Familial Isolated Dilated Cardiomyopathy (CMD Series)

name: Familial Dilated Cardiomyopathy
display_name: Familial Isolated Dilated Cardiomyopathy (CMD Series)
creation_date: "2026-08-23T00:00:00Z"
description: >-
  Familial dilated cardiomyopathy is the Mendelian form of dilated cardiomyopathy:
  left ventricular or biventricular dilation with impaired contraction, not
  explained by abnormal loading conditions or coronary artery disease, arising from
  a heritable defect of the cardiomyocyte and occurring in isolation - that is,
  without the additional cardiac or extracardiac manifestations that would make it
  one feature of a syndrome. The group is conventionally enumerated as the numbered
  CMD series. Members share one clinical endpoint - a dilated, poorly contracting,
  fibrotic ventricle progressing to heart failure and arrhythmia - but differ
  strikingly in which part of the cardiomyocyte fails to reach it. Unlike the
  hypertrophic series, whose causal genes are overwhelmingly sarcomeric, the
  familial dilated cardiomyopathies are mechanistically heterogeneous: the causal
  lesion may be sarcomeric, Z-disc structural, nuclear-envelope,
  protein-quality-control, or post-transcriptional. That heterogeneity, converging on one
  remodelling pathway, is what this grouping records.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped as a curated union rather than as a further Disease entry. DisMech
  already has an umbrella entry for dilated cardiomyopathy at MONDO:0005021
  (`Dilated Cardiomyopathy`, covering the general mechanism plus the acquired and
  secondary causes) and separate entries for the individual familial forms.
  MONDO:0700335 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 isolated subset, *why* the boundary falls where
  it does, and *what* distinguishes each member from its siblings.

  Members are kept as separate Disease entries because the perturbed component
  differs in kind, not merely in identity. Four mechanistic classes are represented:
  a thin-filament or sarcomeric lesion (TNNC1, TNNI3, and the titin spring in TTN);
  a Z-disc structural lesion (ACTN2); a nuclear-envelope lesion (LMNA); a
  protein-quality-control lesion (BAG3); and a post-transcriptional lesion (RBM20).
  They differ further in allele class and dose (dominant missense in TNNC1 versus
  biallelic loss of function in TNNI3; positionally restricted truncation in TTN),
  and in the order in which the myocardium fails - LMNA disease characteristically
  leads with conduction disease and arrhythmia years before dilation, whereas the
  sarcomeric forms lead with contractile failure.

  Only NECESSARY criteria are asserted; the sufficient direction is deliberately
  withheld, and here the reason is concrete rather than theoretical. Both
  qualifying clauses in the class definition - "familial" and "isolated" - are
  precisely the parts that cannot be reduced to a machine-checkable positive
  condition over the KB. A SUFFICIENT criterion built from "manifests dilated
  cardiomyopathy" plus "conforms to the maladaptive remodelling module" was checked
  against the KB and would sweep in three non-members: the `Dilated Cardiomyopathy`
  umbrella entry (this grouping's own superclass), `DSP Cardiomyopathy` (an
  arrhythmogenic desmosomal cardiomyopathy that dilates but belongs to a different
  nosologic class), and `Left Ventricular Noncompaction 8` (a distinct
  morphological entity). Asserting sufficiency would therefore make the criteria
  contradict the grouping's own boundary.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0700335
      label: familial isolated dilated cardiomyopathy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO familial isolated dilated
      cardiomyopathy class as that class is defined ("a rare familial
      cardiomyopathy characterized by the dilation of left ventricle and
      progressively impairing of systolic ventricular function, in the absence of
      abnormal loading conditions or coronary artery disease... isolated when no
      additional atypical cardiac or extracardiac manifestations are present";
      Orphanet:154). MONDO:0700335 is preferred over the broader MONDO:0016333
      (familial dilated cardiomyopathy, which carries the OMIM CMD phenotypic
      series OMIMPS:115200) because the isolated qualifier is exactly the boundary
      this grouping draws. Numbered CMD entities in MONDO without DisMech entries
      are curation gaps rather than evidence that the grouping concept is only a
      close match.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        All thirteen listed members were verified to be direct MONDO children of
        MONDO:0700335, so the grouping's membership does not diverge from MONDO's
        asserted hierarchy - in contrast to the Familial Hypertrophic Cardiomyopathy
        grouping, where syndromic phenocopies inherited from an OMIM phenotypic
        series had to be excluded by hand. One nuance is worth recording rather than
        hiding: MONDO additionally places `dilated cardiomyopathy 1A`
        (MONDO:0007269, LMNA) under `syndromic disease` (MONDO:0002254), reflecting
        the laminopathy spectrum's skeletal-muscle involvement. It is retained as a
        member because the DisMech entry curates the isolated cardiac phenotype,
        with the Emery-Dreifuss/limb-girdle allelic overlap recorded on the member
        rather than treated as a syndromic exclusion.
