Hypertrophic Cardiomyopathy 18 (CMH18; PLN-related HCM): Research Report

Prepared 2026-10-13 for the dismech entry kb/disorders/Hypertrophic_Cardiomyopathy_18.yaml.

How the quotes were checked. Quotes marked [cache] were read word for word from files already in references_cache/: PMID:21167350, PMID:12610310, PMID:16432188, and the ClinGen CGGV: record. Quotes marked [web] came from PubMed abstracts through a summarising fetch tool. That tool limits quote length and is not guaranteed to be verbatim. Before using any [web] quote as a snippet, fetch the reference with just fetch-reference PMID:… and check it with just count-verified-snippets.

How the ontology IDs were checked. Only three identifiers were read from a source in this session: - MONDO:0013475, from the existing draft entry - HGNC:9080 and MONDO:0000591, from the cached ClinGen row

Every other CURIE below is a candidate written from memory. Look each one up before binding it, as the repo's term rule requires.

Executive summary

• What it is. CMH18 is the OMIM-numbered form of familial hypertrophic cardiomyopathy caused by variants in PLN. PLN encodes phospholamban, a 52-amino-acid protein that inhibits the cardiac SR Ca²⁺ pump SERCA2a.
• How much evidence there is. Very little. HCM-specific PLN evidence comes from a handful of probands:
• the truncating variant p.Leu39Ter (L39X / L39stop), seen as a heterozygote in about three families;
• two or three promoter variants: −77A>G, −42C>G, and further rare variants in the Mayo cohort.
• How ClinGen handles it. ClinGen does not treat CMH18 as a separate disease. Its HCM Gene Curation Expert Panel merged CMH18 (MIM 613874) with dilated cardiomyopathy 1P (MIM 609909) into one entity, PLN / intrinsic cardiomyopathy (MONDO:0000591), autosomal dominant, rated Definitive (curated 2017, recurated 2021-02-12).
• Mechanism. The disease follows from abnormal SERCA2a regulation and abnormal Ca²⁺ cycling in cardiomyocytes. L39X behaves as a dose-dependent null allele:
• heterozygotes develop hypertrophy with preserved systolic function;
• homozygotes develop lethal dilated cardiomyopathy (DCM).
• A naming trap to avoid. The well-known PLN p.Arg14del founder variant (Netherlands, Greece) and p.Arg9Cys cause mainly DCM and arrhythmogenic cardiomyopathy, not CMH18. Cite them only as context for the shared mechanism. Do not use them as evidence for HCM phenotypes.

1. Disease information

Overview. Landstrom et al. (2011) frame HCM as "unexplained cardiac hypertrophy" affecting ~1 in 500 people [cache, PMID:21167350]. CMH18 is the subset attributed to PLN, usually found in families whose sarcomere-gene panel came back negative.

Identifiers

Synonyms. CMH18; cardiomyopathy, hypertrophic, 18; PLN-related HCM; familial hypertrophic cardiomyopathy 18.

Data provenance. Everything here comes from aggregated, disease-level resources (OMIM, ClinGen) and from family and case reports. There is no EHR or registry dataset specific to CMH18.

2. Etiology

Primary cause. Germline heterozygous PLN variants: truncating (L39X) and promoter (regulatory).

Key evidence

• Chiu et al. 2007 (PMID:17655857) screened 252 unrelated Australian familial HCM probands across 7 Ca²⁺-handling genes. They found a novel PLN Leu39Ter and concluded that "mutations in Ca(2+) handling genes are an infrequent but important cause of FHC" [web].
• Landstrom et al. 2011 (PMID:21167350) [cache]:
• "one L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel."
• "This mutation cosegregated with incidence of HCM in a multigenerational family."
• "we identified an overall yield of PLN-HCM mutations of 0.65%"
• Minamisawa et al. 2003 (PMID:12705874) found a heterozygous promoter variant −77A>G in 1 of 87 HCM patients. It was absent from 296 controls, and "the mutation, -77A-->G, increased the phospholamban promoter activity" in neonatal rat cardiomyocytes [web].
• Medin et al. 2007 (PMID:16829191) found a −42C>G promoter variant in a Spanish HCM patient with reduced penetrance. This is summarised in Landstrom 2011 [cache]; the Medin abstract itself was not read.

Risk factors. - Genetic: carrying a PLN variant; L39X dosage, since homozygosity shifts the phenotype to DCM. - Environmental: none documented for CMH18. - Protective factors and gene–environment interactions: none reported. - Common PLN promoter variant −36A>C: Landstrom saw no excess in HCM probands (8.3% vs 7.5% in Caucasian controls) [cache]. It should not be recorded as an HCM risk factor.

3. Phenotypes

Data are sparse. Each item below rests on single probands or small pedigrees. HPO IDs are candidates to verify.

No quality-of-life data exist for CMH18. General HCM instruments (KCCQ, NYHA class) apply.

