a private allele" (PMID:41495453).
  • I could not get the full text to confirm which two variants they mean. Gly27Asp and Asp308Asn/Val are the likely candidates, but that is an inference. Check the full text before writing it into the entry.
  • Variant classes: Mostly missense. Frameshifts at codon 359 (two independent alleles) and one synonymous/possible splice allele (c.501G>A).
  • The c.1074dupA frameshift "may result in the absence of protein production… suggesting it is a loss-of-function" (PMID:37308880).
  • Origin: All germline. No somatic involvement.
  • Population frequency: No CMD2D-specific gnomAD summary was found. Pathogenic alleles are rare. p.Ala75Val (an AF risk allele, not CMD2D) has 3.65% allele frequency in Iceland (PMID:30271950).
  • Functional consequence: Likely a mix of loss of function (null and non-hotspot alleles) and toxic gain of function (hotspots). See Section 6.
  • Modifiers: None established. A BXD mouse systems-genetics study proposes Myl4 and Sdha as upstream regulators of Rpl3l expression (PMID:38254943, computational/mouse).
  • Epigenetic / chromosomal: No disease-specific findings. A 2026 preprint reports that nuclear Rpl3l binds its own locus and influences chromatin insulation at the Rpl3l–Cacna1h locus (PMID:42395400). This is mouse/in vitro work, is not peer reviewed, and should not be used as KB evidence yet.

5. Environmental information

There are no environmental, lifestyle, or infectious causes. CMD2D is not an infectious disease.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic germline RPL3L variants, missense in the RPL3 domain or truncating (PMID:32514796, 37308880), lead to abnormal or absent RPL3L protein in cardiomyocytes.

  2. Two branches follow (proposed by Murphy et al., PMID:41495453; partly model-based):

  3. 2a. Loss of function (null and non-hotspot alleles) removes RPL3L-containing ribosomes. Non-hotspot variants "behave more like" knockouts.

  4. 2b. Toxic gain of function (recurrent hotspot alleles). These "induce nucleolar protein aggregation, disrupt rRNA processing and block compensation." The preprint adds that they "sequester 28S rRNA in the nucleus, disrupt ribosome biogenesis" and show increased binding to the RPL3/RPL3L chaperone GRWD1 (PMID:39803500).

  5. This results in impaired muscle-specific ribosome function and biogenesis.

  6. Homology modelling indicates that the variants "specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit" (PMID:32514796, computational).

  7. Compensation normally limits the damage, and its failure may explain disease.

  8. In mice, losing Rpl3l up-regulates RPL3. "deletion of Rpl3l forces maintenance of RPL3 expression within the heart" (PMID:36733907). Knockout hearts are therefore mildly affected: no baseline phenotype, smaller hearts by 18 months.
  9. Human disease is proposed to arise because hotspot alleles block this RPL3 compensation, combined with a second loss-of-function allele (PMID:41495453).

  10. This is a human–model mismatch. A HUMAN_MODEL_MISMATCH discussion fits here.

  11. Altered translation elongation in cardiomyocytes (Shiraishi 2023, PMID:37080962, mouse):

  12. "RPL3L-containing ribosomes were less prone to collisions compared with RPL3-containing canonical ribosomes"

  13. Effects "were most pronounced for transcripts related to cardiac muscle contraction and dilated cardiomyopathy"

  14. Altered ribosome–mitochondria coupling (Milenkovic 2023, PMID:36882085, mouse):

  15. "depletion of RPL3L leads to increased ribosome-mitochondria interactions in cardiomyocytes," which changes mitochondrial activity.
  16. In human explant tissue, "sarcomere and mitochondrial abnormalities" were seen (PMID:40820268).

  17. The link between this mitochondrial change and contractile failure is inferred, not shown.

  18. Reduced contractility followed by cardiomyocyte death and fibrosis.

  19. Rpl3l knockout mice show "impaired cardiac contractility" (PMID:37080962).

  20. Human histology shows "cardiomyocyte death, collagen deposition" (PMID:40820268).

  21. Left ventricular dilatation and systolic failure lead to fulminant neonatal heart failure, secondary atrioventricular-valve regurgitation, and death or transplantation (PMID:35323613, 36291431).

