Familial Hypertrophic Cardiomyopathy (Sarcomeric / CMH Series)

name: Familial Hypertrophic Cardiomyopathy
display_name: Familial Hypertrophic Cardiomyopathy (Sarcomeric / CMH Series)
creation_date: "2026-08-18T00:00:00Z"
description: >-
  Familial hypertrophic cardiomyopathy is the Mendelian form of hypertrophic
  cardiomyopathy: left ventricular hypertrophy that is not explained by
  abnormal loading conditions, arising from a heritable defect of the
  cardiomyocyte contractile apparatus, in the absence of a syndromic,
  metabolic, infiltrative, or acquired predisposing condition. Most members are
  caused by variants in genes encoding sarcomere or sarcomere-associated
  proteins, and the group is conventionally enumerated as the numbered CMH
  series (OMIM phenotypic series PS192600). Members share one clinical
  endpoint - unexplained left ventricular hypertrophy with myocyte disarray and
  interstitial fibrosis, carrying a risk of sudden cardiac death - but differ in
  which component of the contractile machinery is disturbed, in the allele class
  that does it, and in the strength of the underlying gene-disease evidence.
grouping_basis:
- SHARED_MECHANISM
- SHARED_GENE_FAMILY
grouping_rationale: >-
  Grouped as a curated union rather than curated as a third Disease entry.
  DisMech already has an umbrella entry for hypertrophic cardiomyopathy at
  MONDO:0005045 (`Hypertrophic Cardiomyopathy`, which covers the general
  mechanism and the full causal gene spectrum including phenocopies) and
  eleven separate entries for the individual familial forms. MONDO:0024573
  sits between them, and a Disease entry for it would duplicate the umbrella's
  pathograph while asserting nothing the members do not already assert. A
  Grouping is the shape that adds information here: it records *which* curated
  entries constitute the familial/sarcomeric subset, *why* the boundary falls
  where it does, and *what* distinguishes each member from its siblings.

  Members are kept as separate Disease entries because they differ in the
  perturbed component of the contractile apparatus (thin filament regulation:
  TNNT2, TNNI3, TPM1; thick filament and lever arm: MYL3; the cross-bridge
  brake: MYBPC3; the Z-disc and the titin spring: TTN, TCAP, FLNC, NEXN), in
  the operative allele class (MYBPC3 haploinsufficiency from truncating alleles
  versus missense poison-peptide mechanisms; FLNC missense causing hypertrophy
  where FLNC truncation causes arrhythmogenic/dilated disease), and in
  gene-disease validity, which for several numbered loci is limited or
  unresolved.

  Only NECESSARY criteria are asserted; the sufficient direction is
  deliberately withheld. The MONDO definition's qualifying clause - "in the
  absence of predisposing conditions" - is precisely the part that cannot be
  reduced to a machine-checkable positive condition over the KB, and MONDO's
  own asserted descendant set for MONDO:0024573 shows what happens when the
  attempt is made: because it inherits the whole OMIM CMH phenotypic series it
  also subsumes Noonan syndrome, LEOPARD syndrome, Beckwith-Wiedemann
  syndrome, very-long-chain acyl-CoA dehydrogenase deficiency and
  cardiomyopathy-hypotonia-lactic acidosis syndrome, all of which are
  syndromic or metabolic phenocopies that the definition excludes. Any
  SUFFICIENT criterion built from "manifests hypertrophic cardiomyopathy" plus
  "carries a variant in a sarcomere gene" would sweep those in, and would also
  flag the MONDO:0005045 umbrella entry - this grouping's superclass - as a
  candidate member.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0024573
      label: familial hypertrophic cardiomyopathy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO familial hypertrophic
      cardiomyopathy class as that class is defined ("hypertrophic
      cardiomyopathy caused by mutations in the genes encoding components of
      the sarcomere, in the absence of predisposing conditions"; Orphanet:155,
      OMIMPS:192600). exactMatch records the intended conceptual alignment;
      numbered CMH entities in MONDO without DisMech entries (CMH 1, 6, 10-19,
      22-24, 27, 28, 30, 31) are curation gaps rather than evidence that the
      grouping concept is only a close match.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Two divergences from MONDO's *asserted* descendant set, neither of
        which changes the concept. (1) Because MONDO:0024573 absorbs the OMIM
        CMH phenotypic series, its is_a descendants include syndromic and
        metabolic phenocopies - Noonan syndrome and the RASopathies, LEOPARD
        syndrome, Beckwith-Wiedemann syndrome, myotonic dystrophy type 1,
        very-long-chain and multiple acyl-CoA dehydrogenase deficiency,
        cardiomyopathy-hypotonia-lactic acidosis syndrome - which the class
        definition's "in the absence of predisposing conditions" clause
        excludes. This grouping follows the definition, not the asserted
        descendant set, and excludes them. (2) MONDO asserts
        MONDO:0859372 (CMH 29, KLHL24) under this class although its mechanism
        is ubiquitin-ligase/proteostatic rather than sarcomeric; it is retained
        as a member because it is a non-syndromic familial hypertrophic
        cardiomyopathy, with the mechanistic divergence recorded on the member.
