Hypertrophic Cardiomyopathy 21

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Mappings

MONDO

MONDO:0013852 hypertrophic cardiomyopathy 21

Primary MONDO identifier for the CMH21 locus entity (OMIM:614676; MONDO definition cites the 7p12.1-q21 region and PMID:16651466).

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Inheritance

1

Autosomal dominant inheritance HP:0000006

CMH21 is catalogued as an autosomal dominant trait (OMIM:614676). The single reported kindred spans four generations with vertical transmission, which is consistent with dominant inheritance, but the anchoring abstract does not state the mode of inheritance explicitly, so this assignment rests on the pedigree structure and the OMIM/MONDO classification rather than on a stated segregation model.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"genome-wide linkage analysis was used to study one kindred (4 generations, 32 individuals) with predominant clinical features of left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death."

Documents a four-generation kindred with disease transmitted across generations, consistent with (but not explicitly stated as) autosomal dominant inheritance.

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Discussions and Knowledge Gaps

4

Which gene within the 27.2 Mb 7p12.1-q21 interval carries the CMH21 disease allele?

KNOWLEDGE GAP OPEN cmh21_causal_gene_unidentified

Attached to

pathophysiology#Unidentified 7p12.1-q21 Disease Allele genetic#CMH21 linkage locus (7p12.1-q21)

CMH21 is one of the few members of the CMH numbered series that remains defined by a chromosomal region rather than a gene. The MONDO definition ("material basis in region 7p12.1-q21 variation") and the OMIM entry both stop at the interval. The anchoring linkage study identified the interval but explicitly left the causal mutation for future work, and no subsequent publication has reported a gene for this entity. Until a gene is established, every downstream mechanistic node in this entry is an observation about a phenotype, not a molecular pathway. Assigning a plausible-looking gene from the interval (for example on the basis of cardiac expression or of a neighbouring cardiomyopathy locus) would be an unsupported inference.

Proposed experiments

Whole-genome sequencing and re-analysis of the index kindred

cmh21_wgs_reanalysis

Perform whole-genome (not exome-only) sequencing on the surviving affected and unaffected members of the original 4-generation kindred and filter for variants segregating with disease within the D7S506-D7S3314 interval. Genome-wide coverage is required because the 2006 study excluded only coding sarcomere genes, leaving non-coding, regulatory, and structural variation within the interval untested.

Decision criterion

A rare variant segregating with the phenotype inside the D7S506-D7S3314 interval and absent from population databases would nominate the causal gene; finding none on whole-genome coverage would raise the possibility that the original single-family linkage signal was a false positive.

Would support

pathophysiology#Unidentified 7p12.1-q21 Disease Allele

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"Identification of the causal gene mutation and additional genotype-phenotype correlation studies will provide fundamental insight into mechanisms of cardiac remodeling."

The authors state that the causal gene mutation had not been identified and frame its identification as future work — the gap this discussion records.

Should GATAD1 (7q21.2), the gene for an autosomal recessive dilated cardiomyopathy that maps inside the CMH21 interval, be treated as a candidate gene for CMH21?

INTERPRETATION OPEN cmh21_gatad1_regional_overlap_not_causation

Attached to

genetic#CMH21 linkage locus (7p12.1-q21)

A curator or automated tool searching the 7p12.1-q21 interval for cardiomyopathy genes will find GATAD1, whose autosomal recessive DCM locus at 7q21 overlaps the distal end of the CMH21 interval. Regional overlap is not evidence of shared causation. The GATAD1 entity is recessive, was ascertained in descendants of first cousins, presents as dilated cardiomyopathy, and has unaffected heterozygous carriers — none of which matches the dominant, hypertrophy-predominant, four-generation CMH21 kindred. No study has tested GATAD1 in the CMH21 family or otherwise linked the two. This discussion is recorded so the coincidence is documented and explicitly rejected rather than silently re-discovered and mis-asserted.

Show evidence (2 references)

PMID:21965549 SUPPORT Human Clinical

"The mutation, absent in HapMap, 1000 Genomes, and 474 ethnically matched controls, altered a conserved residue of GATAD1, encoding GATA zinc finger domain-containing protein 1."

Identifies GATAD1 as the gene for the recessive 7q21 DCM entity, i.e. for a different disease that happens to map inside the CMH21 interval.

PMID:21965549 SUPPORT Human Clinical

"Thirteen relatives were heterozygous mutation carriers with no evidence of myocardial disease, even at advanced ages."

Heterozygous GATAD1 carriers are unaffected, which is incompatible with the dominant transmission pattern of the CMH21 kindred and argues against transferring this gene to CMH21.

Is CMH21 a replicable disease entity, or a single-family linkage result that has not been independently confirmed?

OPEN QUESTION OPEN cmh21_entity_rests_on_a_single_kindred

Attached to

pathophysiology#Unidentified 7p12.1-q21 Disease Allele

The entire evidence base for CMH21 is one kindred reported in 2006 with a two-point LOD of 4.11. No second family, no gene, and no genotype-phenotype series have been published since. The clinical description (hypertrophy plus dilation plus end-stage heart failure, without myocyte disarray) also does not match the typical sarcomeric HCM phenotype that the CMH series name implies, so the entity's placement under hypertrophic cardiomyopathy in MONDO is itself a nosological question. Curators should treat this entry as a faithful record of a single well-conducted linkage study rather than as an established disease mechanism.

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"genome-wide linkage analysis was used to study one kindred (4 generations, 32 individuals)"

Confirms that the entity derives from a single kindred.

Should the OMIM/MedGen clinical-synopsis features for CMH21 that cannot be quoted from the paywalled full text (atrial fibrillation, mitral valve prolapse) be curated as phenotypes, and how should the synopsis's listing of myofiber disarray be reconciled with the primary paper's report that disarray was absent?

CURATION TODO OPEN cmh21_omim_synopsis_features_unquotable

Attached to

histopathology#Absence of Myocyte Disarray and Interstitial Fibrosis

The OMIM/MedGen clinical synopsis for CMH21 (OMIM:614676, MedGen CUI C3553442) lists six HPO-mapped features: Hypertrophic cardiomyopathy (HP:0001639), Left ventricular hypertrophy (HP:0001712), Sudden death (HP:0001699), Atrial fibrillation (HP:0005110), Mitral valve prolapse (HP:0001634), and Myofiber disarray (HP:0031318). Two problems block direct curation. First, atrial fibrillation and mitral valve prolapse presumably derive from the Circulation full text, which is not open access and is not in the abstract, so no exact snippet can be verified for them; per dismech evidence policy they are recorded here rather than asserted as unevidenced phenotypes. Second, the synopsis's inclusion of myofiber disarray directly contradicts the paper's abstract, which states that histopathology in two family members "did not demonstrate myocyte disarray and fibrosis". The most plausible explanation is that the OMIM synopsis inherits the generic CMH template rather than this family's actual pathology. Resolving this requires the Circulation full text (institutional access), after which the two unquotable phenotypes can be added with real evidence and the disarray conflict can be settled.

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Pathophysiology

3

Unidentified 7p12.1-q21 Disease Allele

The proximal lesion is a germline variant segregating with disease within a 27.2 Mb interval on chromosome 7 (7p12.1-7q21). Neither the gene nor the variant class (coding, regulatory, structural) has been identified, so no molecular function, protein complex, or biological process can be assigned to this node. It is modelled explicitly as an unresolved trigger so that the downstream chain is not attributed to a fabricated molecular cause.

Downstream

Non-Sarcomeric Left Ventricular Hypertrophy The intermediate steps between the 7p12.1-q21 allele and the hypertrophic phenotype are entirely unknown; the edge records co-segregation, not a characterized mechanism.

Show evidence (2 references)

PMID:16651466 SUPPORT Human Clinical

"Recombination events refine the disease interval between D7S506 and D7S3314, corresponding to a distance of 27.2 megabases."

Defines the physical interval containing the disease allele while leaving the gene unspecified.

PMID:16651466 SUPPORT Human Clinical

"Identification of the causal gene mutation and additional genotype-phenotype correlation studies will provide fundamental insight into mechanisms of cardiac remodeling."

The authors state the causal gene mutation was not identified and remains to be found.

Non-Sarcomeric Left Ventricular Hypertrophy

Affected individuals develop left ventricular hypertrophy that is not attributable to a sarcomere-protein mutation. Myocardial histopathology in two family members lacked myocyte disarray and interstitial fibrosis, the histological signature of sarcomeric HCM, indicating that the hypertrophy in this kindred arises through a pathway distinct from the canonical sarcomere mechanism. The authors interpret this as evidence that pathways to inherited cardiac hypertrophy extend beyond the sarcomere.

left ventricle myocardium UBERON:0006566

Downstream

Ventricular Dilation and End-Stage Heart Failure Within the index kindred, hypertrophy coexisted with cardiac dilation and progression to end-stage heart failure; whether dilation is a sequela of the hypertrophic phase or an independent expression of the same allele is not resolved by the available data.

Show evidence (2 references)

PMID:16651466 SUPPORT Human Clinical

"Of note, histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM."

Directly documents hypertrophy without the sarcomeric-HCM histological signature in this kindred.

PMID:16651466 SUPPORT Human Clinical

"The discovery of a novel genetic locus in this family provides more evidence that molecular pathways leading to inherited cardiac hypertrophy extend beyond the sarcomere."

The authors' own framing that this hypertrophy is mechanistically non-sarcomeric.

Ventricular Dilation and End-Stage Heart Failure

Beyond left ventricular hypertrophy, the reported kindred manifested cardiac dilation, end-stage heart failure, and sudden death — a mixed hypertrophic-to-dilated remodeling course rather than the pure obstructive hypertrophic phenotype implied by the CMH series name. This node is curated at the level of the observed clinical/structural outcome; the neurohormonal and cellular remodeling steps described in the `cardiomyopathy_maladaptive_remodeling` module are the generic umbrella account and have not been demonstrated for this specific entity.

heart left ventricle UBERON:0002084

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"predominant clinical features of left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death."

Documents the dilated/heart-failure arm of the phenotype in the index kindred.

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Histopathology

1

Absence of Myocyte Disarray and Interstitial Fibrosis

Myocardial histopathology available from two affected family members did NOT show myocyte disarray or fibrosis. This is a discriminating negative finding: myocyte disarray with interstitial fibrosis is the expected histological signature of sarcomere-mutation HCM, and its absence was the authors' basis for concluding that this kindred's phenotype is not typical sarcomeric HCM. Only two individuals were examined, so the finding is not established as a general feature of the entity.

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"Of note, histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM."

Exact statement of the negative histological finding and the authors' interpretation of it.

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Pathograph

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Phenotypes

5

Cardiovascular 4

Left Ventricular Hypertrophy HP:0001712

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"one kindred (4 generations, 32 individuals) with predominant clinical features of left ventricular hypertrophy"

Names left ventricular hypertrophy as the predominant feature of the kindred that defines this entity.

Cardiac Dilation Dilated cardiomyopathy HP:0001644

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death."

The abstract reports cardiac dilation in the kindred. PARTIAL because the abstract states dilation as a clinical feature without meeting or stating formal diagnostic criteria for dilated cardiomyopathy in each affected individual.

End-Stage Heart Failure Congestive heart failure HP:0001635

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"cardiac dilation, end-stage heart failure, and sudden death."

End-stage heart failure is explicitly listed among the kindred's clinical features.

Sudden Death Sudden cardiac death HP:0001645

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death."

Supports the occurrence of sudden death in this cardiomyopathy kindred. PARTIAL because the abstract says "sudden death" rather than "sudden cardiac death" and does not describe the arrhythmic mechanism.

Other 1

Myofiber Disarray HP:0031318

Do not convert this to a SUPPORT phenotype on the strength of the OMIM synopsis. The only primary observation available for this entity is negative, and it is what distinguishes CMH21 from sarcomeric HCM in the differential. The negative finding is also carried in histopathology, where it belongs as a tissue observation; this phenotype entry exists to make the source conflict machine-queryable. Note the sample is two individuals, so the correct reading is "refuted in the only individuals examined", not "established as absent across the entity" - see the cmh21_omim_synopsis_features_unquotable discussion.

Show evidence (1 reference)

PMID:16651466 REFUTE Human Clinical

"Of note, histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM."

Direct refutation of myofiber disarray in the only CMH21 individuals whose myocardium has been examined, contradicting the OMIM clinical synopsis.

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Genetic Associations

1

CMH21 linkage locus (7p12.1-q21)

relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:16651466 SUPPORT Human Clinical

"Linkage was then established to a novel locus on chromosome 7 (7p12.1-7q21). A maximum 2-point logarithm of odds score of 4.11 was obtained. Recombination events refine the disease interval between D7S506 and D7S3314, corresponding to a distance of 27.2 megabases."

Establishes the locus, its boundaries, and its statistical support, which is the entire genetic basis on which this MONDO/OMIM entity rests.

PMID:16651466 SUPPORT Human Clinical

"Direct DNA sequencing was performed on sarcomere genes known to cause HCM and dilated cardiomyopathy, and no mutations were identified."

Excludes the known sarcomeric causes in this kindred, supporting a non-sarcomeric, still-unidentified molecular lesion.

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Medical Actions

4

Genetic Counseling and Lifelong Cascade Clinical Screening

Action: Genetic Counseling NCIT:C15240

The highest-value intervention in this entity, and the one most shaped by its gene-less status. Three things must be conveyed and are easy to get wrong. First, inheritance is autosomal dominant across four generations, so first-degree relatives carry a 50% prior risk and all require evaluation. Second, a negative cardiomyopathy panel does not exclude a relative - because no CMH21 allele has ever been identified, there is nothing to test for, and cascade *genetic* testing is simply unavailable; surveillance is therefore clinical, and lifelong. Third, and following from the same fact, preimplantation genetic testing and prenatal diagnosis are not options for this family, which is a material difference from every gene-solved cardiomyopathy and should be stated plainly rather than discovered later.

Show evidence (2 references)

PMID:16651466 SUPPORT Human Clinical

"Direct DNA sequencing was performed on sarcomere genes known to cause HCM and dilated cardiomyopathy, and no mutations were identified."