membership_criteria:
- description: >-
    Every member manifests dilated cardiomyopathy - left ventricular or
    biventricular dilation with impaired contraction that is not explained by
    abnormal loading conditions or coronary artery disease - annotated as
    dilated cardiomyopathy (HP:0001644). Members must additionally be Mendelian
    (familial) and isolated (without the additional cardiac or extracardiac
    manifestations that would make the cardiomyopathy one feature of a syndrome);
    both clauses are stated here in prose rather than as structured leaves, because
    neither HAS_INHERITANCE nor "absence of extracardiac features" is
    machine-evaluable and an UNKNOWN leaf inside this conjunction would mask the
    clause that is checkable.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_PHENOTYPE
    phenotype_term:
      preferred_term: Dilated cardiomyopathy
      term:
        id: HP:0001644
        label: Dilated cardiomyopathy
    description: >-
      Annotated with dilated cardiomyopathy, or one of its descendants.
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      States the defining clinical criterion used by this block, including the
      exclusion of loading conditions and coronary disease. Evidence source is
      OTHER because this is a Nature Reviews Disease Primers review.
  - reference: PMID:21353195
    reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial dilated cardiomyopathy has been shown to be caused by rare variant
      mutations in more than 30 genes but only ~35% of its genetic cause has been
      identified, principally by using linkage-based or candidate gene discovery
      approaches.
    explanation: >-
      Supports the Mendelian/familial clause of this criterion and quantifies the
      genetic heterogeneity that makes the group large and incompletely resolved -
      the reason a locus-only member such as CMD1B belongs in it.
- description: >-
    Every member's dilation is a primary, heritable disorder of the cardiomyocyte
    that reaches the dilated phenotype through the conserved maladaptive
    remodelling pathway - primary cardiomyocyte insult, neurohormonal activation,
    ventricular remodelling, progressive contractile dysfunction, heart failure -
    rather than through pressure or volume overload, ischaemia, or an infiltrative
    process. In the KB this is recorded as declared conformance to the
    cardiomyopathy_maladaptive_remodeling module.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: cardiomyopathy_maladaptive_remodeling
    description: >-
      Declares conformance to the conserved structural/contractile cardiomyopathy
      remodelling module.
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mutations in several genes can cause DCM, including genes encoding structural
      components of the sarcomere and desmosome.
    explanation: >-
      Establishes the heritable structural basis shared by the group. Evidence
      source is OTHER because this is a review.