        The MONDO descendant set should therefore not be treated as an
        exhaustive DisMech curation gap list for this grouping.
membership_criteria:
- description: >-
    Every member manifests hypertrophic cardiomyopathy - left ventricular
    hypertrophy that is not explained by abnormal loading conditions or by an
    acquired secondary cause - annotated either as hypertrophic cardiomyopathy
    (HP:0001639, or a descendant such as asymmetric septal hypertrophy) or as
    left ventricular hypertrophy (HP:0001712). Members must additionally be
    Mendelian (familial, most commonly autosomal dominant with variable and
    age-related penetrance); that clause is stated here in prose rather than as
    a structured leaf because, when this grouping was written, HAS_INHERITANCE
    was not machine-evaluable and an UNKNOWN leaf inside this conjunction would
    have masked the clauses that are checkable. The predicate now accepts an
    `inheritance_term` payload and is evaluated, so restoring the clause as a
    structured leaf is possible; doing so requires first checking that every
    member carries a bound inheritance block, and is left as a follow-up rather
    than done blind.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      phenotype_term:
        preferred_term: Hypertrophic cardiomyopathy
        term:
          id: HP:0001639
          label: Hypertrophic cardiomyopathy
      description: >-
        Annotated with hypertrophic cardiomyopathy or one of its descendants
        (asymmetric septal, concentric, or apical hypertrophic cardiomyopathy).
    - criterion_predicate: HAS_PHENOTYPE
      phenotype_term:
        preferred_term: Left ventricular hypertrophy
        term:
          id: HP:0001712
          label: Left ventricular hypertrophy
      description: >-
        Annotated with left ventricular hypertrophy. HP:0001712 is not a
        descendant of HP:0001639 in HPO, so it is asserted as a separate
        disjunct rather than relied on through closure.
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction."
    explanation: >-
      States the defining clinical criterion used by this block - unexplained
      left ventricular hypertrophy - and the exclusion of secondary causes.
  - reference: PMID:31006259
    reference_title: "Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertrophic cardiomyopathy (HCM) is a heritable myocardial disease with age-related penetrance."
    explanation: >-
      Supports the Mendelian/heritable clause of this criterion, and the
      age-related penetrance that makes phenotype-based ascertainment of family
      members incomplete at any single timepoint.
- description: >-
    Every member's hypertrophy is a primary, heritable disorder of the
    cardiomyocyte contractile apparatus and its maladaptive remodelling
    response, rather than a response to pressure overload or to an infiltrative
    or storage process. In the KB this is recorded either as a curated cardiac
    muscle hypertrophy process annotation (GO:0003300, or a descendant such as
    cardiac muscle hypertrophy in response to stress) or as declared
    conformance to the cardiomyopathy_maladaptive_remodeling module. Either
    form of annotation satisfies the criterion; both are accepted because the
    numbered CMH entries were curated at different times and the module
    predates only some of them.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      biological_processes:
      - preferred_term: cardiac muscle hypertrophy
        term:
          id: GO:0003300
          label: cardiac muscle hypertrophy
      description: >-
        Curates cardiac muscle hypertrophy, or a descendant such as cardiac
        muscle hypertrophy in response to stress (GO:0014898), as a
        pathophysiological process.
    - criterion_predicate: CONFORMS_TO_MODULE
      module: cardiomyopathy_maladaptive_remodeling
      description: >-
        Declares conformance to the conserved structural/contractile
        cardiomyopathy remodelling module.
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM."
    explanation: >-
      Establishes the shared mechanistic basis of the group - a primary lesion
      of the sarcomere and its associated proteins.