The absence of an identifiable variant in the defining kindred is precisely what makes genetic cascade testing unavailable and clinical surveillance unending.

PMID:16651466 SUPPORT Human Clinical

"one kindred (4 generations, 32 individuals) with predominant clinical features of left ventricular hypertrophy"

Four-generation transmission establishes the dominant pattern underlying the 50% recurrence risk counseling is built on.

Implantable Cardioverter-Defibrillator

Action: Implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Sudden death is a documented feature of the defining kindred, which puts arrhythmic risk stratification squarely in scope for this entity. What CMH21 cannot supply is the stratification itself: the established sudden-death risk models for hypertrophic cardiomyopathy are built on sarcomeric cohorts, and this entity has one published family, no event rates, and a histology that the authors said is not typical sarcomeric HCM - so it is not clear those models transfer. Decisions are therefore made on generic criteria and family history, and the gap is recorded rather than papered over.

Target Phenotypes: Sudden cardiac death HP:0001645

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death."

Establishes sudden death in the kindred, which is the indication for considering an ICD. PARTIAL because the source records the events and does not evaluate device therapy, report an event rate, or adjudicate mechanism.

Heart Transplantation and Advanced Heart Failure Management

Action: Heart Transplantation NCIT:C15246

Affected members of the kindred progressed to end-stage heart failure, so advanced therapy is a documented endpoint of this disease rather than a theoretical one. The trajectory is also the reason the drug class most associated with hypertrophic cardiomyopathy is absent from this entry: this family moved from hypertrophy toward dilation and end-stage failure, and cardiac myosin inhibitors are indicated for obstructive disease and are inappropriate once systolic function falls.

Target Phenotypes: Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"cardiac dilation, end-stage heart failure, and sudden death."

Documents progression to end-stage heart failure in the kindred, the clinical state for which transplantation is evaluated. PARTIAL because no family member is reported as transplanted and the source evaluates no therapy.

Supportive and Guideline-Directed Heart Failure Care

Action: Supportive Care NCIT:C15747

Symptom-directed care and standard guideline-directed medical therapy for ventricular dysfunction, which is what the family's documented course requires between diagnosis and any advanced intervention.

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Diagnosis

4

Transthoracic echocardiography for diagnosis and lifelong family surveillance

Echocardiography carries more weight in this entity than in gene-solved cardiomyopathies, because it is not one arm of surveillance but the whole of it. In a family with an identified pathogenic variant, a relative who tests negative can be discharged. No such test exists for CMH21: the disease allele has never been found anywhere in the 27.2 Mb interval, so no relative can be genetically excluded, and serial clinical imaging must therefore continue indefinitely in every first-degree relative rather than stopping at a single normal study or a negative genetic result. The kindred's own phenotype dictates what to look for - predominant left ventricular hypertrophy, but also ventricular dilation and falling systolic function, since affected members progressed to end-stage heart failure.

Echocardiography NCIT:C16525

Results: Left ventricular hypertrophy; in later disease, ventricular dilation and systolic impairment. A normal study in a relative excludes nothing permanently and does not end surveillance.

The imaging modality and the finding are evidenced; the surveillance interval is not. Screening cadence is guideline-generic (2024 AHA/ACC, PMID:38718139; 2023 ESC, PMID:37622657, both carried in the top-level references) and no CMH21-specific screening study exists. Neither guideline record carries quotable recommendation text in its cached PubMed abstract, so no snippet is claimed for the cadence.

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"one kindred (4 generations, 32 individuals) with predominant clinical features of left ventricular hypertrophy"

Establishes the imaging phenotype that clinical surveillance is looking for, across a four-generation pedigree.

Cardiac magnetic resonance imaging

CMR adds tissue characterisation that echocardiography cannot provide, and in this entity it addresses a specific question rather than a generic one. The two family members whose myocardium was examined showed neither myocyte disarray nor fibrosis - the histological signature that would be expected in sarcomeric disease - so late gadolinium enhancement is the non-invasive way to ask whether that negative finding generalises beyond those two individuals. It also discriminates several of the phenocopies that a sarcomere-negative, disarray-negative family should be screened for.

Cardiac magnetic resonance imaging NCIT:C16809

Results: Wall-thickness quantification and late gadolinium enhancement pattern; infiltrative and storage phenocopies produce characteristic enhancement distributions distinct from sarcomeric hypertrophy.

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"Of note, histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM."

Supplies the tissue question CMR is being asked to answer at scale. PARTIAL because the source reports histology in two individuals and makes no statement about imaging - the inference that CMR is the way to generalise the finding is this entry's, not the paper's.

Cardiomyopathy gene panel, with a negative result that does not exclude

Panel testing is indicated, and its most important property in this entity is what it cannot do. Sequencing serves two purposes here - excluding sarcomeric HCM and DCM, which was done in the index kindred and was negative, and excluding the phenocopy genes below. What it cannot do is confirm or exclude CMH21 itself, because CMH21 has no gene: a completely negative panel is the expected result in a genuinely affected CMH21 patient. Reporting such a result as "no pathogenic variant identified" without that context invites the reader to conclude the family is unaffected.

Cardiomyopathy gene panel testing NCIT:C15709

Results: Negative for sarcomere and known cardiomyopathy genes. This is consistent with - not evidence against - CMH21, and cannot be used to discharge relatives.

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"Direct DNA sequencing was performed on sarcomere genes known to cause HCM and dilated cardiomyopathy, and no mutations were identified."

Documents the negative sequencing result in the defining kindred, which is simultaneously the exclusion of the main differential and the demonstration that a negative panel is the expected CMH21 finding.

Phenocopy exclusion testing

For a family that is sarcomere-negative and disarray-negative, the non-sarcomeric causes of unexplained left ventricular hypertrophy become the highest-yield remaining workup - several are treatable, which is what makes the distinction actionable rather than academic. The relevant set is Fabry disease (alpha-galactosidase A activity and GLA sequencing), cardiac amyloidosis (serum free light chains with immunofixation, and bone scintigraphy), Danon disease (LAMP2), and PRKAG2 glycogen storage cardiomyopathy, which is suggested by pre-excitation on the ECG.

Phenocopy exclusion testing NCIT:C15709

Results: A positive result reclassifies the family out of CMH21 entirely and into a disease with its own management; a negative result strengthens, without confirming, the locus-defined diagnosis.

No CMH21-specific diagnostic-yield data exist for any of these tests; the panel composition is standard practice for unexplained left ventricular hypertrophy and is guideline-derived rather than entity-derived.

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"Of note, histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM."

The authors' own conclusion that this is not typical sarcomeric HCM is what raises the prior probability of a non-sarcomeric cause and motivates this workup. PARTIAL because the paper draws no conclusion about phenocopies and names none of these tests - the workup is standard practice for unexplained hypertrophy, applied here because of the paper's finding.

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Prevalence

1

Worldwide published cases

Cases In Literature Ultra Rare

No population prevalence estimate exists. The published evidence base for CMH21 is a single four-generation kindred of 32 individuals reported in 2006; no additional family has been described since, and no gene test exists that would allow the entity to be ascertained in unrelated populations.

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"genome-wide linkage analysis was used to study one kindred (4 generations, 32 individuals)"

Establishes that the entity's entire published case base is a single kindred of 32 individuals.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Hypertrophic Cardiomyopathy 21:

Sarcomeric Hypertrophic Cardiomyopathy Not Yet Curated MONDO:0024573

Overlapping Features Autosomal dominant HCM caused by mutations in sarcomere-protein genes is the principal alternative in any kindred with inherited left ventricular hypertrophy, and must be excluded by sequencing before a novel locus is invoked. In the CMH21 kindred, sarcomere-gene sequencing was negative and the myocardial histology lacked disarray and fibrosis.

Distinguishing Features

Sarcomeric HCM: a pathogenic variant in a sarcomere-protein gene is identifiable. CMH21: sarcomere genes were sequenced in the index kindred and no mutations were found.
Sarcomeric HCM: myocyte disarray with interstitial fibrosis on myocardial histology. CMH21: neither disarray nor fibrosis in the two family members examined.
CMH21 is defined only by linkage to 7p12.1-q21, with no gene identified anywhere in the 27.2 Mb interval.

Show evidence (1 reference)

PMID:16651466 SUPPORT Human Clinical

"Direct DNA sequencing was performed on sarcomere genes known to cause HCM and dilated cardiomyopathy, and no mutations were identified."

Documents the exclusion of the main differential (sarcomeric HCM/DCM) in the defining kindred.

GATAD1-Related Autosomal Recessive Dilated Cardiomyopathy Not Yet Curated MONDO:0013848

Overlapping Features A separate autosomal recessive dilated cardiomyopathy maps to chromosome arm 7q21 and is caused by a homozygous GATAD1 missense mutation. Its linkage region overlaps the distal part of the CMH21 interval, which makes it a tempting but incorrect candidate assignment for CMH21. The two entities differ in mode of inheritance (recessive vs. the dominant four-generation CMH21 pedigree), in primary phenotype, and in cohort; no study has linked GATAD1 to CMH21.

Distinguishing Features

GATAD1 DCM is autosomal recessive (homozygous GATAD1 missense variant in descendants of first cousins, with unaffected heterozygous carriers); the CMH21 kindred shows dominant transmission across four generations.
GATAD1 DCM presents as dilated cardiomyopathy; CMH21 presents with predominant left ventricular hypertrophy, with dilation as an additional feature.
GATAD1 is an identified gene; CMH21 has no gene identified anywhere in its 27.2 Mb interval, and GATAD1 has never been tested in the CMH21 kindred.

Show evidence (2 references)

PMID:21965549 SUPPORT Human Clinical

"Genotyping and linkage analysis mapped an AR DCM locus to chromosome arm 7q21, which was validated and refined by high-density homozygosity mapping."

Confirms that a distinct, autosomal recessive cardiomyopathy locus lies on 7q21, overlapping the CMH21 interval — the basis for flagging it as a differential rather than a candidate gene for CMH21.

PMID:21965549 SUPPORT Human Clinical

"We performed genome-wide mapping and exome sequencing in a unique family wherein DCM segregated as an autosomal recessive (AR) trait."