Why onset is neonatal (hypothesis). RPL3L replaces RPL3 in the heart after birth. Chaillou's review notes that during growth stimuli "the expression of Rpl3 is markedly increased, while that of Rpl3l is highly reduced" (PMID:30605395). This links disease onset to the perinatal ribosome paralog switch. It has not been demonstrated in humans.

Process and cell-type terms to look up (GO / CL)

Concept Term label to look up
Translation cytoplasmic translation; translational elongation
Ribosome assembly ribosomal large subunit biogenesis; rRNA processing
Contraction cardiac muscle contraction
Cell death cardiac muscle cell apoptotic process (or cell death)
Fibrosis collagen fibril organization / extracellular matrix organization
Compartments cytosolic large ribosomal subunit; nucleolus; mitochondrion
Cell types cardiac muscle cell; cardiac fibroblast (fibrosis node)

Scale tags: MOLECULAR (variant / ribosome) → CELLULAR (translation, mitochondria, death) → TISSUE (fibrosis, LV dilatation) → ORGANISM (heart failure).

Omics: No CMD2D patient transcriptomic, proteomic, or single-cell datasets were found. Mouse Ribo-seq and Nano-TRAP data come from PMID:36882085 and PMID:37080962. Any GEO accessions must be checked with just verify-datasets and triaged for relevance.

7. Anatomical structures affected

  • Primary: heart, specifically the left ventricle and myocardium. UBERON labels to look up: heart; heart left ventricle; myocardium.
  • Secondary: mitral and tricuspid valves (functional regurgitation); pulmonary vasculature (pulmonary hypertension, one case).
  • Cells: cardiomyocytes, with fibroblast-driven fibrosis.
  • Subcellular: ribosome (60S), nucleolus (hotspot aggregation), mitochondria, sarcomere.
  • Skeletal muscle: expresses RPL3L, but no clinical involvement has been reported.
  • Lateralization: not applicable (whole-organ disease).

8. Temporal development

  • Onset: from day 1 to about 2.5 months of life (day 1, 6, 12, 48, 54, 75 in the Das table; 31 days in PMID:37308880; 2 months in PMID:42156347). Onset is acute to subacute.
  • Progression: rapid. Most untreated infants died between day 15 and day 124.
  • Remission: one exception has been reported. A 2-month-old with EF 31% improved, and cardiac function was normal after 6 months of drug therapy (PMID:42156347). Her genotype included a synonymous allele, which may be hypomorphic; that is an inference.
  • Critical window: the neonatal period, during the RPL3→RPL3L switch. Early listing for mechanical support or transplantation is the main intervention point.
  • Stages for progression:: neonatal onset → fulminant decompensation → death, or bridge-to-transplant / transplant survival.

9. Inheritance and population

  • Inheritance: autosomal recessive (PMID:32514796, 35323613). Unaffected heterozygous parents are documented.
  • Penetrance: appears complete for biallelic genotypes, but numbers are small. Expressivity varies, from death in the first weeks to survival on medication alone.
  • Anticipation and mosaicism: none reported.
  • Founder effects: none established. p.Gly27Asp recurs in unrelated Spanish, US, and Chinese families, which suggests a recurrent rather than founder allele (inference).
  • Prevalence: unknown. Fewer than 20 cases are published. Use measure_type: CASES_IN_LITERATURE with a qualitative ULTRA_RARE or RARE tier.
  • Geography: Germany, Spain, Colombia, USA, China, and possibly Saudi Arabia (PMID:32870709).
  • Sex ratio: no bias (both sexes affected).

10. Diagnostics

  • Imaging: echocardiography (LV dilatation, reduced EF/FS, AV-valve regurgitation). Cardiac MRI for fibrosis is rarely feasible in neonates.
  • ECG: ST-T abnormalities, RBBB.
  • Laboratory: heart-failure markers (NT-proBNP, troponin). These are not specific and are not reported systematically.
  • Pathology: cardiomyocyte death, fibrosis, and sarcomere and mitochondrial ultrastructural abnormalities on explant tissue (PMID:40820268).
  • Genetic testing:
  • Exome (singleton or trio) is the main route. Every reported case was found by WES.
  • RPL3L is on the Genomics England "Dilated and arrhythmogenic cardiomyopathy" panel. Confirm that commercial DCM panels include it.
  • In the Al-Hassnan cohort, "targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing" (PMID:32870709).
  • Trio WES in critically ill paediatric cardiomyopathy gave a 45% diagnostic rate (PMID:41270882).
  • Differential diagnosis:
  • Myocarditis
  • Other recessive infantile DCMs: CMD2A TNNI3, CMD2B GATAD1, CMD2C PPA2
  • Mitochondrial cardiomyopathies (e.g. TAZ / Barth syndrome; ACAD9)
  • Endocardial fibroelastosis
  • Anomalous left coronary artery from the pulmonary artery (ALCAPA)
  • Metabolic cardiomyopathies (Pompe disease; carnitine deficiency)
  • Dominant de novo sarcomeric DCM
  • Screening: cascade carrier testing in families, and prenatal or preimplantation testing once both familial variants are known. There is no newborn screening.
  • GeneReviews: no CMD2D-specific chapter was found. Run just check-genereviews to confirm offline.