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."
    explanation: >-
      Names the shared tissue-level consequence that the maladaptive
      remodelling arm of this criterion refers to.
members:
- member: Hypertrophic Cardiomyopathy 1
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 1
    term:
      id: MONDO:0008647
      label: hypertrophic cardiomyopathy 1
  differentiating_mechanisms:
  - description: >-
      Beta-cardiac myosin heavy chain (MYH7), the force-generating molecular
      motor of the thick filament itself, and the founding molecular diagnosis of
      the field (the R403Q missense variant, 1990). It is, with MYBPC3, one of
      the two commonest causes of the disease, and it is the mechanistic mirror
      image of its MYBPC3 sibling: where MYBPC3 disease is predominantly
      truncating and acts by haploinsufficiency (loss of the cross-bridge brake),
      MYH7 disease is predominantly missense and acts by a gain of contractile
      function in a stably expressed mutant motor — destabilization of the
      super-relaxed state, increased intrinsic force, and raised tension cost.
      Beta-cardiac myosin is the direct molecular target of the cardiac myosin
      inhibitors (mavacamten, aficamten).
    gene:
      preferred_term: MYH7
      term:
        id: hgnc:7577
        label: MYH7
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Hypertrophic Cardiomyopathy 2
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 2
    term:
      id: MONDO:0007266
      label: hypertrophic cardiomyopathy 2
  differentiating_mechanisms:
  - description: >-
      Thin-filament troponin T (TNNT2), the tropomyosin-anchoring subunit of
      the troponin complex. Variants act on the Ca2+-dependent regulation of
      cross-bridge cycling rather than on force generation itself, and the
      resulting phenotype is the group's clearest dissociation of hypertrophy
      from risk: wall thickening is often mild while myocyte disarray and
      sudden-death risk are disproportionate, so hypertrophy-based risk
      stratification underperforms in this member.
    gene:
      preferred_term: TNNT2
      term:
        id: hgnc:11949
        label: TNNT2
- member: Hypertrophic Cardiomyopathy 3
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 3
    term:
      id: MONDO:0007267
      label: hypertrophic cardiomyopathy 3
  differentiating_mechanisms:
  - description: >-
      Alpha-tropomyosin (TPM1), the thin-filament regulatory strand itself.
      Variants perturb tropomyosin positioning over the actin myosin-binding
      sites, shifting thin-filament Ca2+ sensitivity across the whole
      regulatory unit rather than at a single troponin subunit. Distinguished
      from its thin-filament siblings by a documented digenic interaction with
      MYH7 and by a reported recessive form, so it is one of the few members
      where inheritance is not uniformly autosomal dominant.
    gene:
      preferred_term: TPM1
      term:
        id: hgnc:12010
        label: TPM1
- member: Hypertrophic Cardiomyopathy 4
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 4
    term:
      id: MONDO:0007268
      label: hypertrophic cardiomyopathy 4
  differentiating_mechanisms:
  - description: >-
      Cardiac myosin-binding protein C (MYBPC3), the brake on actomyosin
      cross-bridge cycling and the most frequently implicated gene in the
      group. Uniquely among the members, the dominant allele class is
      truncating and the operative mechanism is haploinsufficiency - transcript
      loss through nonsense-mediated decay and degradation of any residual
      truncated protein - rather than incorporation of a poison peptide into
      the sarcomere. This underlies its characteristically later onset in
      heterozygotes and its severe biallelic neonatal form, and it is why
      founder alleles recur at appreciable population frequency.
    gene:
      preferred_term: MYBPC3
      term:
        id: hgnc:7551
        label: MYBPC3
- member: Hypertrophic Cardiomyopathy 7
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 7
    term:
      id: MONDO:0013369
      label: hypertrophic cardiomyopathy 7
  differentiating_mechanisms:
  - description: >-
      Cardiac troponin I (TNNI3), the inhibitory subunit that holds the thin
      filament off at low Ca2+. Variants weaken that inhibition, so the
      characteristic functional lesion is failure of relaxation rather than
      excess systolic force; TNNI3 is accordingly the member most associated
      with restrictive physiology and diastolic dysfunction, and the same gene
      causes primary restrictive cardiomyopathy at the allele level.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
- member: Hypertrophic Cardiomyopathy 8
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 8
    term:
      id: MONDO:0012111
      label: hypertrophic cardiomyopathy 8
  differentiating_mechanisms:
  - description: >-
      Essential myosin light chain (MYL3), which stabilises the myosin lever
      arm. The lesion is in force transmission by the thick filament rather
      than in thin-filament Ca2+ regulation, and the entry carries both
      autosomal dominant missense alleles and a recessive branch (the Glu143Lys
      allele and biallelic loss of function), so like TPM1, MYBPC3 and KLHL24 it
      is one of the members whose inheritance is not purely dominant.