Establishes the recessive inheritance of the GATAD1 entity, distinguishing it from the dominant CMH21 kindred.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 21
creation_date: '2026-08-01T00:00:00Z'
synonyms:
- CMH21
- cardiomyopathy, hypertrophic, 21
- cardiomyopathy, familial hypertrophic, 21
- hypertrophic cardiomyopathy type 21
description: >-
  Hypertrophic cardiomyopathy 21 (CMH21) is a locus-defined inherited
  cardiomyopathy entity with no established causal gene. It was delineated
  in a single large kindred by genome-wide linkage to a 27.2-Mb interval on
  chromosome 7 (7p12.1-7q21), after direct sequencing of the known HCM and
  dilated-cardiomyopathy sarcomere genes was negative. The affected family
  members showed left ventricular hypertrophy together with cardiac dilation,
  end-stage heart failure, and sudden death; myocardial histopathology in two
  members lacked the myocyte disarray and fibrosis typical of sarcomeric HCM.
  MONDO and OMIM therefore define this entity by chromosomal region rather than
  by gene, and the molecular lesion within 7p12.1-q21 remains unidentified.
  Because the anchoring report describes a mixed hypertrophic-and-dilated,
  non-disarray phenotype, the "hypertrophic cardiomyopathy" label inherited from
  the CMH numbered series should be read as a nosological placeholder rather
  than as a claim of typical sarcomeric HCM biology.
category: Mendelian
disease_term:
  preferred_term: hypertrophic cardiomyopathy 21
  term:
    id: MONDO:0013852
    label: hypertrophic cardiomyopathy 21
parents:
- Hypertrophic Cardiomyopathy
- Cardiovascular Disease
- Genetic Disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0013852
      label: hypertrophic cardiomyopathy 21
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for the CMH21 locus entity (OMIM:614676;
      MONDO definition cites the 7p12.1-q21 region and PMID:16651466).
prevalence:
- population: Worldwide published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate exists. The published evidence base for
    CMH21 is a single four-generation kindred of 32 individuals reported in
    2006; no additional family has been described since, and no gene test
    exists that would allow the entity to be ascertained in unrelated
    populations.
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genome-wide linkage analysis was used to study one kindred (4 generations,
      32 individuals)
    explanation: >-
      Establishes that the entity's entire published case base is a single
      kindred of 32 individuals.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    CMH21 is catalogued as an autosomal dominant trait (OMIM:614676). The single
    reported kindred spans four generations with vertical transmission, which is
    consistent with dominant inheritance, but the anchoring abstract does not
    state the mode of inheritance explicitly, so this assignment rests on the
    pedigree structure and the OMIM/MONDO classification rather than on a stated
    segregation model.
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genome-wide linkage analysis was used to study one kindred (4 generations,
      32 individuals) with predominant clinical features of left ventricular
      hypertrophy in addition to cardiac dilation, end-stage heart failure, and
      sudden death.
    explanation: >-
      Documents a four-generation kindred with disease transmitted across
      generations, consistent with (but not explicitly stated as) autosomal
      dominant inheritance.
genetic:
- name: CMH21 linkage locus (7p12.1-q21)
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    CMH21 is defined by a linkage interval, not by a gene. Two-point linkage in
    the index kindred reached a maximum LOD score of 4.11 on chromosome 7, and
    recombinants narrowed the disease interval to the 27.2 Mb between markers
    D7S506 and D7S3314 (7p12.1-7q21). No causal gene or variant within this
    interval has been reported. Sarcomere genes known to cause hypertrophic and
    dilated cardiomyopathy were sequenced in this family and were negative.
    This block is deliberately curated WITHOUT a gene_term. Do not populate a
    gene here unless a causal gene inside 7p12.1-q21 is established for this
    entity in primary literature and reconciled with the MONDO/OMIM record.
    GATAD1 (7q21.2) is a gene for a DIFFERENT entity (autosomal recessive
    dilated cardiomyopathy, PMID:21965549) and must not be assigned to CMH21 on
    the basis of regional overlap alone.
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Linkage was then established to a novel locus on chromosome 7
      (7p12.1-7q21). A maximum 2-point logarithm of odds score of 4.11 was
      obtained. Recombination events refine the disease interval between D7S506
      and D7S3314, corresponding to a distance of 27.2 megabases.
    explanation: >-
      Establishes the locus, its boundaries, and its statistical support, which
      is the entire genetic basis on which this MONDO/OMIM entity rests.
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Direct DNA sequencing was performed on sarcomere genes known to cause HCM
      and dilated cardiomyopathy, and no mutations were identified.
    explanation: >-
      Excludes the known sarcomeric causes in this kindred, supporting a
      non-sarcomeric, still-unidentified molecular lesion.
pathophysiology:
- name: Unidentified 7p12.1-q21 Disease Allele
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The proximal lesion is a germline variant segregating with disease within a
    27.2 Mb interval on chromosome 7 (7p12.1-7q21). Neither the gene nor the
    variant class (coding, regulatory, structural) has been identified, so no
    molecular function, protein complex, or biological process can be assigned
    to this node. It is modelled explicitly as an unresolved trigger so that the
    downstream chain is not attributed to a fabricated molecular cause.
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recombination events refine the disease interval between D7S506 and
      D7S3314, corresponding to a distance of 27.2 megabases.
    explanation: >-
      Defines the physical interval containing the disease allele while leaving
      the gene unspecified.
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of the causal gene mutation and additional
      genotype-phenotype correlation studies will provide fundamental insight
      into mechanisms of cardiac remodeling.
    explanation: >-
      The authors state the causal gene mutation was not identified and remains
      to be found.
  downstream:
  - target: Non-Sarcomeric Left Ventricular Hypertrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The intermediate steps between the 7p12.1-q21 allele and the hypertrophic
      phenotype are entirely unknown; the edge records co-segregation, not a
      characterized mechanism.
- name: Non-Sarcomeric Left Ventricular Hypertrophy
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Affected individuals develop left ventricular hypertrophy that is not
    attributable to a sarcomere-protein mutation. Myocardial histopathology in
    two family members lacked myocyte disarray and interstitial fibrosis, the
    histological signature of sarcomeric HCM, indicating that the hypertrophy in
    this kindred arises through a pathway distinct from the canonical sarcomere
    mechanism. The authors interpret this as evidence that pathways to inherited
    cardiac hypertrophy extend beyond the sarcomere.
  locations:
  - preferred_term: left ventricle myocardium
    term:
      id: UBERON:0006566
      label: left ventricle myocardium
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, histopathology from 2 family members did not demonstrate myocyte
      disarray and fibrosis, indicating that this phenotype is not typical
      sarcomere mutation HCM.
    explanation: >-
      Directly documents hypertrophy without the sarcomeric-HCM histological
      signature in this kindred.
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The discovery of a novel genetic locus in this family provides more
      evidence that molecular pathways leading to inherited cardiac hypertrophy
      extend beyond the sarcomere.
    explanation: >-
      The authors' own framing that this hypertrophy is mechanistically
      non-sarcomeric.
  downstream:
  - target: Ventricular Dilation and End-Stage Heart Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Within the index kindred, hypertrophy coexisted with cardiac dilation and
      progression to end-stage heart failure; whether dilation is a sequela of
      the hypertrophic phase or an independent expression of the same allele is
      not resolved by the available data.
- name: Ventricular Dilation and End-Stage Heart Failure
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  conforms_to: cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure
  description: >-
    Beyond left ventricular hypertrophy, the reported kindred manifested cardiac
    dilation, end-stage heart failure, and sudden death — a mixed
    hypertrophic-to-dilated remodeling course rather than the pure obstructive
    hypertrophic phenotype implied by the CMH series name. This node is curated
    at the level of the observed clinical/structural outcome; the neurohormonal
    and cellular remodeling steps described in the
    `cardiomyopathy_maladaptive_remodeling` module are the generic umbrella
    account and have not been demonstrated for this specific entity.
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      predominant clinical features of left ventricular hypertrophy in addition
      to cardiac dilation, end-stage heart failure, and sudden death.
    explanation: >-
      Documents the dilated/heart-failure arm of the phenotype in the index
      kindred.
phenotypes:
- category: Cardiovascular
  name: Left Ventricular Hypertrophy
  description: >-
    The predominant clinical feature of the CMH21 kindred was left ventricular
    hypertrophy.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      one kindred (4 generations, 32 individuals) with predominant clinical
      features of left ventricular hypertrophy
    explanation: >-
      Names left ventricular hypertrophy as the predominant feature of the
      kindred that defines this entity.
- category: Cardiovascular
  name: Cardiac Dilation
  description: >-
    Cardiac (ventricular) dilation was observed in the index kindred alongside
    hypertrophy, giving a mixed hypertrophic/dilated cardiomyopathy picture.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      left ventricular hypertrophy in addition to cardiac dilation, end-stage
      heart failure, and sudden death.
    explanation: >-
      The abstract reports cardiac dilation in the kindred. PARTIAL because the
      abstract states dilation as a clinical feature without meeting or stating
      formal diagnostic criteria for dilated cardiomyopathy in each affected
      individual.
- category: Cardiovascular
  name: End-Stage Heart Failure
  description: >-
    Affected members progressed to end-stage heart failure.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
    clinical_course: PROGRESSIVE
  severity: SEVERE
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cardiac dilation, end-stage heart failure, and sudden death.
    explanation: >-
      End-stage heart failure is explicitly listed among the kindred's clinical
      features.
- category: Cardiovascular
  name: Sudden Death
  description: >-
    Sudden death occurred in the index kindred. The abstract reports "sudden
    death" among the family's clinical features in a cardiomyopathy context; it
    does not further adjudicate the mechanism of death.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      left ventricular hypertrophy in addition to cardiac dilation, end-stage
      heart failure, and sudden death.
    explanation: >-
      Supports the occurrence of sudden death in this cardiomyopathy kindred.
      PARTIAL because the abstract says "sudden death" rather than
      "sudden cardiac death" and does not describe the arrhythmic mechanism.
- category: Cardiovascular
  name: Myofiber Disarray
  description: >-
    Recorded as a REFUTED feature, not an observed one. The OMIM clinical
    synopsis for CMH21 lists myofiber disarray among the entity's features, but
    the anchoring publication states the opposite: histopathology from the two
    family members examined did not demonstrate myocyte disarray or fibrosis,
    and the authors treated that absence as their basis for concluding the
    kindred does not have typical sarcomere-mutation HCM. This entry follows the
    primary source. The phenotype is curated with refuting evidence so that the
    conflict between the OMIM synopsis and the primary literature is resolvable
    by a downstream consumer rather than only by a human reading prose.
  phenotype_term:
    preferred_term: Myofiber disarray
    term:
      id: HP:0031318
      label: Myofiber disarray
  notes: >-
    Do not convert this to a SUPPORT phenotype on the strength of the OMIM
    synopsis. The only primary observation available for this entity is negative,
    and it is what distinguishes CMH21 from sarcomeric HCM in the differential.
    The negative finding is also carried in histopathology, where it belongs as
    a tissue observation; this phenotype entry exists to make the source conflict
    machine-queryable. Note the sample is two individuals, so the correct reading
    is "refuted in the only individuals examined", not "established as absent
    across the entity" - see the cmh21_omim_synopsis_features_unquotable
    discussion.
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, histopathology from 2 family members did not demonstrate myocyte
      disarray and fibrosis, indicating that this phenotype is not typical
      sarcomere mutation HCM.
    explanation: >-
      Direct refutation of myofiber disarray in the only CMH21 individuals whose
      myocardium has been examined, contradicting the OMIM clinical synopsis.
histopathology:
- name: Absence of Myocyte Disarray and Interstitial Fibrosis
  description: >-
    Myocardial histopathology available from two affected family members did NOT
    show myocyte disarray or fibrosis. This is a discriminating negative
    finding: myocyte disarray with interstitial fibrosis is the expected
    histological signature of sarcomere-mutation HCM, and its absence was the
    authors' basis for concluding that this kindred's phenotype is not typical
    sarcomeric HCM. Only two individuals were examined, so the finding is not
    established as a general feature of the entity.
  diagnostic: false
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, histopathology from 2 family members did not demonstrate myocyte
      disarray and fibrosis, indicating that this phenotype is not typical
      sarcomere mutation HCM.
    explanation: >-
      Exact statement of the negative histological finding and the authors'
      interpretation of it.
diagnosis:
- name: Transthoracic echocardiography for diagnosis and lifelong family surveillance
  diagnosis_term:
    preferred_term: Echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  description: >-
    Echocardiography carries more weight in this entity than in gene-solved
    cardiomyopathies, because it is not one arm of surveillance but the whole of
    it. In a family with an identified pathogenic variant, a relative who tests
    negative can be discharged. No such test exists for CMH21: the disease allele
    has never been found anywhere in the 27.2 Mb interval, so no relative can be
    genetically excluded, and serial clinical imaging must therefore continue
    indefinitely in every first-degree relative rather than stopping at a single
    normal study or a negative genetic result. The kindred's own phenotype
    dictates what to look for - predominant left ventricular hypertrophy, but
    also ventricular dilation and falling systolic function, since affected
    members progressed to end-stage heart failure.
  results: >-
    Left ventricular hypertrophy; in later disease, ventricular dilation and
    systolic impairment. A normal study in a relative excludes nothing
    permanently and does not end surveillance.
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      one kindred (4 generations, 32 individuals) with predominant clinical
      features of left ventricular hypertrophy
    explanation: >-
      Establishes the imaging phenotype that clinical surveillance is looking
      for, across a four-generation pedigree.
  notes: >-
    The imaging modality and the finding are evidenced; the surveillance
    interval is not. Screening cadence is guideline-generic (2024 AHA/ACC,
    PMID:38718139; 2023 ESC, PMID:37622657, both carried in the top-level
    references) and no CMH21-specific screening study exists. Neither guideline
    record carries quotable recommendation text in its cached PubMed abstract,
    so no snippet is claimed for the cadence.
- name: Cardiac magnetic resonance imaging
  diagnosis_term:
    preferred_term: Cardiac magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    CMR adds tissue characterisation that echocardiography cannot provide, and
    in this entity it addresses a specific question rather than a generic one.
    The two family members whose myocardium was examined showed neither myocyte
    disarray nor fibrosis - the histological signature that would be expected in
    sarcomeric disease - so late gadolinium enhancement is the non-invasive way
    to ask whether that negative finding generalises beyond those two
    individuals. It also discriminates several of the phenocopies that a
    sarcomere-negative, disarray-negative family should be screened for.
  results: >-
    Wall-thickness quantification and late gadolinium enhancement pattern;
    infiltrative and storage phenocopies produce characteristic enhancement
    distributions distinct from sarcomeric hypertrophy.
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, histopathology from 2 family members did not demonstrate myocyte
      disarray and fibrosis, indicating that this phenotype is not typical
      sarcomere mutation HCM.
    explanation: >-
      Supplies the tissue question CMR is being asked to answer at scale.
      PARTIAL because the source reports histology in two individuals and makes
      no statement about imaging - the inference that CMR is the way to
      generalise the finding is this entry's, not the paper's.
- name: Cardiomyopathy gene panel, with a negative result that does not exclude
  diagnosis_term:
    preferred_term: Cardiomyopathy gene panel testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Panel testing is indicated, and its most important property in this entity is
    what it cannot do. Sequencing serves two purposes here - excluding sarcomeric
    HCM and DCM, which was done in the index kindred and was negative, and
    excluding the phenocopy genes below. What it cannot do is confirm or exclude
    CMH21 itself, because CMH21 has no gene: a completely negative panel is the
    expected result in a genuinely affected CMH21 patient. Reporting such a
    result as "no pathogenic variant identified" without that context invites
    the reader to conclude the family is unaffected.
  results: >-
    Negative for sarcomere and known cardiomyopathy genes. This is consistent
    with - not evidence against - CMH21, and cannot be used to discharge
    relatives.
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Direct DNA sequencing was performed on sarcomere genes known to cause HCM
      and dilated cardiomyopathy, and no mutations were identified.
    explanation: >-
      Documents the negative sequencing result in the defining kindred, which is
      simultaneously the exclusion of the main differential and the demonstration
      that a negative panel is the expected CMH21 finding.
- name: Phenocopy exclusion testing
  diagnosis_term:
    preferred_term: Phenocopy exclusion testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    For a family that is sarcomere-negative and disarray-negative, the
    non-sarcomeric causes of unexplained left ventricular hypertrophy become the
    highest-yield remaining workup - several are treatable, which is what makes
    the distinction actionable rather than academic. The relevant set is Fabry
    disease (alpha-galactosidase A activity and GLA sequencing), cardiac
    amyloidosis (serum free light chains with immunofixation, and bone
    scintigraphy), Danon disease (LAMP2), and PRKAG2 glycogen storage
    cardiomyopathy, which is suggested by pre-excitation on the ECG.
  results: >-
    A positive result reclassifies the family out of CMH21 entirely and into a
    disease with its own management; a negative result strengthens, without
    confirming, the locus-defined diagnosis.
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, histopathology from 2 family members did not demonstrate myocyte
      disarray and fibrosis, indicating that this phenotype is not typical
      sarcomere mutation HCM.
    explanation: >-
      The authors' own conclusion that this is not typical sarcomeric HCM is what
      raises the prior probability of a non-sarcomeric cause and motivates this
      workup. PARTIAL because the paper draws no conclusion about phenocopies and
      names none of these tests - the workup is standard practice for
      unexplained hypertrophy, applied here because of the paper's finding.
  notes: >-
    No CMH21-specific diagnostic-yield data exist for any of these tests; the
    panel composition is standard practice for unexplained left ventricular
    hypertrophy and is guideline-derived rather than entity-derived.
treatments:
- name: Genetic Counseling and Lifelong Cascade Clinical Screening
  description: >-
    The highest-value intervention in this entity, and the one most shaped by its
    gene-less status. Three things must be conveyed and are easy to get wrong.
    First, inheritance is autosomal dominant across four generations, so
    first-degree relatives carry a 50% prior risk and all require evaluation.
    Second, a negative cardiomyopathy panel does not exclude a relative -
    because no CMH21 allele has ever been identified, there is nothing to test
    for, and cascade *genetic* testing is simply unavailable; surveillance is
    therefore clinical, and lifelong. Third, and following from the same fact,
    preimplantation genetic testing and prenatal diagnosis are not options for
    this family, which is a material difference from every gene-solved
    cardiomyopathy and should be stated plainly rather than discovered later.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Direct DNA sequencing was performed on sarcomere genes known to cause HCM
      and dilated cardiomyopathy, and no mutations were identified.
    explanation: >-
      The absence of an identifiable variant in the defining kindred is precisely
      what makes genetic cascade testing unavailable and clinical surveillance
      unending.
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      one kindred (4 generations, 32 individuals) with predominant clinical
      features of left ventricular hypertrophy
    explanation: >-
      Four-generation transmission establishes the dominant pattern underlying
      the 50% recurrence risk counseling is built on.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Sudden death is a documented feature of the defining kindred, which puts
    arrhythmic risk stratification squarely in scope for this entity. What CMH21
    cannot supply is the stratification itself: the established sudden-death risk
    models for hypertrophic cardiomyopathy are built on sarcomeric cohorts, and
    this entity has one published family, no event rates, and a histology that
    the authors said is not typical sarcomeric HCM - so it is not clear those
    models transfer. Decisions are therefore made on generic criteria and family
    history, and the gap is recorded rather than papered over.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_phenotypes:
  - preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      left ventricular hypertrophy in addition to cardiac dilation, end-stage
      heart failure, and sudden death.
    explanation: >-
      Establishes sudden death in the kindred, which is the indication for
      considering an ICD. PARTIAL because the source records the events and does
      not evaluate device therapy, report an event rate, or adjudicate mechanism.
  notes: >-
    No CMH21-specific risk calculator, event rate, or ICD outcome data exist.
    Practice is guideline-generic (2024 AHA/ACC, PMID:38718139; 2023 ESC,
    PMID:37622657), and neither guideline's cached abstract carries quotable
    recommendation text, so no snippet is claimed for the indication threshold.
- name: Heart Transplantation and Advanced Heart Failure Management
  description: >-
    Affected members of the kindred progressed to end-stage heart failure, so
    advanced therapy is a documented endpoint of this disease rather than a
    theoretical one. The trajectory is also the reason the drug class most
    associated with hypertrophic cardiomyopathy is absent from this entry: this
    family moved from hypertrophy toward dilation and end-stage failure, and
    cardiac myosin inhibitors are indicated for obstructive disease and are
    inappropriate once systolic function falls.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cardiac dilation, end-stage heart failure, and sudden death.
    explanation: >-
      Documents progression to end-stage heart failure in the kindred, the
      clinical state for which transplantation is evaluated. PARTIAL because no
      family member is reported as transplanted and the source evaluates no
      therapy.
  notes: >-
    No CMH21 patient is reported as having undergone transplantation; this
    records the indication implied by the documented disease course, not an
    outcome. Guideline-generic, as above.
- name: Supportive and Guideline-Directed Heart Failure Care
  description: >-
    Symptom-directed care and standard guideline-directed medical therapy for
    ventricular dysfunction, which is what the family's documented course
    requires between diagnosis and any advanced intervention.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: >-
    Deliberately carries no evidence item. There is no CMH21-specific supportive
    or heart-failure therapy study, and the two guideline records cached for this
    entry contain no quotable recommendation text - the AHA/ACC abstract has only
    AIM/METHODS/STRUCTURE sections and the ESC record has no abstract at all. The
    entry states the basis rather than attaching a citation that does not support
    the claim.
differential_diagnoses:
- name: Sarcomeric Hypertrophic Cardiomyopathy
  disease_term:
    preferred_term: familial hypertrophic cardiomyopathy
    term:
      id: MONDO:0024573
      label: familial hypertrophic cardiomyopathy
  description: >-
    Autosomal dominant HCM caused by mutations in sarcomere-protein genes is the
    principal alternative in any kindred with inherited left ventricular
    hypertrophy, and must be excluded by sequencing before a novel locus is
    invoked. In the CMH21 kindred, sarcomere-gene sequencing was negative and
    the myocardial histology lacked disarray and fibrosis.
  distinguishing_features:
  - 'Sarcomeric HCM: a pathogenic variant in a sarcomere-protein gene is
    identifiable. CMH21: sarcomere genes were sequenced in the index kindred and
    no mutations were found.'
  - 'Sarcomeric HCM: myocyte disarray with interstitial fibrosis on myocardial
    histology. CMH21: neither disarray nor fibrosis in the two family members
    examined.'
  - 'CMH21 is defined only by linkage to 7p12.1-q21, with no gene identified
    anywhere in the 27.2 Mb interval.'
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Direct DNA sequencing was performed on sarcomere genes known to cause HCM
      and dilated cardiomyopathy, and no mutations were identified.
    explanation: >-
      Documents the exclusion of the main differential (sarcomeric HCM/DCM) in
      the defining kindred.
- name: GATAD1-Related Autosomal Recessive Dilated Cardiomyopathy
  disease_term:
    preferred_term: dilated cardiomyopathy 2B
    term:
      id: MONDO:0013848
      label: dilated cardiomyopathy 2B
  description: >-
    A separate autosomal recessive dilated cardiomyopathy maps to chromosome arm
    7q21 and is caused by a homozygous GATAD1 missense mutation. Its linkage
    region overlaps the distal part of the CMH21 interval, which makes it a
    tempting but incorrect candidate assignment for CMH21. The two entities
    differ in mode of inheritance (recessive vs. the dominant four-generation
    CMH21 pedigree), in primary phenotype, and in cohort; no study has linked
    GATAD1 to CMH21.
  distinguishing_features:
  - 'GATAD1 DCM is autosomal recessive (homozygous GATAD1 missense variant in
    descendants of first cousins, with unaffected heterozygous carriers); the
    CMH21 kindred shows dominant transmission across four generations.'
  - 'GATAD1 DCM presents as dilated cardiomyopathy; CMH21 presents with
    predominant left ventricular hypertrophy, with dilation as an additional
    feature.'
  - 'GATAD1 is an identified gene; CMH21 has no gene identified anywhere in its
    27.2 Mb interval, and GATAD1 has never been tested in the CMH21 kindred.'
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genotyping and linkage analysis mapped an AR DCM locus to chromosome arm
      7q21, which was validated and refined by high-density homozygosity
      mapping.
    explanation: >-
      Confirms that a distinct, autosomal recessive cardiomyopathy locus lies on
      7q21, overlapping the CMH21 interval — the basis for flagging it as a
      differential rather than a candidate gene for CMH21.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed genome-wide mapping and exome sequencing in a unique family
      wherein DCM segregated as an autosomal recessive (AR) trait.
    explanation: >-
      Establishes the recessive inheritance of the GATAD1 entity, distinguishing
      it from the dominant CMH21 kindred.
discussions:
- discussion_id: cmh21_causal_gene_unidentified
  prompt: >-
    Which gene within the 27.2 Mb 7p12.1-q21 interval carries the CMH21 disease
    allele?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Unidentified 7p12.1-q21 Disease Allele
  - genetic#CMH21 linkage locus (7p12.1-q21)
  rationale: >-
    CMH21 is one of the few members of the CMH numbered series that remains
    defined by a chromosomal region rather than a gene. The MONDO definition
    ("material basis in region 7p12.1-q21 variation") and the OMIM entry both
    stop at the interval. The anchoring linkage study identified the interval
    but explicitly left the causal mutation for future work, and no subsequent
    publication has reported a gene for this entity. Until a gene is
    established, every downstream mechanistic node in this entry is an
    observation about a phenotype, not a molecular pathway. Assigning a
    plausible-looking gene from the interval (for example on the basis of
    cardiac expression or of a neighbouring cardiomyopathy locus) would be an
    unsupported inference.
  proposed_experiments:
  - experiment_id: cmh21_wgs_reanalysis
    name: Whole-genome sequencing and re-analysis of the index kindred
    description: >-
      Perform whole-genome (not exome-only) sequencing on the surviving affected
      and unaffected members of the original 4-generation kindred and filter for
      variants segregating with disease within the D7S506-D7S3314 interval.
      Genome-wide coverage is required because the 2006 study excluded only
      coding sarcomere genes, leaving non-coding, regulatory, and structural
      variation within the interval untested.
    decision_criterion: >-
      A rare variant segregating with the phenotype inside the
      D7S506-D7S3314 interval and absent from population databases would
      nominate the causal gene; finding none on whole-genome coverage would
      raise the possibility that the original single-family linkage signal was
      a false positive.
    would_support:
    - pathophysiology#Unidentified 7p12.1-q21 Disease Allele
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of the causal gene mutation and additional
      genotype-phenotype correlation studies will provide fundamental insight
      into mechanisms of cardiac remodeling.
    explanation: >-
      The authors state that the causal gene mutation had not been identified
      and frame its identification as future work — the gap this discussion
      records.
- discussion_id: cmh21_gatad1_regional_overlap_not_causation
  prompt: >-
    Should GATAD1 (7q21.2), the gene for an autosomal recessive dilated
    cardiomyopathy that maps inside the CMH21 interval, be treated as a
    candidate gene for CMH21?
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - genetic#CMH21 linkage locus (7p12.1-q21)
  rationale: >-
    A curator or automated tool searching the 7p12.1-q21 interval for
    cardiomyopathy genes will find GATAD1, whose autosomal recessive DCM locus
    at 7q21 overlaps the distal end of the CMH21 interval. Regional overlap is
    not evidence of shared causation. The GATAD1 entity is recessive, was
    ascertained in descendants of first cousins, presents as dilated
    cardiomyopathy, and has unaffected heterozygous carriers — none of which
    matches the dominant, hypertrophy-predominant, four-generation CMH21
    kindred. No study has tested GATAD1 in the CMH21 family or otherwise linked
    the two. This discussion is recorded so the coincidence is documented and
    explicitly rejected rather than silently re-discovered and mis-asserted.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation, absent in HapMap, 1000 Genomes, and 474 ethnically matched
      controls, altered a conserved residue of GATAD1, encoding GATA zinc finger
      domain-containing protein 1.
    explanation: >-
      Identifies GATAD1 as the gene for the recessive 7q21 DCM entity, i.e. for
      a different disease that happens to map inside the CMH21 interval.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen relatives were heterozygous mutation carriers with no evidence of
      myocardial disease, even at advanced ages.
    explanation: >-
      Heterozygous GATAD1 carriers are unaffected, which is incompatible with
      the dominant transmission pattern of the CMH21 kindred and argues against
      transferring this gene to CMH21.
- discussion_id: cmh21_entity_rests_on_a_single_kindred
  prompt: >-
    Is CMH21 a replicable disease entity, or a single-family linkage result that
    has not been independently confirmed?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Unidentified 7p12.1-q21 Disease Allele
  rationale: >-
    The entire evidence base for CMH21 is one kindred reported in 2006 with a
    two-point LOD of 4.11. No second family, no gene, and no genotype-phenotype
    series have been published since. The clinical description (hypertrophy plus
    dilation plus end-stage heart failure, without myocyte disarray) also does
    not match the typical sarcomeric HCM phenotype that the CMH series name
    implies, so the entity's placement under hypertrophic cardiomyopathy in
    MONDO is itself a nosological question. Curators should treat this entry as
    a faithful record of a single well-conducted linkage study rather than as an
    established disease mechanism.
  evidence:
  - reference: PMID:16651466
    reference_title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genome-wide linkage analysis was used to study one kindred (4 generations,
      32 individuals)
    explanation: >-
      Confirms that the entity derives from a single kindred.
- discussion_id: cmh21_omim_synopsis_features_unquotable
  prompt: >-
    Should the OMIM/MedGen clinical-synopsis features for CMH21 that cannot be
    quoted from the paywalled full text (atrial fibrillation, mitral valve
    prolapse) be curated as phenotypes, and how should the synopsis's listing of
    myofiber disarray be reconciled with the primary paper's report that
    disarray was absent?
  kind: CURATION_TODO
  status: OPEN
  attaches_to:
  - histopathology#Absence of Myocyte Disarray and Interstitial Fibrosis
  rationale: >-
    The OMIM/MedGen clinical synopsis for CMH21 (OMIM:614676, MedGen CUI
    C3553442) lists six HPO-mapped features: Hypertrophic cardiomyopathy
    (HP:0001639), Left ventricular hypertrophy (HP:0001712), Sudden death
    (HP:0001699), Atrial fibrillation (HP:0005110), Mitral valve prolapse
    (HP:0001634), and Myofiber disarray (HP:0031318). Two problems block direct
    curation. First, atrial fibrillation and mitral valve prolapse presumably
    derive from the Circulation full text, which is not open access and is not
    in the abstract, so no exact snippet can be verified for them; per dismech
    evidence policy they are recorded here rather than asserted as unevidenced
    phenotypes. Second, the synopsis's inclusion of myofiber disarray directly
    contradicts the paper's abstract, which states that histopathology in two
    family members "did not demonstrate myocyte disarray and fibrosis". The most
    plausible explanation is that the OMIM synopsis inherits the generic CMH
    template rather than this family's actual pathology. Resolving this requires
    the Circulation full text (institutional access), after which the two
    unquotable phenotypes can be added with real evidence and the disarray
    conflict can be settled.
notes: >-
  Curation guardrail: this entry deliberately contains NO causal gene. MONDO
  (MONDO:0013852) and OMIM (614676) both define CMH21 by the 7p12.1-q21 region,
  and the anchoring publication (PMID:16651466) is a linkage study that
  explicitly did not identify the gene. Any future edit that adds a gene_term to
  the `genetic` block must cite primary literature establishing that gene for
  THIS entity and must reconcile the assignment with the MONDO and OMIM records.
  Regional overlap with GATAD1 (7q21.2, autosomal recessive DCM) is not
  sufficient — see the `cmh21_gatad1_regional_overlap_not_causation` discussion.
  Management scope: the treatments and diagnosis blocks are entity-scoped, not
  an import of parent-disease HCM management. Each item is there because it is a
  consequence of this entity's defining feature - that the disease allele has
  never been identified - or of a phenotype this entry curates from the kindred:
  cascade surveillance must be clinical and lifelong because no genetic test can
  discharge a relative; PGT-M and prenatal diagnosis are unavailable for the same
  reason; ICD is in scope because sudden death is documented in the kindred; and
  transplantation is in scope because affected members reached end-stage heart
  failure. What is deliberately excluded: cardiac myosin inhibitors
  (mavacamten, aficamten), which are indicated for obstructive hypertrophic
  cardiomyopathy and are inappropriate in the dilated, low-ejection-fraction
  phase this family traversed; and all sarcomeric-HCM mechanism, GWAS and
  mouse-model material, which would misrepresent the evidence for a
  sarcomere-negative, disarray-negative entity. Where an item rests on
  guideline-generic practice rather than CMH21 evidence, it says so in its own
  notes and claims no snippet - the two guideline records cached here
  (PMID:38718139, PMID:37622657) contain no quotable recommendation text, the
  AHA/ACC abstract carrying only AIM/METHODS/STRUCTURE sections and the ESC
  record carrying no abstract at all.