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As DCM eventually leads to impaired contractility, standard approaches to
      prevent or treat heart failure are the first-line treatment for patients with
      DCM.
    explanation: >-
      Names the shared convergence on impaired contractility and heart failure that
      the maladaptive remodelling arm of this criterion refers to.
members:
- member: Dilated Cardiomyopathy 1A
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1A
    term:
      id: MONDO:0007269
      label: dilated cardiomyopathy 1A
  differentiating_mechanisms:
  - description: >-
      Lamin A/C (LMNA), the A-type intermediate filaments of the nuclear lamina -
      the group's only nuclear-envelope lesion, and the member whose distinctiveness
      is temporal rather than structural. What sets CMD1A apart is the order in
      which the myocardium fails: sinus node dysfunction, progressive
      atrioventricular block and atrial arrhythmia typically precede ventricular
      dilation by years. Malignant ventricular arrhythmia and sudden death can occur
      with minimal or no systolic dysfunction, so defibrillator decisions here follow
      gene-specific risk models rather than ejection fraction - a property it shares
      with RBM20 (CMD1DD) and with no other member. A skeletal myopathy with
      contractures occurs in part of the spectrum, reflecting allelic overlap with
      Emery-Dreifuss and limb-girdle muscular dystrophy 1B.
    gene:
      preferred_term: LMNA
      term:
        id: hgnc:6636
        label: LMNA
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 1AA
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1AA
    term:
      id: MONDO:0012808
      label: dilated cardiomyopathy 1AA
  differentiating_mechanisms:
  - description: >-
      Alpha-actinin-2 (ACTN2), the principal cross-linker of antiparallel actin
      filaments at the Z-disc, which also anchors the titin N-terminus and scaffolds
      Z-disc partners - a lesion of the sarcomere's anchoring apparatus rather than
      of the contractile stroke or its regulation. Distinguished within the group by
      the breadth of its allelic series and by a nosological disagreement the entry
      preserves: the phenotype may occur alone or with left ventricular
      noncompaction, and ACTN2 also causes hypertrophic (CMH23), restrictive and
      left-dominant arrhythmogenic cardiomyopathy plus a skeletal myopathy. ClinGen
      lumps that whole spectrum into a single ACTN2-related entity with Definitive
      validity, while MONDO keeps the phenotype-specific nodes separate; this
      grouping follows MONDO's split.
    gene:
      preferred_term: ACTN2
      term:
        id: hgnc:164
        label: ACTN2
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 1B
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1B
    term:
      id: MONDO:0010951
      label: dilated cardiomyopathy 1B
  differentiating_mechanisms:
  - description: >-
      The linkage-defined member: an autosomal dominant familial dilated
      cardiomyopathy locus mapped in 1995 to chromosome 9q13-q22 in which no causal
      gene has been identified in the three decades since, so MONDO defines the
      entity by chromosomal region rather than by gene. It carries no gene descriptor
      for that reason, and it is the group's representative of the substantial
      fraction of familial dilated cardiomyopathy that remains genetically
      unexplained - a reminder that the grouping's boundary is drawn on phenotype,
      inheritance and mechanism, not on possession of a named causal gene. It is the
      direct counterpart of Hypertrophic Cardiomyopathy 21 in the hypertrophic
      series.
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 1D
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1D
    term:
      id: MONDO:0011095
      label: dilated cardiomyopathy 1D
  differentiating_mechanisms:
  - description: >-
      Cardiac troponin T (TNNT2), the tropomyosin-binding subunit anchoring the
      troponin complex to the thin filament. It is the member whose separation from
      its hypertrophic counterpart is experimentally measured rather than inferred:
      in one system the dilated alleles (DeltaK210, R141W) decreased the calcium
      sensitivity of force generation while the hypertrophic allele R94L increased
      it. Notably the two dilated alleles sit in different parts of the molecule -
      one inside the strong tropomyosin-binding region, one outside it - yet
      desensitize equally, so the direction of the calcium shift rather than variant
      location tracks with phenotype.