    gene:
      preferred_term: MYL3
      term:
        id: hgnc:7584
        label: MYL3
- member: Hypertrophic Cardiomyopathy 9
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 9
    term:
      id: MONDO:0013412
      label: hypertrophic cardiomyopathy 9
  differentiating_mechanisms:
  - description: >-
      Titin (TTN), the sarcomeric molecular spring and assembly scaffold. The
      claimed mechanism is mechanosensing and myofibril assembly rather than
      cross-bridge kinetics, which sets it apart from every other member.
      Membership caveat: TTN truncating variants are established in dilated,
      not hypertrophic, cardiomyopathy, and the TTN-HCM association rests on
      rare missense reports; this member is included as the curated CMH9
      entity, not as an assertion of definitive gene-disease validity for HCM.
    gene:
      preferred_term: TTN
      term:
        id: hgnc:12403
        label: TTN
- member: Hypertrophic Cardiomyopathy 10
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 10
    term:
      id: MONDO:0012112
      label: hypertrophic cardiomyopathy 10
  differentiating_mechanisms:
  - description: >-
      Ventricular regulatory myosin light chain (MYL2), which binds the myosin
      lever arm and tunes force and calcium sensitivity. One of the eight
      ClinGen-definitive HCM genes. Distinguished by two inheritance modes — the
      common autosomal dominant missense form (R58Q archetype) and a severe
      autosomal recessive infantile cardioskeletal form from biallelic loss of
      function — and, because MYL2 is expressed in slow-twitch skeletal muscle,
      by a possible cardioskeletal component.
    gene:
      preferred_term: MYL2
      term:
        id: hgnc:7583
        label: MYL2
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Hypertrophic Cardiomyopathy 11
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 11
    term:
      id: MONDO:0012799
      label: hypertrophic cardiomyopathy 11
  differentiating_mechanisms:
  - description: >-
      Alpha-cardiac actin (ACTC1), the thin-filament track for the myosin motor,
      and one of the eight ClinGen-definitive HCM genes. The lesion is a mutant
      actin incorporated into the thin filament that reduces actin-myosin
      interaction (stimulating the beta-myosin ATPase to only ~50% of wild type)
      rather than a myosin or Z-disc defect. As a thin-filament gene it follows
      the thin-filament clinical profile (milder hypertrophy, greater diastolic
      dysfunction, comparable arrhythmic risk) and is allelically pleiotropic
      with dilated cardiomyopathy, noncompaction, and atrial septal defect.
    gene:
      preferred_term: ACTC1
      term:
        id: hgnc:143
        label: ACTC1
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Hypertrophic Cardiomyopathy 13
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 13
    term:
      id: MONDO:0013195
      label: hypertrophic cardiomyopathy 13
  differentiating_mechanisms:
  - description: >-
      Cardiac troponin C (TNNC1), the calcium-sensing subunit of the thin-filament
      troponin complex, and a ClinGen-definitive HCM gene. It is the most direct
      myofilament calcium-sensitization lesion in the group — variants increase
      calcium sensitivity of contraction (e.g. A31S) rather than acting on
      cross-bridge force or the thick filament — and is distinguished by a
      reported fatal arrhythmogenic subtype with childhood ventricular
      fibrillation and aborted sudden death out of proportion to hypertrophy.
    gene:
      preferred_term: TNNC1
      term:
        id: hgnc:11943
        label: TNNC1
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Hypertrophic Cardiomyopathy 20
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 20
    term:
      id: MONDO:0013477
      label: hypertrophic cardiomyopathy 20
  differentiating_mechanisms:
  - description: >-
      Nexilin (NEXN), an F-actin-binding Z-disc protein - a lesion of the
      sarcomere's anchoring apparatus rather than of the contractile stroke
      itself. Membership caveat: the DisMech entry itself records limited
      gene-disease validity for HCM, NEXN being better supported as a dilated
      cardiomyopathy gene. It is retained as the curated CMH20 entity with that
      caveat preserved rather than silently dropped.
    gene:
      preferred_term: NEXN
      term:
        id: hgnc:29557
        label: NEXN
- member: Hypertrophic Cardiomyopathy 21
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 21
    term:
      id: MONDO:0013852
      label: hypertrophic cardiomyopathy 21
  differentiating_mechanisms:
  - description: >-
      The linkage-defined member: a familial HCM locus mapped to 7p12.1-q21 in
      which no causal gene has been identified. It carries no gene descriptor
      for that reason, and it is the group's representative of the substantial
      fraction of familial HCM that remains genetically unexplained - a
      reminder that the grouping's boundary is drawn on mechanism and
      inheritance, not on possession of a named sarcomere variant.