  GeneReviews baseline: there is no CMH21-specific GeneReviews chapter. The
  parent-disease overview (PMID:20301725, "Nonsyndromic Hypertrophic
  Cardiomyopathy Overview") is tagged in the top-level `references` block for
  completeness, but its PubMed record carries only a scope statement rather than
  quotable Clinical Characteristics text, so it contributes no phenotype
  baseline for this entity. Deep research: the falcon/Edison provider was
  unavailable in this environment (no EDISON_API_KEY/FUTUREHOUSE_API_KEY), so
  the `claude_code` provider was used instead; its report is in
  `research/Hypertrophic_Cardiomyopathy_21-deep-research-claude_code.md`. That
  report independently reached the same conclusion (locus unsolved, no gene) and
  every PMID and snippet used from it was re-fetched with `just fetch-reference`
  and verified against the cached abstract.
references:
- reference: PMID:16651466
  title: Novel locus for an inherited cardiomyopathy maps to chromosome 7.
  found_in:
  - Hypertrophic_Cardiomyopathy_21-deep-research-claude_code.md
- reference: PMID:21965549
  title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
  found_in:
  - Hypertrophic_Cardiomyopathy_21-deep-research-claude_code.md
- reference: PMID:20301725
  title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
  tags:
  - GeneReviews
  found_in:
  - Hypertrophic_Cardiomyopathy_21-deep-research-claude_code.md
- reference: PMID:38718139
  title: "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines."
  found_in:
  - Hypertrophic_Cardiomyopathy_21-deep-research-claude_code.md
- reference: PMID:37622657
  title: 2023 ESC Guidelines for the management of cardiomyopathies.
  found_in:
  - Hypertrophic_Cardiomyopathy_21-deep-research-claude_code.md