11. Outcome and prognosis

  • Mortality: about 70% died in infancy in the 2020–2022 series (5/7 in the Das table, plus additional deaths such as the sibling in PMID:42156347).
  • Transplant survivors: "At three months follow-up after heart transplantation, she has been doing well" (PMID:36291431). Survival to 9–10 years after transplant is documented (PMC9600237).
  • Medical recovery: one case (PMID:42156347).
  • Complications: pulmonary hypertension, need for a VAD, and death from pump failure.
  • Prognostic factors: none validated. Genotype class (hotspot plus a null allele versus hypomorphic alleles) has been proposed as relevant; this is speculative.

12. Treatment

All treatments are supportive or replacement. There is no disease-specific therapy.

Treatment NCIT term to look up Modality Evidence
Heart-failure pharmacotherapy (diuretics, inotropes such as milrinone, ACE inhibitors, β-blockers) Pharmacotherapy (NCIT:C15986 per CLAUDE.md) SMALL_MOLECULE "Drug therapy improved the patient's cardiac function" (PMID:42156347)
Ventricular assist device as bridge to transplant (Berlin Heart EXCOR) Bind a clinical action (e.g. a surgical procedure term), not the device term DEVICE / SURGERY PMID:36291431
Heart transplantation Organ Transplantation (NCIT:C15289 per CLAUDE.md); look for a more specific heart-transplant term SURGERY PMID:36291431; PMC9600237
Genetic counseling Genetic Counseling (NCIT:C15240 per CLAUDE.md) — Recessive recurrence risk
  • Experimental: no clinical trials. Murphy et al. suggest that boosting RPL3 compensation, or allele-specific suppression of toxic hotspot alleles, could be therapeutic. That is a hypothesis only.
  • Related skeletal-muscle work (not cardiac): AAV knockdown of Rpl3l in skeletal muscle increased specific force in dystrophic mice (PMID:34081545). This argues that RPL3L knockdown is not a cardiac option given CMD2D.
  • Pharmacogenomics: none.

13. Prevention

  • Primary: genetic counseling, carrier testing of relatives, and PGT-M or prenatal diagnosis for couples who are known carriers.
  • Secondary: early echocardiography in at-risk newborn siblings.
  • Tertiary: early referral for mechanical circulatory support and transplant evaluation.
  • Not applicable: vaccination and environmental measures.

14. Other species

  • Naturally occurring disease: none found in OMIA.
  • Conservation: RPL3L is conserved in vertebrates.
  • Chicken: RPL3L overexpression "could promote the proliferation and inhibit the differentiation of chicken myoblasts" (PMID:36407004). This concerns muscle growth, not disease.

15. Model organisms

Model Key finding Recapitulation Ref
Rpl3l⁻/⁻ mouse (Grimes) No baseline or pressure-overload phenotype; RPL3 up-regulated; smaller hearts by 18 months FAILS_TO_RECAPITULATE (no DCM) PMID:36733907
Rpl3l⁻/⁻ mouse (Milenkovic) Viable; RPL3 replaces RPL3L; more ribosome–mitochondria contact PARTIALLY (mechanism only) PMID:36882085
Rpl3l KO male mouse (Shiraishi) "impaired cardiac contractility"; altered elongation dynamics PARTIALLY PMID:37080962
Hotspot-variant cellular models (Murphy) Nucleolar aggregation, rRNA processing defect, severe cellular toxicity Mechanism PMID:41495453 / 39803500 (cell type not confirmed)
BXD mouse panel Rpl3l expression correlates with cardiac traits Computational PMID:38254943
C2C12 myotubes RPL3L impairs myotube growth and fusion Skeletal muscle only PMID:26684695
  • Modelling gap: a knockout cannot reproduce the human disease because of RPL3 compensation. Hotspot knock-in mice or patient iPSC-derived cardiomyocytes are the obvious missing models. Neither was confirmed as published.
  • Suggested KB discussion: HUMAN_MODEL_MISMATCH attached to the compensation and loss-of-function nodes.