- member: Hypertrophic Cardiomyopathy 25
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 25
    term:
      id: MONDO:0011843
      label: hypertrophic cardiomyopathy 25
  differentiating_mechanisms:
  - description: >-
      Telethonin/T-cap (TCAP), which caps titin at the Z-disc. Like NEXN and
      FLNC this is a Z-disc rather than a cross-bridge lesion, but it is
      specifically the titin-anchoring and stretch-sensing node, and the
      DisMech entry curates detection of muscle stretch and T-tubule
      organisation as the perturbed processes. Gene-disease evidence for the
      HCM association is limited.
    gene:
      preferred_term: TCAP
      term:
        id: hgnc:11610
        label: TCAP
- member: Hypertrophic Cardiomyopathy 26
  member_type: DISEASE
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 26
    term:
      id: MONDO:0014883
      label: hypertrophic cardiomyopathy 26
  differentiating_mechanisms:
  - description: >-
      Filamin C (FLNC), the Z-disc actin cross-linker. Unique among the members
      in that the phenotype is allele-class-dependent in the opposite direction
      to MYBPC3: non-truncating (missense) variants act through protein
      aggregation and impaired refolding to give hypertrophic disease, whereas
      FLNC truncating variants cause arrhythmogenic and dilated cardiomyopathy.
      Membership therefore holds for the non-truncating allele class only,
      which is how the DisMech entry is scoped.
    gene:
      preferred_term: FLNC
      term:
        id: hgnc:3756
        label: FLNC
- member: KLHL24-Related Hypertrophic Cardiomyopathy
  member_type: DISEASE
  disease_term:
    preferred_term: cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies
    term:
      id: MONDO:0859372
      label: cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies
  differentiating_mechanisms:
  - description: >-
      The mechanistic outlier, and deliberately so. KLHL24 is a Cullin-3 E3
      ubiquitin-ligase substrate adaptor, so CMH29 hypertrophy arises from
      dysregulated proteostasis and intermediate-filament turnover with
      polyglucosan body accumulation, not from a lesion of the contractile
      apparatus; inheritance is autosomal recessive rather than dominant. It is
      retained because MONDO asserts CMH29 under MONDO:0024573 and it is a
      non-syndromic, familial hypertrophic cardiomyopathy, but it is the member
      that the grouping's sarcomere-centred rationale fits least well, and a
      future decision to move it out would be defensible on the class
      definition alone.
    gene:
      preferred_term: KLHL24
      term:
        id: hgnc:25947
        label: KLHL24
references:
- reference: PMID:30681346
  title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
  findings:
  - statement: >-
      The eight genes with definitive gene-disease validity for hypertrophic
      cardiomyopathy are all sarcomere genes, which is the evidential basis for
      building this grouping on a sarcomeric core; DisMech curates numbered CMH
      entries for five of them (TNNT2, TPM1, MYBPC3, TNNI3, MYL3), and the
      remaining members sit outside that definitive set.
    supporting_text: >-
      Those classified as definitive included well-known disease genes that
      have been included in diagnostic gene panels for over a decade (MYBPC3,
      MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL3, and MYL2).
  - statement: >-
      Most genes historically reported as HCM genes do not survive systematic
      gene-disease validity curation, which is why several members here carry
      an explicit limited-validity caveat rather than an unqualified causal
      claim.
    supporting_text: >-
      The majority (n=22; 66.7%) of genes had limited or no evidence of HCM
      association.
  - statement: >-
      The metabolic storage genes that mimic HCM - including PRKAG2 - are
      definitively associated with their own storage phenotypes, supporting
      their exclusion from this grouping as predisposing conditions rather than
      familial sarcomeric HCM.
    supporting_text: >-
      Four genes, all associated with metabolic storage phenotypes that can
      mimic HCM (GLA: Fabry disease, LAMP2: Danon disease, PRKAG2: PRKAG2
      cardiomyopathy, and TTR: transthyretin amyloidosis), were classified as
      definitive.