📚

References & Deep Research

References

5

PMID:16651466

Novel locus for an inherited cardiomyopathy maps to chromosome 7.

No top-level findings curated for this source.

PMID:21965549

Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.

No top-level findings curated for this source.

PMID:20301725

Nonsyndromic Hypertrophic Cardiomyopathy Overview.

No top-level findings curated for this source.

PMID:38718139

2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

No top-level findings curated for this source.

PMID:37622657

2023 ESC Guidelines for the management of cardiomyopathies.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 28 citations 2026-08-01T21:17:54.739135

1. Disease Information

Overview

Hypertrophic cardiomyopathy 21 designates a locus on chromosome 7 (7p12.1–7q21) linked to autosomal-dominant inherited cardiomyopathy in one large kindred, in which the predominant clinical feature was left ventricular hypertrophy but the phenotype also encompassed cardiac dilation, end-stage heart failure, and sudden death. The family was sarcomere-genotype-negative by direct sequencing of the then-known HCM and DCM sarcomere genes.

From the cached abstract (PMID:16651466, verbatim, verified against references_cache/PMID_16651466.md):

"To explore novel genetic causes of inherited cardiomyopathies, genome-wide linkage analysis was used to study one kindred (4 generations, 32 individuals) with predominant clinical features of left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death."

"The discovery of a novel genetic locus in this family provides more evidence that molecular pathways leading to inherited cardiac hypertrophy extend beyond the sarcomere. Identification of the causal gene mutation and additional genotype-phenotype correlation studies will provide fundamental insight into mechanisms of cardiac remodeling."

The parent-disease framing (from OMIM 614676 / MedGen 766356, which reuse the shared CMH preamble): HCM is "unexplained cardiac hypertrophy: thickening of the myocardial wall in the absence of any other identifiable cause for left ventricular hypertrophy such as systemic hypertension or valvular heart disease"; myocyte hypertrophy, disarray, and fibrosis are the histopathologic hallmarks; clinical features include arrhythmias, sudden cardiac death, and heart failure.

Key identifiers

Resource	Identifier	Notes
MONDO	MONDO:0013852	`hypertrophic cardiomyopathy 21`; `is_a` MONDO:0024573 familial hypertrophic cardiomyopathy
OMIM	614676	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 21; CMH21 (phenotype entry, gene unknown)
MedGen	766356 (CUI C3553442)	Hypertrophic cardiomyopathy 21
DOID	DOID:0110311
GARD	GARD:0024956
UMLS	C3553442
NCBI Gene	100909387 ("CMH21")	Gene type: unknown — a phenotype/locus placeholder record, cytoband 7p12.1-q21, MIM:614676. Do not treat as a protein-coding gene or assign an HGNC ID.
HGNC	none	No HGNC record — there is no gene.
Orphanet	no CMH21-specific code	Orphanet does not subdivide familial isolated HCM by numbered locus; the applicable parent is ORPHA:155 (familial isolated hypertrophic cardiomyopathy). Not currently in `references_cache/` — run `just structured-rebuild-orphanet --id 155` if you want to cite it.
ICD-10	I42.2 (other hypertrophic cardiomyopathy) / I42.1 (obstructive HCM)	Parent-level only
ICD-11	BC43.0 Hypertrophic cardiomyopathy	Parent-level only
MeSH	D024741 Cardiomyopathy, Hypertrophic, Familial; D002312 Cardiomyopathy, Hypertrophic	Parent-level only
SNOMED CT	233873004 (Hypertrophic cardiomyopathy)	Parent-level only
ClinGen	no gene-disease validity assertion possible	ClinGen curates gene–disease pairs; a gene-less locus cannot be curated. No `CGGV:` reference exists for CMH21.

Synonyms

CMH21 (EXACT), cardiomyopathy, hypertrophic, 21 (EXACT), hypertrophic cardiomyopathy type 21 (EXACT), cardiomyopathy, familial hypertrophic, 21 (RELATED), familial hypertrophic cardiomyopathy 21 (MedGen).

Data provenance type

Aggregated disease-level resources built on a single pedigree study — i.e., OMIM/MONDO/MedGen/DOID all trace to one Circulation linkage paper. There is no EHR-derived, registry-derived, or cohort-derived data specific to CMH21. No ICEES/COHD comorbidity signal can be attributed to this entity (any such signal would be for HCM generally, MONDO:0005045 / MONDO:0024573).

2. Etiology

Disease causal factors

Primary cause: an as-yet-unidentified germline variant segregating with disease within chromosome 7p12.1–7q21, transmitted as an autosomal-dominant trait in one kindred. Mode of action (LOF/GOF/dominant-negative), variant class, and the affected gene are all unknown.
Explicitly excluded causes (per PMID:16651466, verbatim):

"Direct DNA sequencing was performed on sarcomere genes known to cause HCM and dilated cardiomyopathy, and no mutations were identified."

This is a negative mechanistic finding of real curation value: it justifies an evidence item with supports: SUPPORT for the claim "CMH21 is not caused by variants in the classical sarcomere genes." - Not established: whether the causal lesion is coding, non-coding/regulatory, a structural variant, or a repeat expansion. Note that 2006-era sequencing would not have detected deep-intronic, regulatory, or copy-number lesions — a live hypothesis for why the locus remains unsolved.

Risk factors

Genetic. The only established genetic risk factor is inheritance of the linked 7p12.1–q21 haplotype in this family (2-point LOD 4.11 — above the 3.0 genome-wide significance threshold, so linkage itself is statistically robust). No population-level susceptibility variant, modifier gene, or GWAS locus has been assigned to CMH21.

For general context on non-Mendelian genetic risk in sarcomere-negative HCM — the category this family falls into — the relevant landmark data are: - PMID:33495597 (Harper AR et al., Nat Genet 2021, "Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity"): GWAS of 2,780 cases / 47,486 controls identified 12 genome-wide-significant HCM susceptibility loci; SNP heritability showed "a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h²g = 0.34 ± 0.02)". A genetic risk score halved HCM odds in the lowest quintile and doubled it in the highest. None of the 12 loci is reported to lie in 7p12.1–q21 — do not conflate. - PMID:33495596 (Tadros R et al., Nat Genet 2021): 16 HCM loci, 13 DCM loci, 23 LV-trait loci, with "strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM"; Mendelian randomization supported "a causal association linking increased LV contractility with HCM risk."

Environmental. No environmental risk factor is reported for CMH21. Generic HCM-relevant factors (all parent-disease level, not CMH21-specific): - Diastolic blood pressure is the standout modifiable factor for sarcomere-negative HCM specifically — per PMID:33495597, "a one standard deviation increase in DBP increasing the HCM risk fourfold" (Mendelian randomization). Given the index family is sarcomere-negative, this is the most defensible environmental-modifier claim to attach, with the caveat that it is a population-level finding, not a family-level one. - Age, male sex, and hypertension predict nonfamilial HCM (PMID:28408708: adjusted ORs — older age 1.04/yr; male sex 1.96; hypertension 2.80) — again parent-level, and this family is explicitly familial. - Intense competitive athletic activity is a trigger for sudden death in HCM generally, not a cause of disease.

Protective factors. None known, genetic or environmental, for CMH21. At the parent level, low-DBP genetic background and a low polygenic risk score are associated with reduced HCM odds (PMID:33495597). No protective allele has been described in the 7p12.1–q21 region.

Gene–environment interactions. Not studied for CMH21. The general HCM paradigm — that polygenic background plus blood-pressure exposure modulates penetrance and expressivity of a rare Mendelian lesion (PMID:33495597, PMID:33495596) — is a plausible but untested framing for this family; curate as hypothesis (mechanistic_hypotheses, status: EMERGING) rather than as fact if included at all.

3. Phenotypes

CMH21-specific phenotype set (from the index kindred, PMID:16651466)

The paper's abstract establishes the following as the family's clinical spectrum, in these words:

"…one kindred (4 generations, 32 individuals) with predominant clinical features of left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death."

"Of note, histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM."

OMIM Clinical Synopsis features (via MedGen 766356)

MedGen renders the OMIM clinical synopsis for CMH21 with these HPO-mapped features:

Feature	Suggested HP term	Verified label (OAK, `sqlite:obo:hp`)
Hypertrophic cardiomyopathy	HP:0001639	Hypertrophic cardiomyopathy ✅
Left ventricular hypertrophy	HP:0001712	Left ventricular hypertrophy ✅
Sudden death / sudden cardiac death	HP:0001645	Sudden cardiac death ✅
Atrial fibrillation	HP:0005110	Atrial fibrillation ✅
Mitral valve prolapse	HP:0001634	Mitral valve prolapse ✅
Myofiber disarray	HP:0031318	Myofiber disarray ✅

⚠️ Curation conflict — resolve explicitly. MedGen/OMIM lists myofiber disarray among CMH21 features, but the primary paper states disarray was absent in the two family members examined. The most likely explanation is that OMIM's synopsis inherits the generic CMH template rather than the family's actual pathology. Recommended handling: either omit HP:0031318, or curate it with supports: REFUTE / WRONG_STATEMENT against PMID:16651466 with the verbatim "did not demonstrate myocyte disarray and fibrosis" snippet — this is exactly the kind of source-conflict the dismech evidence model is designed to capture.

Additional phenotype terms defensible from the paper's own wording

Phenotype	HP term	Verified label
Dilated cardiomyopathy / cardiac dilation	HP:0001644	Dilated cardiomyopathy ✅
End-stage heart failure	HP:0001635	Congestive heart failure ✅ (use `severity: SEVERE`, `clinical_course: PROGRESSIVE`)

Parent-disease phenotypes (HCM generally — label clearly as inherited context, NOT CMH21-observed)

Phenotype	HP term	Verified label	Typical HCM frequency
Asymmetric septal hypertrophy	HP:0001670	Asymmetric septal hypertrophy ✅	Most common morphology
LV outflow tract obstruction	HP:0032092	Left ventricular outflow tract obstruction ✅	~⅓ at rest, ~⅓ provocable (PMID:28912181)
LV diastolic dysfunction	HP:0025168	Left ventricular diastolic dysfunction ✅	Near-universal
Myocardial fibrosis	HP:0001685	Myocardial fibrosis ✅	Hallmark in sarcomeric HCM
Dyspnea	HP:0002094	Dyspnea ✅	Most common symptom
Angina pectoris	HP:0001681	Angina pectoris ✅	Common
Syncope	HP:0001279	Syncope ✅	SCD risk marker
Palpitations	HP:0001962	Palpitations ✅	Common
Ventricular tachycardia (NSVT)	HP:0004756	Ventricular tachycardia ✅	SCD risk marker
Cardiac arrest	HP:0001695	Cardiac arrest ✅
Arrhythmia	HP:0011675	Arrhythmia ✅
Reduced LVEF ("burnt-out" phase)	HP:0012664	Reduced left ventricular ejection fraction ✅	~2–5% of HCM; relevant here given the family's dilation/end-stage HF
Abnormal QT interval	HP:0031547	Abnormal QT interval ✅
Inheritance	HP:0000006	Autosomal dominant inheritance ✅
Onset	HP:0003581	Adult onset ✅	Family's onset ages not extractable from abstract

Phenotype characteristics

Age of onset: Not stated in the abstract for the CMH21 family. The four-generation structure with end-stage HF and sudden death implies adult onset with substantial lifetime morbidity, but specific ages require the full text (paywalled at ahajournals.org; both AHA and OMIM return HTTP 403 to automated fetch). If you need per-individual ages, wall thickness, LV dimensions, or the pedigree table, obtain the PDF through institutional access — UNC has AHA journal access via the HSL.
Severity: Variable within the kindred, ranging (per the abstract) from LVH to end-stage heart failure and sudden death.
Progression: Progressive, with evolution from hypertrophy to dilation — a "burnt-out"/end-stage trajectory. Use clinical_course: PROGRESSIVE.
Frequency among affected individuals: Not quantified. Do not assign HPO FrequencyEnum bands to any CMH21 phenotype — there is no numerator/denominator anywhere in the source. Per docs/frequency-evidence-guidelines.md, omit frequency: rather than fabricate.
Quality-of-life impact: No CMH21-specific QoL data. HCM-generic instruments: KCCQ (Kansas City Cardiomyopathy Questionnaire, the primary PRO in EXPLORER-HCM and SEQUOIA-HCM), SF-36, EQ-5D. HCM QoL is dominated by exertional dyspnea, activity restriction, ICD-related anxiety, and sports-participation limitation.