Limits and verification to do before curation

  • OMIM 619371 and gene 617416 come from secondary sources. Confirm them.
  • The identities of the Murphy hotspot variants are not confirmed (see Section 4).
  • Preprints: PMID:39803500 and PMID:42395400 are preprints. Prefer the peer-reviewed PMID:41495453.
  • All quotes need fetching and verification via just fetch-reference and just count-verified-snippets before use as snippets. In particular, some Das et al. quotes come from PMC full text, not the abstract.
  • Evidence-source grading:
  • Mouse studies: MODEL_ORGANISM
  • Homology modelling in Ganapathi: COMPUTATIONAL (split it from the human genetic findings)
  • Case reports: HUMAN_CLINICAL

Sources

  • Case reports and series
  • Ganapathi 2020, Hum Genet, PMID:32514796 — https://link.springer.com/doi/10.1007/s00439-020-02188-6
  • Nannapaneni 2022, J Cardiovasc Dev Dis, PMID:35323613
  • Das 2022, Children, PMID:36291431 — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600237/
  • Yang 2023, BMC Med Genomics, PMID:37308880 — https://doaj.org/article/4415fabeab54407e9db0c554fef68740
  • Zhang 2025/26, Am J Med Genet A, PMID:40820268
  • Mai 2026, J Int Med Res, PMID:42156347
  • Xu 2026, Clin Chim Acta, PMID:41270882
  • Al-Hassnan 2020, Circ Genom Precis Med, PMID:32870709
  • Gene–disease validity
  • Jordan 2026, Circulation, PMID:42708185
  • Mechanism
  • Murphy 2026, Nat Cardiovasc Res, PMID:41495453; preprint PMID:39803500
  • Shiraishi 2023, Nat Commun, PMID:37080962
  • Grimes 2023, Front Physiol, PMID:36733907
  • Milenkovic 2023, Nucleic Acids Res, PMID:36882085 — https://repositori.upf.edu/items/e573c402-8434-4039-bd67-c1ea6752d007/full
  • Bajpai 2023, Genes, PMID:38254943
  • Atrial fibrillation (separate phenotype)
  • Thorolfsdottir 2018, Commun Biol, PMID:30271950 — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123807/
  • Zöller 2023, PMID:38390584
  • Weng 2020, PMID:32822252
  • Skeletal muscle and paralog biology
  • Chaillou 2016, PMID:26684695
  • Chaillou 2019, PMID:30605395
  • Kao 2021, PMID:34081545
  • Lin 2022, PMID:36407004
  • Nakamura 2026 (preprint), PMID:42395400
  • Databases
  • MalaCards CMD2D — https://malacards.org/card/cardiomyopathy_dilated_2d
  • Genomics England PanelApp — https://panelapp.genomicsengland.co.uk/panels/652/gene/RPL3L
  • GenCC — https://search.thegencc.org/submissions/GENCC_000102-HGNC_10351-MONDO_0005021-HP_0000007-GENCC_100003
  • NORD/MONDO — https://rarediseases.org/mondo-disease/cardiomyopathy-dilated-2d/
  • Disease Ontology — https://disease-ontology.org/term/DOID:0081160

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 26
Resolved 26
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 19
Quoted claims found in source 17
Quoted claims not found in source 2
References weighed for topical relevance 26
On topic 10
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMC:PMC9600237 (abstract only): "exclusively expressed in cardiac and skeletal muscles"
  • Text part not found as substring: 'exclusively expressed in cardiac and skeletal muscles' (note: only abstract available for PMID:36291431, full text may contain this excerpt)
  • PMID:37308880 (abstract only): "may result in the absence of protein production… suggesting it is a loss-of-function"
  • closest text in source: "The latter novel variant may result in the absence of protein production with a significant decrease in mRNA level, suggesting it is a loss-of-function mutation"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 7
Resolved 6
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • DOID:0081160 (3 mentions) - the report calls it "DOID"; DOID calls it dilated cardiomyopathy 2D