Hypertrophic Cardiomyopathy 21

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

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:

⚠️ 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

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

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."

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:

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:

1. 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."
2. 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."
3. 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

CL cell types

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)

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

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):

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

⚠️ 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

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):

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

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Consider conforms_to: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling — defensible, adds structure, asserts nothing unknown.
7. prevalence: use measure_type: CASES_IN_LITERATURE, prevalence_class: UNKNOWN (§9). Do not import HCM's 1-in-500 figure as CMH21's prevalence.
8. 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.
9. 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.

Sources

• Novel locus for an inherited cardiomyopathy maps to chromosome 7 — PubMed (PMID:16651466) · Circulation full text
• OMIM Entry #614676 — CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 21; CMH21
• MedGen: Hypertrophic cardiomyopathy 21 (C3553442, UID 766356)
• NCBI Gene: CMH21 (Gene ID 100909387)
• MalaCards: Cardiomyopathy, Familial Hypertrophic, 21
• Local sqlite:obo:mondo, :hp, :go, :cl, :uberon, :ncit, :chebi via OAK (all ontology IDs/labels in this report verified 2026-08-01)
• Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy (PMID:21965549) · OMIM *614518 GATAD1
• Europe PMC citation list for PMID:16651466
• Prevalence of hypertrophic cardiomyopathy in a general population of young adults — CARDIA (PMID:7641357)
• New perspectives on the prevalence of hypertrophic cardiomyopathy (PMID:25814232)
• Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications (PMID:28408708)
• Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy (PMID:28912181)
• Genotype and Lifetime Burden of Disease in HCM — SHaRe registry (PMID:30297972)
• Common genetic variants and modifiable risk factors underpin HCM susceptibility and expressivity (PMID:33495597)
• Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies (PMID:33495596)
• 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of HCM (PMID:38718139)
• 2023 ESC Guidelines for the management of cardiomyopathies (PMID:37622657)
• EXPLORER-HCM: Mavacamten for symptomatic obstructive HCM (PMID:32871100)
• SEQUOIA-HCM: Aficamten for Symptomatic Obstructive HCM (PMID:38739079)
• HCM Risk-SCD prediction model (PMID:24126876)
• Nonsyndromic Hypertrophic Cardiomyopathy Overview — GeneReviews (PMID:20301725)
• Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative HCM (PMID:38853772)
• A mouse model of familial hypertrophic cardiomyopathy (PMID:8614836)
• A cardiac myosin binding protein C mutation in the Maine Coon cat (PMID:16236761) · Ragdoll MYBPC3 mutation (PMID:17521870)
• Genotype-Negative Patients With Familial HCM: Traveling to the "Middle Earth" — JACC: Advances 2025
• Familial hypertrophic cardiomyopathy — MedlinePlus Genetics