4. Genetic / Molecular Information

Causal gene: UNKNOWN

There is no causal gene, no OMIM gene entry, no HGNC ID, no protein, no variant nomenclature, and no ClinVar record for CMH21. The genetic: block of a dismech entry for CMH21 should either be empty or contain only a locus-level statement. No gene_term binding is possible.

The locus

From PMID:16651466 (verbatim):

"Linkage was then established to a novel locus on chromosome 7 (7p12.1-7q21). A maximum 2-point logarithm of odds score of 4.11 was obtained. Recombination events refine the disease interval between D7S506 and D7S3314, corresponding to a distance of 27.2 megabases."

Parameter	Value
Cytogenetic location	7p12.1–7q21 (spans the centromere)
Flanking markers	D7S506 (proximal/p-arm boundary) — D7S3314 (q-arm boundary)
Interval size	27.2 Mb
Max 2-point LOD	4.11 (exceeds the 3.0 significance threshold)
Mapping method	Genome-wide microsatellite linkage in one 4-generation, 32-individual pedigree

Approximate physical coordinates (my derivation — flag as computational, not from the paper). D7S3314 is reported at ~79.81 Mb on chr7 (UCSC hg17); D7S506 lies on 7p12 telomeric to EGFR, in the vicinity of GRB10 (the hGrb10 gene has been mapped between D7S506 and D7S499). Subtracting the stated 27.2 Mb from D7S3314 places the proximal boundary near ~52.6 Mb. So the interval is roughly chr7:~52–80 Mb (hg17/hg38 approximate), i.e. 7p12.1 → 7q11.23/7q21.11, crossing the pericentromere. This is consistent with OMIM's "7p12.1-q21" cytoband string. Verify against the paper's Figure/Table before committing coordinates to the KB.

Positional candidate genes in the interval — offered strictly as a computational/positional annotation by this report, not as candidates named in the literature. Song et al.'s abstract names none. Notable cardiovascularly plausible genes falling in ~52–80 Mb of chr7: GRB10, EGFR, CHCHD2, GBAS, PSPH, HIP1, AUTS2, CALN1, the 7q11.23 Williams–Beuren region including ELN (elastin), LIMK1, GTF2I, BAZ1B, MLXIPL, STX1A, plus MDH2, HSPB1 (small heat-shock chaperone), YWHAG (14-3-3γ), POR, and — at/just beyond the distal boundary — CACNA2D1. Do not curate any of these as CMH21 candidates in a genetic: block. At most they belong in a discussions KNOWLEDGE_GAP rationale describing what a modern re-analysis would target.

The GATAD1 / 7q21 adjacency (why PMID:21965549 is on this branch)

From the cached abstract of PMID:21965549 (Theis JL et al., Circ Cardiovasc Genet 2011; verbatim from references_cache/PMID_21965549.md):

"Genotyping and linkage analysis mapped an AR DCM locus to chromosome arm 7q21, which was validated and refined by high-density homozygosity mapping."

"The mutation, absent in HapMap, 1000 Genomes, and 474 ethnically matched controls, altered a conserved residue of GATAD1, encoding GATA zinc finger domain-containing protein 1. Thirteen relatives were heterozygous mutation carriers with no evidence of myocardial disease, even at advanced ages."

"GATAD1 binds to a histone modification site that regulates gene expression. Consistent with murine DCM caused by genetic disruption of histone deacetylases, the data implicate an inherited basis for epigenetic dysregulation in human heart failure."

Key distinctions to preserve if this is cited at all:

	CMH21 (PMID:16651466)	GATAD1 / CMD2B (PMID:21965549)
Phenotype	LVH-predominant, with dilation/end-stage HF	Dilated cardiomyopathy
Inheritance	Autosomal dominant	Autosomal recessive (heterozygotes unaffected even at advanced ages)
Locus	7p12.1–7q21 (~52–80 Mb)	7q21 (GATAD1 at ~92.5 Mb, distal to the CMH21 interval)
Gene	Unknown	GATAD1 (OMIM:614518), p.Ser102Pro
OMIM phenotype	614676	614672 (CMD2B)

GATAD1 screening in 273 additional DCM probands found no further mutations, so it is a rare cause even of DCM. Curating GATAD1 as the CMH21 gene would be a textbook NEC error. If you cite PMID:21965549, do so only to document that a mechanistically distinct 7q21 cardiomyopathy locus exists nearby and was excluded, and use evidence_source: HUMAN_CLINICAL.

Other genetic dimensions

Variant classification / ACMG: N/A — no variant.
Allele frequency (gnomAD etc.): N/A — no variant.
Somatic vs germline: Germline (inherited through four generations).
Functional consequence: Unknown.
Modifier genes: None described for CMH21. Parent-level: polygenic score modifies expressivity in rare-variant carriers (PMID:33495596, PMID:33495597).
Epigenetics: No CMH21 data. (Note only the conceptual adjacency that the neighboring 7q21 DCM gene GATAD1 is chromatin-associated — this is not evidence about CMH21.)
Chromosomal abnormalities: None reported. No CNV, translocation, or microdeletion has been associated with CMH21. Notably, the interval contains the 7q11.23 Williams–Beuren critical region, whose recurrent deletion causes a well-characterized, mechanistically unrelated cardiovascular syndrome (supravalvular aortic stenosis) — a useful negative differential, not an etiologic link.

5. Environmental Information

Environmental factors: None reported for CMH21. No toxin, radiation, pollutant, or occupational exposure is implicated.
Lifestyle factors: None reported for CMH21. Parent-level HCM: blood pressure (see §2), competitive athletics as an SCD trigger, alcohol/dehydration/vasodilators as provocateurs of outflow obstruction in obstructive HCM.
Infectious agents: Not applicable. CMH21 is a Mendelian, non-infectious condition. Viral myocarditis is a differential diagnosis for unexplained cardiomyopathy, not an etiology here.

6. Mechanism / Pathophysiology

What is actually known about CMH21 mechanism

Essentially nothing at the molecular level. The only mechanistic claims that can be evidenced from PMID:16651466 are:

Negative claim (well-evidenced): the disease in this family is not caused by classical sarcomere-gene mutation — "Direct DNA sequencing was performed on sarcomere genes known to cause HCM and dilated cardiomyopathy, and no mutations were identified."
Negative claim (well-evidenced): the tissue-level pathology differs from sarcomeric HCM — "histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM."
Positive inference (author-stated, appropriately hedged): "molecular pathways leading to inherited cardiac hypertrophy extend beyond the sarcomere."

Recommended dismech pathophysiology graph for CMH21 — a deliberately short, honest chain:

[Unidentified 7p12.1–q21 germline variant]  (biological_scale: MOLECULAR)
↓  (mechanism unknown — hypothesis group: extra-sarcomeric hypertrophy)
[Non-sarcomeric hypertrophic signaling]      (biological_scale: CELLULAR; speculative)
↓
[Left ventricular hypertrophy without myocyte disarray]  (biological_scale: TISSUE)
↓
[Ventricular dilation and contractile failure]           (biological_scale: TISSUE)
↓
[End-stage heart failure / sudden cardiac death]         (biological_scale: ORGANISM)

Only the last three nodes are evidenced. The second node should be marked as belonging to an EMERGING/SPECULATIVE mechanistic_hypotheses group, or dropped.

Conformance opportunity

The chain "cardiomyocyte insult → remodeling → contractile dysfunction → heart failure" is exactly the existing dismech module cardiomyopathy_maladaptive_remodeling (key conformance target: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling). Declaring conforms_to at the ventricular-remodeling and contractile-dysfunction nodes is defensible and adds value without asserting unknown molecular content. Conformance to cardiac_ion_channel_repolarization is not warranted (no channelopathy evidence).

Parent-disease mechanism (import only with explicit labeling)

For general sarcomeric HCM, the canonical chain (PMID:28912181, Marian AJ & Braunwald E, Circ Res 2017) is: sarcomere variant → altered actin–myosin cross-bridge kinetics and increased myofilament Ca²⁺ sensitivity → hypercontractility with increased energetic cost per unit force → impaired relaxation and diastolic dysfunction → stress-responsive hypertrophic signaling in cardiomyocytes → myocyte hypertrophy, myofibrillar disarray, interstitial fibrosis → dynamic LVOT obstruction (in ~⅓ at rest, ~⅓ provocable), microvascular ischemia, arrhythmogenic substrate → heart failure and sudden death. The paper states "Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. MYH7 and MYBPC3 … are the 2 most common genes involved, together accounting for ≈50% of the HCM families" and that ~40% of HCM patients lack identified causal genes. Hypercontractility as the therapeutic target is confirmed by EXPLORER-HCM (PMID:32871100): "Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction."

Critically, this chain is the one the CMH21 family's histopathology contradicts. Import it only as contrast.

Sarcomere-negative HCM mechanism — the most relevant parent literature

Because CMH21 is sarcomere-negative, the most apt mechanistic context is the emerging biology of genotype-negative HCM:

PMID:38853772 (Nollet EE et al., Circ Genom Precis Med 2024, "Integrating Clinical Phenotype With Multiomics Analyses of Human Cardiac Tissue Unveils Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative Patients With Hypertrophic Cardiomyopathy"). Reported findings: HCM myectomy samples exhibited "(1) increased glucose and glycogen metabolism, (2) downregulation of fatty acid oxidation, and (3) reduced ceramide formation and lipid storage." Crucially, remodeling in genotype-negative patients correlated with depleted acylcarnitines, amino acids, nucleotide precursors and redox compounds (a mitochondrial-dysfunction signature), whereas in genotype-positive patients the same metabolites were positively associated with hypertrophy — "suggesting fundamentally different disease mechanisms between groups." Also reported: upregulated proteasomal proteins and downregulated mitochondrial translation machinery across HCM samples. This is the single best citation for "sarcomere-negative HCM is mechanistically distinct," and is directly on-point for CMH21's category, though not about this locus.
Polygenic contribution: sarcomere-negative HCM has substantial common-variant heritability (h²g = 0.34 ± 0.02; PMID:33495597).

Suggested ontology terms for mechanism nodes (all OAK-verified)

GO biological processes

GO ID	Verified label	Use
GO:0003300	cardiac muscle hypertrophy	Core hypertrophy node; `modifier: INCREASED`
GO:0055008	cardiac muscle tissue morphogenesis	Remodeling
GO:0060047	heart contraction	Contractile output
GO:0086003	cardiac muscle cell contraction	Cell-level contraction
GO:0002026	regulation of the force of heart contraction	Hypercontractility (parent-disease)
GO:0055117	regulation of cardiac muscle contraction
GO:0006942	regulation of striated muscle contraction
GO:0006936	muscle contraction
GO:0030239	myofibril assembly	Relevant to disarray (here: absent)
GO:0010659	cardiac muscle cell apoptotic process	Late remodeling / dilation
GO:0030199	collagen fibril organization	Fibrosis (here: absent in the 2 examined members)
GO:0046034	ATP metabolic process	Energetics
GO:0006006	glucose metabolic process	`modifier: INCREASED` (PMID:38853772)
GO:0019395	fatty acid oxidation	`modifier: DECREASED` (PMID:38853772)

CL cell types

CL ID	Verified label
CL:0000746	cardiac muscle cell
CL:0002131	regular ventricular cardiac myocyte
CL:0002548	fibroblast of cardiac tissue
CL:0000071	blood vessel endothelial cell
CL:0000669	pericyte

Subcellular (GO cellular component, unverified in this session — verify before use): sarcomere (GO:0030017), myofibril (GO:0030016), mitochondrion (GO:0005739), Z disc (GO:0030018).

7. Anatomical Structures Affected

Organ level. Primary: the heart, specifically the left ventricle and interventricular septum. Secondary: left atrium (dilation, AF substrate), mitral valve apparatus (prolapse per the OMIM synopsis; SAM in obstructive HCM generally), pulmonary circulation and systemic organs via heart failure. Body system: cardiovascular. No extracardiac involvement is reported — CMH21 is a nonsyndromic, cardiac-restricted entity as described.

Tissue and cell level. Myocardium (cardiac muscle tissue); cardiomyocytes are the hypertrophying cell; cardiac fibroblasts and the microvasculature are involved in general HCM but fibrosis was not observed in the two CMH21 family members examined.

Subcellular. Unknown for CMH21. In sarcomeric HCM: sarcomere/myofibril, Z-disc, mitochondria.

Localization and laterality. Left-sided/left-ventricular predominance; asymmetric septal involvement is the usual HCM pattern but the CMH21 family's specific morphology (septal vs concentric vs apical) is not stated in the abstract — obtain from the full text before curating a morphology claim.