4. Genetic and molecular information

Gene. PLN (6q22.31) has a single coding exon and encodes a 52-amino-acid SR transmembrane protein. ClinGen [cache]: - "PLN is encoded by one exon … many of the mutations (even LOF) result in a protein product." - "The monomeric form is thought to inhibit SERCA2 activity. PLN-mediated SERCA2 inhibition is released upon phosphorylation of monomeric PLN by either PKA or CAMKII."

Variants attributed to HCM

Landstrom also reports that "We did not observe any PLN coding sequence genetic variation in 600 reference alleles" [cache]. Check gnomAD for L39X before writing any allele frequency.

Mechanism by variant. L39X is a loss-of-function allele with a dosage effect (ClinGen calls it "semidominance") [cache]. The promoter variants plausibly cause gain of expression, but this is shown in vitro only.

Other points - Germline origin. - No modifier genes, epigenetic data or chromosomal abnormalities have been reported for CMH18. - ClinGen validity: Definitive, AD, for intrinsic cardiomyopathy (MONDO:0000591). That record's MONDO is not CMH18's disease_term. Under the repo's rules it is a "broader ClinGen lumping": cite it as evidence, but do not record it as a gene_disease_validity assertion for MONDO:0013475 unless an exactMatch mapping justifies it. The ARVC/Moderate record is a separate disease.

5. Environmental information

None documented. No infectious agent is involved.

6. Mechanism / pathophysiology

Causal chain (L39X arm; steps marked inferred are not directly shown in CMH18 patients)

1. Heterozygous PLN L39X produces truncated phospholamban that is unstable or mislocalised. Cell work shows "no PLN inhibition of SR Ca(2+)-ATPase" [web, PMID:12639993]. The result is reduced functional PLN dosage.
2. Less PLN means SERCA2a is released from inhibition: faster SR Ca²⁺ reuptake and altered Ca²⁺ transients. The mouse evidence is Luo 1994: PLN-null mice "exhibited enhanced myocardial performance" and PLN "acts as a critical repressor of basal myocardial contractility" [web, PMID:8062415].
3. Chronically altered Ca²⁺ cycling then leads to Ca²⁺-dependent hypertrophic signalling in cardiomyocytes, with left ventricular hypertrophy and preserved contractility in heterozygotes. Inferred: no study of a CMH18 patient has shown the specific signalling pathway (calcineurin–NFAT or CaMKII).
4. Branch A (heterozygote). HCM with atrial fibrillation and ventricular ectopy or NSVT. The association with AF is notable but unexplained: "further studies are required to elucidate any potential association between PLN function and atrial fibrillation" [cache].
5. Branch B (homozygote, total loss). Lethal DCM and heart failure, needing transplant in adolescence or young adulthood. Human PLN loss is therefore harmful, unlike in mice. This is a HUMAN_MODEL_MISMATCH candidate.
6. ClinGen synthesis [cache]: "the overall disease mechanism for PLN associated cardiomyopathy is dysregulation of SERCA2 function, Ca2+ handling, and disrupted relaxation and contraction of the heart."

Promoter arm. The −77A>G variant increases promoter activity, which should mean more PLN and more SERCA2a inhibition. That is the opposite direction to L39X. Why both directions would end in HCM is unresolved; record it as a knowledge gap.

Contrast, for context only. R9C traps PKA and blocks PLN phosphorylation [cache, PMID:12610310]. R14del "superinhibits" SERCA [cache, PMID:16432188]. Both cause DCM.

Ontology suggestions (verify)

There are no omics, single-cell or CRISPR-screen data specific to CMH18.

7. Anatomical structures

• Organ and system: heart; cardiovascular system.
• Sites: interventricular septum, LV apex, left atrium.
• Tissue and cell: myocardium; ventricular and atrial cardiomyocytes.
• Subcellular: sarcoplasmic reticulum membrane.
• Laterality: left-sided predominance.
• Candidate UBERON terms: heart (UBERON:0000948), interventricular septum (UBERON:0002094), left cardiac atrium (UBERON:0002079), myocardium (UBERON:0002349).

8. Temporal development

• Onset: typically adult, diagnosed at 51–67 in the reported probands. One heterozygous child was phenotype-positive at 3 years [cache]. Onset is insidious.
• Course: chronic and lifelong. Progression to DCM has been seen in homozygotes, and ClinGen notes a hypertrophic-to-dilated course [cache].
• Penetrance: incomplete. A 38-year-old carrier daughter was unaffected [cache].
• Staging: no CMH18-specific staging exists.

