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

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.

• 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)

• 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)

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.

• 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

• 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.

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.

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