UBERON terms (OAK-verified)

UBERON ID	Verified label
UBERON:0000948	heart
UBERON:0002084	heart left ventricle
UBERON:0002094	interventricular septum
UBERON:0002349	myocardium
UBERON:0002135	mitral valve
UBERON:0002079	left cardiac atrium

8. Temporal Development

Onset age: Not specified in the available abstract for CMH21. Four-generation segregation with adult end-stage heart failure and sudden death implies adolescent-to-adult onset. HP:0003581 (Adult onset) is the defensible default, but flag as inferred, not sourced.
Onset pattern: Insidious/chronic; disease is typically detected on family screening or after symptom onset. Sudden death may be the sentinel event.
Stages: The family's course maps onto the recognized HCM trajectory: (i) subclinical/gene-positive-phenotype-negative → (ii) hypertrophic phase with preserved EF → (iii) transition to dilation with declining EF ("burnt-out"/end-stage HCM) → (iv) advanced heart failure requiring transplant/MCS. The explicit mention of "cardiac dilation, end-stage heart failure" in the abstract makes stage (iii)–(iv) a documented, not merely theoretical, feature of this kindred — unusual, since only ~2–5% of unselected HCM reaches this phase.
Progression rate: Variable; not quantified for CMH21.
Course pattern: Chronic and progressive, punctuated by arrhythmic events (AF, sudden death).
Duration: Lifelong.
Remission: None spontaneous. Treatment can relieve symptoms and obstruction but does not reverse the genetic substrate; regression of hypertrophy is not an established outcome.
Critical periods: Adolescence/early adulthood for phenotypic conversion in at-risk relatives (drives serial screening intervals); the window before ventricular dilation is the plausible window for disease-modifying intervention.

9. Inheritance and Population

Epidemiology of CMH21 specifically

Prevalence: unknown; likely ultra-rare or private to one kindred. One family has ever been reported. Recommended dismech Prevalence record:

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Reported in a single 4-generation kindred (32 individuals genotyped);
    no additional families or population estimates published as of 2026-08.
  evidence:
  - reference: PMID:16651466
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one kindred (4 generations, 32 individuals)"
    explanation: Establishes that CMH21 rests on a single reported family.

Parent-disease epidemiology (HCM), for context only

PMID:7641357 (Maron BJ et al., Circulation 1995, CARDIA echocardiographic study of 4,111 young adults): "Probable or definite echocardiographic evidence of HCM was present in 7 subjects (0.17%)"; "Prevalence in men and women was 0.26:0.09%; in blacks and whites, 0.24:0.10%"; conclusion: "HCM was present in about 2 of 1000 young adults." → the classic 1 in 500 figure (200 per 100,000).
PMID:25814232 (Semsarian C et al., JACC 2015): argues HCM "is more common than previously estimated" once gene-positive/phenotype-negative individuals and modern imaging are accounted for — the basis of the widely quoted 1 in 200 genetic prevalence (500 per 100,000).
PMID:28408708 (Ingles J et al., Circ Cardiovasc Genet 2017): "Approximately 40% of HCM probands have a nonfamilial subtype, with later onset and less severe clinical course."

Inheritance parameters for CMH21

Parameter	Value / status
Pattern	Autosomal dominant (HP:0000006) — four-generation vertical transmission
Penetrance	Not quantified; the LOD of 4.11 is consistent with high penetrance under the assumed model, but the paper's penetrance assumption is not in the abstract. Do not state a penetrance figure.
Expressivity	Variable — the same haplotype produced LVH, dilation, end-stage HF, and sudden death within one family
Anticipation	Not reported; no repeat-expansion mechanism proposed
Germline mosaicism	Not reported
Founder effect	Not applicable/not assessed (single family)
Consanguinity	Not reported; irrelevant to a dominant model
Carrier frequency	Not applicable (dominant; no variant identified)

Population demographics

Affected populations: One kindred; ancestry not stated in the abstract. No ethnic, geographic, or founder association can be asserted.
Geographic distribution: Study conducted at Harvard Medical School / Brigham (Boston, USA); family origin not specified in the abstract.
Sex ratio: Not reported; autosomal dominant inheritance predicts ~1:1 transmission.
Age distribution: Not reported.

10. Diagnostics

There is no CMH21-specific diagnostic test. No clinical genetic test can diagnose CMH21, because there is no gene to sequence; a linkage-based diagnosis is possible only within the original informative pedigree. Everything below is HCM-generic and should be curated as such.

Clinical tests

Echocardiography (first-line): maximal LV wall thickness ≥15 mm (or ≥13 mm with family history) unexplained by loading conditions; LV cavity size; LVEF; LVOT gradient at rest and with provocation (Valsalva, exercise); systolic anterior motion of the mitral valve; diastolic indices (E/e′, LA volume index); mitral valve morphology and prolapse.
Cardiac magnetic resonance (CMR): the reference standard for wall-thickness measurement and apical/anterolateral segments; late gadolinium enhancement (LGE) quantifies replacement fibrosis and is both a diagnostic and prognostic marker. In this family CMR would be especially informative given the reported absence of fibrosis histologically.
ECG (12-lead): abnormal in most HCM; LVH voltage, repolarization abnormalities, pathologic Q waves, deep T-wave inversion. In CARDIA, "ECGs were abnormal in 5 of the 7 subjects" (PMID:7641357).
Ambulatory ECG monitoring (24–48 h Holter or extended): detects NSVT (an SCD risk factor) and atrial fibrillation — directly relevant given AF is in the CMH21 synopsis.
Exercise testing / CPET: functional capacity, provocable obstruction, blood-pressure response (abnormal BP response is a risk marker).
Laboratory / biomarkers: NT-proBNP and high-sensitivity troponin (prognostic in HCM, not diagnostic). Phenocopy exclusion labs are essential and are arguably the highest-yield workup for a sarcomere-negative, disarray-negative family like this one: α-galactosidase A activity and GLA genotyping (Fabry), serum/urine immunofixation + free light chains and bone-scintigraphy (cardiac amyloidosis), creatine kinase and LAMP2/Danon workup in young males, PRKAG2 glycogen-storage cardiomyopathy (pre-excitation + conduction disease).
Endomyocardial biopsy / explant histopathology: normally shows myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis in sarcomeric HCM (HP:0031318, HP:0001685). In this kindred, two members showed neither disarray nor fibrosis — a defining negative finding.

Genetic testing

Recommended approach (parent-disease): an HCM/cardiomyopathy multigene panel covering the eight core sarcomere genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1) plus phenocopy genes (GLA, LAMP2, PRKAG2, TTR, PTPN11 and other RASopathy genes, DES, FHL1). See GeneReviews PMID:20301725 ("Nonsyndromic Hypertrophic Cardiomyopathy Overview," updated 2025-03-06) and the 2024 AHA/ACC guideline (PMID:38718139).
Expected result in CMH21: negative. The index family was sarcomere-negative by direct sequencing.
WES/WGS: the appropriate modern strategy for this family and for the locus. WGS is specifically indicated because it can detect the lesion classes 2006 Sanger sequencing of coding exons would have missed: deep-intronic/splice-altering, promoter/enhancer, and structural variants. Combining WGS with the existing linkage interval (~27 Mb) would be a high-yield reanalysis — this is the concrete proposed_experiments content for the KNOWLEDGE_GAP discussion.
CMA / karyotype / FISH: no indication; no chromosomal abnormality reported. CMA would nonetheless be a reasonable adjunct if a structural variant in the interval is hypothesized.
mtDNA / repeat-expansion testing: not indicated (dominant nuclear transmission, no anticipation).
Cascade / linkage-based testing: within the original pedigree, haplotype segregation at D7S506–D7S3314 could in principle stratify at-risk relatives — but with a 27 Mb interval and no functional variant, this is research-grade, not clinical-grade, and should not be presented as a clinical test.

Clinical criteria

Diagnosis follows generic HCM criteria (2024 AHA/ACC, PMID:38718139; 2023 ESC cardiomyopathy guidelines, PMID:37622657): unexplained LV wall thickness ≥15 mm in an adult (≥13 mm with a positive family history or positive genotype), in the absence of abnormal loading conditions sufficient to explain it; in children, wall thickness ≥2 SD above the predicted mean (z-score >2).

Differential diagnosis (particularly important here, because absent disarray/fibrosis plus dilation should prompt reconsideration of an infiltrative or metabolic cause):

Condition	Distinguishing features
Hypertensive heart disease	Concentric, history of hypertension, regresses with BP control
Athlete's heart	≤15 mm, LV cavity enlarged, regresses with detraining
Fabry disease (GLA, X-linked)	Low native T1 on CMR, α-Gal A deficiency, extracardiac features
Cardiac amyloidosis (ATTR/AL)	Elevated native T1/ECV, diffuse LGE, positive PYP scan or monoclonal protein
Danon disease (LAMP2)	Young males, extreme LVH, pre-excitation, myopathy, intellectual disability
PRKAG2 glycogen storage cardiomyopathy	Pre-excitation, progressive conduction disease
Noonan/RASopathies	Dysmorphism, pulmonary valve stenosis, short stature
Mitochondrial cardiomyopathy	Maternal inheritance, multisystem involvement, lactate
Other numbered CMH loci (CMH1–CMH27)	Gene-defined; CMH21 is the diagnosis of exclusion here only within the mapped family

Screening

For families with unexplained inherited cardiomyopathy and no identified variant — exactly this situation — guidelines recommend serial clinical screening of first-degree relatives (ECG + echocardiography), typically every 1–2 years in adolescence and every 3–5 years in adulthood, continuing indefinitely because genetic testing cannot discharge relatives from surveillance. There is no newborn screening or population carrier screening for HCM.

11. Outcome / Prognosis

CMH21-specific

No survival data, no cohort, no natural-history study. What the primary source establishes qualitatively: the family's phenotype included end-stage heart failure and sudden death — i.e., a severe, fully-penetrant-appearing, malignant course in at least some members. That is the extent of defensible prognostic content.

Parent-disease prognosis (label as HCM-general)

PMID:30297972 (Ho CY et al., Circulation 2018, SHaRe registry; 4,591 patients, 2,763 genotyped, mean follow-up 5.4 ± 6.9 years): "Patients <40 years old at diagnosis had a 77% [95% confidence interval: 72%, 80%] cumulative incidence of the overall composite outcome by age 60"; young HCM patients had "4-fold higher mortality than the general United States population"; "Heart failure and atrial fibrillation were the most prevalent adverse events," with younger age at diagnosis and sarcomere mutations predicting worse outcomes. Note the direction: sarcomere-positive status is the adverse marker — the CMH21 family is sarcomere-negative yet clinically severe, so SHaRe's genotype stratification does not transfer.
PMID:28408708: nonfamilial (sarcomere-negative, no family history) HCM "had a less severe clinical course with greater event-free survival from major cardiac events (P=0.04) compared with sarcomere-positive HCM probands." Again, the CMH21 family is familial, so this favorable stratum does not apply.
PMID:28912181: "In the majority of patients, HCM has a relatively benign course. However, HCM is also an important cause of sudden cardiac death, particularly in adolescents and young adults." Major SCD risk factors: nonsustained VT, syncope, family history of SCD, severe hypertrophy.
SCD risk prediction: HCM Risk-SCD (O'Mahony C et al., Eur Heart J 2014, PMID:24126876) — a validated individualized 5-year SCD risk model developed in 3,675 patients over 24,313 patient-years, incorporating seven predictors (age, maximal wall thickness, left atrial diameter, LVOT gradient, family history of SCD, NSVT, unexplained syncope). The ESC guideline uses this; the AHA/ACC guideline uses a risk-marker approach that additionally weighs LGE extent, apical aneurysm, and LVEF <50%.

Morbidity, complications, function

Progressive exertional dyspnea and reduced exercise capacity; atrial fibrillation with thromboembolic stroke risk (AF in HCM warrants anticoagulation largely irrespective of CHA₂DS₂-VASc); ventricular arrhythmias and SCD; progression to end-stage HF requiring transplantation; infective endocarditis (rare, obstructive HCM); ICD-related complications (inappropriate shocks, lead failure, psychological burden). Quality of life is measured with KCCQ, SF-36, EQ-5D; HCMSQ (HCM Symptom Questionnaire) is used in myosin-inhibitor trials.

Prognostic factors and biomarkers

Age at diagnosis, maximal wall thickness, LVOT gradient, LA size, NSVT, unexplained syncope, family history of SCD, LVEF <50%, apical aneurysm, extensive LGE on CMR, elevated NT-proBNP and hs-troponin. Sarcomere-variant status is prognostic in the parent disease but uninformative for CMH21.

12. Treatment

No CMH21-specific, genotype-directed, or locus-directed therapy exists or is in development. Management follows general HCM guidelines — 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR (PMID:38718139) and 2023 ESC (PMID:37622657). Given this family's LVH-with-dilation/end-stage-HF phenotype, advanced heart-failure management and transplant evaluation are as relevant as classic HCM obstruction therapy — an important nuance if you curate treatments for this entry.