- reference: PMID:28912181
  title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
  findings:
  - statement: >-
      Storage-disease genes produce a phenotype that resembles HCM without
      being familial sarcomeric HCM - the genocopy/phenocopy distinction this
      grouping's boundary rests on.
    supporting_text: >-
      Mutations in genes responsible for storage diseases also cause a
      phenotype resembling HCM (genocopy or phenocopy).
- reference: PMID:28408708
  title: "Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications."
  findings:
  - statement: >-
      A substantial minority of HCM probands are neither familial nor
      sarcomere-variant-positive and follow a milder course, which is why
      "familial" is a real restriction on the parent MONDO:0005045 concept
      rather than a synonym for it.
    supporting_text: >-
      Approximately 40% of HCM probands have a nonfamilial subtype, with later
      onset and less severe clinical course.
notes: >-
  Scope decision. This entity was curated as a `kb/groupings/` union rather
  than as a Disease entry. DisMech already covers general hypertrophic
  cardiomyopathy at MONDO:0005045 and the individual familial forms as eleven
  separate entries; MONDO:0024573 is the class between them, and its curatable
  content is exactly the membership boundary and the per-member
  differentiators, which is what a Grouping records.

  Deliberately excluded, with reasons. (1) `Hypertrophic Cardiomyopathy`
  (MONDO:0005045) - the superclass of this grouping, not a member; a grouping
  points down at its members. (2) `PRKAG2 Cardiac Syndrome` (MONDO:0800484) -
  a glycogen-storage cardiomyopathy that mimics HCM; MONDO does not place it
  under MONDO:0024573, and a storage disease is a predisposing condition under
  the class definition. (3) `Immunodeficiency 93 and Hypertrophic
  Cardiomyopathy` (FNIP1) and `Immunodeficiency 80 with or without Congenital
  Cardiomyopathy` - syndromic, with the cardiomyopathy as one feature of a
  multisystem immunodeficiency. (4)
  `Cardiomyopathy-Hypotonia-Lactic_Acidosis_Syndrome` (MONDO:0012557) - a
  MONDO descendant of MONDO:0024573, but a mitochondrial/metabolic syndrome,
  excluded on the same "predisposing condition" clause. (5) The RASopathy
  entries (Noonan syndrome and relatives) and other syndromic MONDO
  descendants inherited from the OMIM CMH phenotypic series - excluded for the
  same reason; see the mapping consistency note. (6) Left ventricular
  noncompaction and dilated/arrhythmogenic cardiomyopathy entries that share
  causal genes with members (MYBPC3, TTN, FLNC, NEXN) - a shared gene is not
  shared membership, since the grouping is defined on the hypertrophic
  phenotype.

  How the advisory evaluator reads these criteria. Both criteria blocks are
  NECESSARY, and both are written as disjunctions so that every listed member
  resolves to SATISFIED rather than UNKNOWN on the annotations the entries
  actually carry: HP:0001639 is absent from CMH9 and CMH21 (which carry
  HP:0001712 instead, and HP:0001712 is not an HPO descendant of HP:0001639),
  and `conforms_to` edges to cardiomyopathy_maladaptive_remodeling are absent
  from CMH9 and CMH29 (which carry GO:0014898 and GO:0003300 instead). The
  Mendelian-inheritance clause is stated in prose only; that was because
  HAS_INHERITANCE evaluated to UNKNOWN and would have masked the checkable
  clauses in the conjunction, which no longer holds now that the predicate takes
  an `inheritance_term` payload - see the note on the first criteria block. The
  same reasoning is why no SUFFICIENT block is asserted.

  Curation gaps. CMH1 (MYH7), CMH10 (MYL2), CMH11 (ACTC1) and CMH13 (TNNC1) have
  now been curated and added as members, completing the ClinGen-definitive
  sarcomere-gene set in the KB (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3, MYL2,
  ACTC1) together with the definitive thin-filament TNNC1. MONDO carries further
  numbered CMH entities without DisMech entries (CMH 6, 12, 14-19, 22-24, 27, 28,
  31; CMH30 is curated as the atrial-restricted Hypertrophic Cardiomyopathy 30,
  Atrial); these are lower-value, most having limited or disputed gene-disease
  validity.