9. Inheritance and population

• Inheritance: autosomal dominant with incomplete penetrance. Recessive or semidominant dosage applies for L39X homozygotes [cache: "autosomal recessive inheritance has been noted and appears to follow a dosage effect or semidominance"]. Candidate HPO terms: HP:0000006 Autosomal dominant inheritance; HP:0003829 Typified by incomplete penetrance.
• Frequency: PLN accounts for ~0.65% of panel-negative HCM probands, counting promoter variants, and 0.13% for coding L39X alone [cache].
• Prevalence: no population figure exists for CMH18. Background HCM prevalence is about 1/500.
• Populations: probands have been reported as Caucasian North American, Australian, Japanese, Spanish and Greek (the L39X families in Haghighi 2003).
• Not reported: founder effect, sex ratio, anticipation, mosaicism.

10. Diagnostics

• Imaging: echocardiography and CMR showing maximal LV wall thickness of at least 13–15 mm without another cause.
• ECG: AF, pre-excitation, conduction block.
• Monitoring: ambulatory ECG for NSVT.
• Genetic testing: a multigene cardiomyopathy panel that includes PLN. Landstrom argues PLN's small size (two amplicons) and very low background variation make it easy to add to panels [cache]. Promoter coverage matters, because several HCM-linked variants are regulatory.
• Differential diagnosis: sarcomeric HCM; phenocopies such as PRKAG2 (which causes WPW), Fabry (GLA), Danon (LAMP2), and amyloid; athlete's heart; hypertensive LVH.
• Cascade screening: first-degree relatives, following the 2024 AHA/ACC HCM guideline (PMID:38718139 / 38727647).
• Candidate NCIT diagnostic actions: echocardiography, electrocardiography, genetic testing.

11. Outcome and prognosis

There are no survival data specific to CMH18. - Heterozygotes: HCM with arrhythmia burden; ICD implanted in the Mayo proband. - Homozygotes: end-stage DCM requiring transplant at 16 and 27.

General HCM prognosis and sudden-death risk models apply (PMID:40088231 validates the guideline's SCD risk recommendations).

12. Treatment

There is no PLN-specific therapy. Treatment follows general HCM management (2024 AHA/ACC guideline, PMID:38718139).

Experimental. PLN-targeted approaches have been explored mainly for R14del DCM: antisense oligonucleotides, AAV-delivered inhibitory PLN, and gene editing. No trials target CMH18.

13. Prevention

• No primary prevention.
• Secondary: cascade genetic and clinical screening of relatives, with periodic echo and ECG for carriers given incomplete and variable-age penetrance.
• Genetic counselling covering homozygosity risk (DCM) in consanguineous or carrier-by-carrier unions.
• Tertiary: SCD risk stratification and AF management.

14. Other species

No naturally occurring PLN-HCM in animals was found (OMIA not searched in depth). PLN is highly conserved across vertebrates.

15. Model organisms

There is no L39X-heterozygous animal or iPSC-cardiomyocyte HCM model. That is an open knowledge gap.

Curation notes for the dismech entry

1. Lump/split. ClinGen merged CMH18 into PLN intrinsic cardiomyopathy. Keep CMH18 as a DISEASE entry, since the MONDO term exists, but quote the ClinGen lumping paragraph and note the overlap with DCM1P.
2. Evidence already cached: PMID:21167350 (full text), PMID:12610310, PMID:16432188, and the CGGV PLN records. To fetch: PMID:12639993, 17655857, 12705874, 16829191, 8062415.
3. Suggested discussion items:
4. a HUMAN_MODEL_MISMATCH for the mouse vs human PLN null;
5. a KNOWLEDGE_GAP on why opposite directions of PLN dosage (L39X null vs promoter up-regulation) would both cause HCM;
6. a KNOWLEDGE_GAP on the AF association.

Sources

• Haghighi 2003 JCI, PMC153772 (PMID:12639993)
• JCI article 17892
• Chiu 2007 (PubAnnotation PMID:17655857)
• Minamisawa 2003 (Scinapse) (PMID:12705874)
• OMIM PLN 172405 (mirror)
• Polish HCM PLN screening (Polish Heart Journal)
• NCBI E-utilities PubMed records
• ClinGen PLN / intrinsic cardiomyopathy
• Local cache: references_cache/PMID_21167350.md, PMID_12610310.md, PMID_16432188.md, and the CGGV PLN records

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:

• PMID:12639993: "critical difference between mouse and human"
• closest text in source: "In this study, the surprising difference between human and mouse PLN-null cardiac phenotypes emphasizes the need to better understand inherent differences in cardiac physiology and Ca2+-cycling mechanisms between mice and humans (31)"

Term Validation

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

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

• HP:0001715 (1 mention) - HP does not contain this term

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• MONDO:0000591 (4 mentions) - the report calls it "intrinsic cardiomyopathy", "ClinGen validity: Definitive, AD, for *intrinsic cardiomyopathy"; MONDO calls it intrinsic cardiomyopathy**
• UBERON:0000948 (1 mention) - the report calls it "Candidate UBERON terms: heart"; UBERON calls it heart**, and lists "chambered heart" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

• MONDO:0000591 - called "intrinsic cardiomyopathy", "ClinGen validity:* Definitive, AD, for intrinsic cardiomyopathy"