Pharmacotherapy

Treatment	NCIT `treatment_term`	`therapeutic_agent`	`therapeutic_modality`	Notes
Beta-blockade (first-line, symptomatic)	NCIT:C15986 Pharmacotherapy ✅	NCIT:C29576 Beta-Adrenergic Antagonist ✅ ; CHEBI:6904 metoprolol ✅	SMALL_MOLECULE	Reduces gradient, improves diastolic filling
Non-dihydropyridine calcium channel blockade	NCIT:C15986 ✅	NCIT:C333 Calcium Channel Blocker ✅ ; CHEBI:9948 verapamil ✅	SMALL_MOLECULE	Alternative when beta-blockers not tolerated; caution in severe obstruction/hypotension
Disopyramide (add-on for obstruction)	NCIT:C15986 ✅	CHEBI:4657 disopyramide ✅	SMALL_MOLECULE	Negative inotrope; anticholinergic effects; QT monitoring
Cardiac myosin inhibitor — mavacamten	NCIT:C15986 ✅	NCIT:C174901 Mavacamten ✅	SMALL_MOLECULE	Obstructive HCM only. EXPLORER-HCM (PMID:32871100): 251 patients, 30 weeks; 37% vs 17% met the composite primary endpoint (p=0.0005); greater reduction in post-exercise LVOT gradient. REMS/echo monitoring for systolic dysfunction.
Cardiac myosin inhibitor — aficamten	NCIT:C15986 ✅	NCIT:C179072 Aficamten ✅	SMALL_MOLECULE	SEQUOIA-HCM (PMID:38739079): 282 patients, 24 weeks; peak VO₂ +1.8 vs 0.0 mL/kg/min (difference 1.7, p<0.001); "The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo."
Antiarrhythmic for AF	NCIT:C15986 ✅	CHEBI:2663 amiodarone ✅	SMALL_MOLECULE	Rhythm control; sotalol/dofetilide alternatives
Anticoagulation for AF	NCIT:C15986 ✅	DOAC or warfarin (verify CHEBI ids before use)	SMALL_MOLECULE	HCM + AF → anticoagulate largely irrespective of CHA₂DS₂-VASc
Guideline-directed HF therapy once EF falls	NCIT:C15986 ✅	ACEi/ARB/ARNI, beta-blocker, MRA, SGLT2i (verify ids)	SMALL_MOLECULE	Applies specifically to the end-stage/dilated phase seen in this kindred; vasodilators are contraindicated while obstruction persists

⚠️ Important caveat for this entry: cardiac myosin inhibitors are approved and studied only for obstructive HCM with preserved EF; they are contraindicated/inappropriate in the dilated, low-EF phase. Since the CMH21 family's described phenotype includes dilation and end-stage HF, curating mavacamten/aficamten under this entry requires an explicit scope note.

Pharmacogenomics: No HCM- or CMH21-specific PGx. Generic relevance only: CYP2D6 metabolizer status for metoprolol; CYP2C9/VKORC1 for warfarin (CPIC guidelines). Of incidental note, the CYP3A cluster lies on 7q22.1 just distal to the linkage interval — coincidental, not mechanistic.

Advanced therapeutics

Gene therapy / gene editing: none for CMH21 (no target). At the parent level, MYBPC3 gene-replacement (e.g. TN-201) and base-editing approaches for MYH7 are in early clinical/preclinical development — not applicable to a gene-less locus.
RNA-based therapies, cell therapy, immunotherapy, targeted therapy: none applicable.

Surgical and interventional

Intervention	NCIT term (OAK-verified)	Notes
Septal myectomy (Morrow procedure)	NCIT:C51591 Myectomy ✅ (or NCIT:C15329 Surgical Procedure ✅)	Gold standard for drug-refractory obstruction at experienced centers; `therapeutic_modality: SURGERY`
Alcohol septal ablation	NCIT:C80439 Septal Ablation ✅	Catheter-based alternative for suitable anatomy; `therapeutic_modality: SURGERY` (procedure bucket)
ICD implantation (primary/secondary SCD prevention)	NCIT:C80435 Implantable Cardioverter-Defibrillator Placement ✅ ; device NCIT:C93238 Implantable Cardioverter-Defibrillator ✅	Driven by HCM Risk-SCD / AHA-ACC risk markers; highly relevant to this kindred given documented sudden death
Heart transplantation	NCIT:C15246 Heart Transplantation ✅ (parent NCIT:C15289 Organ Transplantation ✅)	For end-stage disease — explicitly relevant given "end-stage heart failure" in the family
Mechanical circulatory support (LVAD)	NCIT:C49236 Therapeutic Procedure ✅	Technically challenging in small, hypertrophied cavities; more feasible once dilated
AF catheter ablation	NCIT:C49236 ✅	Symptomatic AF

Supportive, rehabilitative, experimental

Supportive care (NCIT:C15747 ✅): symptom management, volume/BP optimization, avoidance of dehydration and vasodilators in obstructive physiology.
Genetic counseling (NCIT:C15240 ✅) — arguably the highest-value "treatment" for this entry: counseling must explain that a negative gene panel does not exclude disease in relatives, that surveillance is clinical and lifelong, and that research WGS re-analysis may be offered.
Exercise counseling: 2024 guideline liberalized recommendations; mild-to-moderate recreational exercise is encouraged, with shared decision-making for higher intensity/competitive sport.
Experimental: HCM trials of myosin inhibitors, ninerafaxstat (cardiac mitotrope), and gene therapies are all enrolling by phenotype (obstructive/nonobstructive HCM) or by specific genotype — a CMH21 patient could be eligible on phenotype only. No trial targets this locus. Search ClinicalTrials.gov by "hypertrophic cardiomyopathy," not by CMH21; there are no CMH21 NCT records.

Treatment strategy

Algorithm: (1) confirm HCM and exclude phenocopies; (2) stratify SCD risk → ICD decision; (3) if obstructive and symptomatic → beta-blocker → verapamil → add disopyramide or a myosin inhibitor → septal reduction therapy; (4) if nonobstructive and symptomatic → symptom-directed therapy, evaluate for microvascular ischemia/diastolic HF; (5) if EF falls / cavity dilates → switch to guideline-directed HF therapy, stop negative inotropes and myosin inhibitors, evaluate for transplant; (6) manage AF aggressively with anticoagulation; (7) screen and counsel the family. Step (5) is the pathway this kindred actually traversed.

13. Prevention

Primary prevention (of the disease itself): not possible — CMH21 is a germline Mendelian condition. Reproductive options for known carriers within an informative family are the only true primary prevention: genetic counseling, prenatal diagnosis, and preimplantation genetic testing (PGT-M) — but all require a known variant, which CMH21 lacks. This is a concrete, patient-facing harm of the unsolved locus and belongs in the entry's knowledge-gap rationale.
Secondary prevention (early detection): cascade clinical screening (ECG + echocardiography ± CMR) of first-degree relatives, at the intervals in §10. Because no variant exists, no relative can be released from surveillance — the family carries the full lifetime screening burden.
Tertiary prevention (complication avoidance): ICD for SCD prevention in high-risk individuals; anticoagulation for AF-related stroke prevention; blood-pressure control (biologically motivated by the DBP–sarcomere-negative-HCM Mendelian randomization result, PMID:33495597); avoidance of dehydration and vasodilators in obstructive physiology; individualized exercise prescription; heart-failure prevention through GDMT once systolic function declines.
Immunization: not applicable to etiology; routine influenza/COVID-19/pneumococcal vaccination is standard supportive care in heart failure.
Genetic screening programs: no newborn or population screening exists for HCM. Pre-participation athletic screening (ECG-inclusive in Italy and per some societies) detects HCM generally, not CMH21.
Public health / environmental interventions: not applicable.
Prophylaxis: no pharmacologic prophylaxis prevents phenotype development in at-risk relatives. (Trials of pre-clinical intervention — e.g. VANISH with valsartan in sarcomere-variant carriers — were conducted in genotyped cohorts and cannot enroll CMH21 relatives.)

14. Other Species / Natural Disease

No CMH21 ortholog can exist — the locus has no gene, so there is no ortholog to identify and no comparative-genomics analysis to perform. The 7p12.1–q21 human region is broadly syntenic with portions of mouse chromosomes 5, 6, and 11, but stating anything more specific would be speculation.

Naturally occurring HCM in other species (parent-disease context only):

Species	NCBI Taxon	Findings
Domestic cat (Felis catus)	NCBITaxon:9685	The premier spontaneous animal model of HCM. Maine Coon: MYBPC3 p.A31P — "The discovery represents the first documented spontaneous mutation causing HCM in a non-human species" (Meurs KM et al., Hum Mol Genet 2005, PMID:16236761). Ragdoll: a separate MYBPC3 mutation converting a conserved arginine to tryptophan, in a different protein domain, arising independently (Meurs KM et al., Genomics 2007, PMID:17521870). Feline HCM is the most common feline heart disease and causes congestive heart failure, aortic thromboembolism, and sudden death. VBO breed terms exist for Maine Coon and Ragdoll (verify VBO IDs with OAK before curating).
Dog (Canis lupus familiaris)	NCBITaxon:9615	HCM is rare in dogs; DCM predominates
Pig, rhesus macaque	—	Engineered/experimental HCM models only

OMIA records exist for feline HCM (Maine Coon and Ragdoll MYBPC3). Zoonotic potential / cross-species transmission: not applicable — this is a genetic, non-transmissible disease.

15. Model Organisms

There is no CMH21 model of any kind — no mouse, zebrafish, fly, iPSC line, or organoid — because there is no gene to knock out, knock in, or edit. Any DR-report claim of a "CMH21 mouse model" is fabricated; treat as an automatic discard signal.

Models of the parent disease (import only with explicit evidence_source: MODEL_ORGANISM and a scope note):

αMHC⁴⁰³/⁺ mouse (Geisterfer-Lowrance AA et al., Science 1996, PMID:8614836): the founding HCM mouse, made by introducing the "Arg 403 --> Gln mutation into the alpha cardiac myosin heavy chain (MHC) gene." Homozygotes died at ~7 days; heterozygotes survived ~1 year with "cardiac histopathology and dysfunction" resembling human disease, and importantly "Cardiac dysfunction preceded histopathologic changes, and myocyte disarray, hypertrophy, and fibrosis increased with age," with more severe disease in young males than females. Directly illustrates the disarray-and-fibrosis pathology the CMH21 family lacked.
Mybpc3-targeted mice (knockout and knock-in): model haploinsufficiency/truncation biology; the platform for MYBPC3 gene-therapy proof-of-concept.
Patient-derived hiPSC-cardiomyocytes and engineered heart tissue: the leading in-vitro system for sarcomeric HCM hypercontractility, Ca²⁺ handling, and energetics; could in principle be derived from CMH21 family members and is a sensible proposed_experiments item alongside WGS reanalysis.
Zebrafish and Drosophila cardiac models: used for candidate-gene functional triage — the natural downstream assay if a candidate emerges from the 7p12.1–q21 interval.

Model limitations relevant here: every existing HCM model is sarcomere-driven and reproduces the disarray/fibrosis phenotype that the CMH21 kindred conspicuously lacked. None models a sarcomere-negative, disarray-negative hypertrophy-to-dilation trajectory. Per dismech convention, if you curate model-organism content on this entry, pair it with a discussions entry of kind: HUMAN_MODEL_MISMATCH rather than plain KNOWLEDGE_GAP — evidence exists in models, but its fidelity to this disease is precisely the open question.

Curation Recommendations for the dismech Entry

Frame the entry honestly as a mapped-but-unsolved locus. The description should lead with "linkage locus, causal gene unidentified," not with generic HCM prose.
Do not populate genetic: with any gene. No gene_term, no HGNC ID. Put the locus in the description and, if desired, a locus-level Inheritance block bound to HP:0000006.
Curate the two negative findings as first-class evidence — sarcomere-gene-negative, and disarray/fibrosis-negative. Both have clean verbatim snippets in references_cache/PMID_16651466.md.
Handle the HP:0031318 (Myofiber disarray) conflict explicitly (§3) — this is a genuine OMIM-vs-primary-source discrepancy and a good demonstration of the supports: REFUTE machinery.
Add a discussions entry, kind: KNOWLEDGE_GAP, attaches_to the locus node, with proposed_experiments: (a) WGS of surviving affected/unaffected family members restricted to the 27 Mb linkage interval, prioritizing non-coding and structural variation invisible to 2006 Sanger sequencing; (b) RNA-seq / long-read sequencing of available myocardium or hiPSC-CMs to catch splice-altering and regulatory lesions; (c) re-contact and re-phenotyping of the kindred with CMR/LGE.
Consider conforms_to: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling — defensible, adds structure, asserts nothing unknown.
prevalence: use measure_type: CASES_IN_LITERATURE, prevalence_class: UNKNOWN (§9). Do not import HCM's 1-in-500 figure as CMH21's prevalence.
Reference hygiene: only PMID:16651466 and PMID:21965549 are currently in references_cache/ on this branch and have been read verbatim by me. Every other PMID in this report was retrieved through a summarizing web fetch and its snippets must be re-verified — run just fetch-reference PMID:<id> and then just validate-references kb/disorders/Hypertrophic_Cardiomyopathy_21.yaml before committing any quote. Candidate references to fetch: 7641357, 25814232, 28408708, 28912181, 30297972, 33495596, 33495597, 38718139, 37622657, 32871100, 38739079, 38853772, 24126876, 20301725, 8614836, 16236761, 17521870.
Full-text gap: the Circulation full text (per-individual ages, wall thicknesses, LV dimensions, pedigree figure, marker map, LOD table) is behind HTTP 403 for automated access. If you need pedigree-level detail — particularly the age-of-onset data that would let you justify HP:0003581 with evidence rather than inference — retrieve the PDF via UNC institutional access.

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OpenScientist Report

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

Overview

Key identifiers

Synonyms

Data provenance type

2. Etiology

Disease causal factors

Risk factors

3. Phenotypes

CMH21-specific phenotype set (from the index kindred, PMID:16651466)

OMIM Clinical Synopsis features (via MedGen 766356)

Additional phenotype terms defensible from the paper's own wording

Parent-disease phenotypes (HCM generally — label clearly as inherited context, NOT CMH21-observed)

Phenotype characteristics

4. Genetic / Molecular Information

Causal gene: UNKNOWN

The locus

The GATAD1 / 7q21 adjacency (why PMID:21965549 is on this branch)

Other genetic dimensions

5. Environmental Information

6. Mechanism / Pathophysiology

What is actually known about CMH21 mechanism

Conformance opportunity

Parent-disease mechanism (import only with explicit labeling)

Sarcomere-negative HCM mechanism — the most relevant parent literature

Suggested ontology terms for mechanism nodes (all OAK-verified)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

Epidemiology of CMH21 specifically

Parent-disease epidemiology (HCM), for context only

Inheritance parameters for CMH21

Population demographics

10. Diagnostics

Clinical tests

Genetic testing

Clinical criteria

Screening

11. Outcome / Prognosis

CMH21-specific

Parent-disease prognosis (label as HCM-general)

Morbidity, complications, function

Prognostic factors and biomarkers

12. Treatment

Pharmacotherapy

Advanced therapeutics

Surgical and interventional

Supportive, rehabilitative, experimental

Treatment strategy

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Curation Recommendations for the dismech Entry

Sources