    gene:
      preferred_term: TNNT2
      term:
        id: hgnc:11949
        label: TNNT2
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 1DD
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1DD
    term:
      id: MONDO:0013168
      label: dilated cardiomyopathy 1DD
  differentiating_mechanisms:
  - description: >-
      RNA binding motif protein 20 (RBM20), a heart-enriched splicing factor - the
      group's only post-transcriptional lesion, acting one level above the sarcomere
      by mis-building its transcripts rather than by damaging its proteins. Its
      principal client is titin: RBM20 governs the N2B/N2BA isoform switch that sets
      passive myocardial stiffness, so CMD1DD and CMD1G converge on titin from
      opposite directions. Disease alleles cluster as a missense hotspot in the RS
      domain. Clinically it sits with the arrhythmogenic left ventricular
      cardiomyopathy genes: early malignant ventricular arrhythmia occurs
      disproportionate to systolic impairment, and left ventricular systolic function
      is an insensitive predictor of arrhythmic risk.
    gene:
      preferred_term: RBM20
      term:
        id: hgnc:27424
        label: RBM20
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 1E
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1E
    term:
      id: MONDO:0011003
      label: dilated cardiomyopathy 1E
  differentiating_mechanisms:
  - description: >-
      The cardiac voltage-gated sodium channel Nav1.5 (SCN5A) - the group's
      mechanistic outlier, and the only member whose causal protein is an ion
      channel with no structural, regulatory or maintenance role in the myocyte.
      The same gene's other alleles cause the primary channelopathies (Brugada
      syndrome, progressive cardiac conduction disease), so this member sits at the
      boundary between electrical and structural heart disease. The founding allele
      D1275N cosegregates with a composite phenotype of dilated cardiomyopathy,
      atrial fibrillation, impaired automaticity and conduction delay, and the route
      from channel defect to ventricular dilation remains unestablished.
    gene:
      preferred_term: SCN5A
      term:
        id: hgnc:10593
        label: SCN5A
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 1G
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1G
    term:
      id: MONDO:0011400
      label: dilated cardiomyopathy 1G
  differentiating_mechanisms:
  - description: >-
      Titin (TTN), the sarcomeric molecular ruler, elastic spring and mechanosensing
      scaffold, and by a wide margin the group's largest contributor - truncating
      variants account for roughly 25% of familial and 18% of sporadic idiopathic
      dilated cardiomyopathy. It is also the member with the most distinctive
      interpretive rule: pathogenicity is positional, concentrated in the
      inextensible A-band, and TTN truncating variants occur in the general
      population, so a truncating variant is not by itself a diagnosis. Penetrance
      accordingly splits by ascertainment - above 95% in clinically ascertained
      families over 40, substantially lower among population carriers.
    gene:
      preferred_term: TTN
      term:
        id: hgnc:12403
        label: TTN
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 1HH
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1HH
    term:
      id: MONDO:0013479
      label: dilated cardiomyopathy 1HH
  differentiating_mechanisms:
  - description: >-
      BCL2-associated athanogene 3 (BAG3), the co-chaperone that organizes
      chaperone-assisted selective autophagy (CASA) at the Z-disc - the group's
      protein-quality-control lesion, and the member whose causal protein is not
      part of the contractile apparatus at all. Working with Hsc70 and HSPB8, BAG3
      disposes of force-unfolded Z-disc components such as filamin so they can be
      replaced; a loss-of-function allele removes maintenance capacity rather than
      force-generating capacity, and impaired CASA leads to Z-disc disintegration.
      It is the dilated-series counterpart of KLHL24 (CMH29) in the hypertrophic
      series, where the causal lesion is likewise proteostatic rather than
      sarcomeric.
    gene:
      preferred_term: BAG3
      term:
        id: hgnc:939
        label: BAG3
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 1I
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1I
    term:
      id: MONDO:0011482
      label: dilated cardiomyopathy 1I
  differentiating_mechanisms:
  - description: >-
      Desmin (DES), the muscle-specific intermediate filament that links successive
      Z-discs to each other, to the sarcolemma, to mitochondria and to the nuclear
      envelope - the group's cytoskeletal-scaffold lesion, degrading lateral force
      transmission and mechanical registration rather than force generation.
      Distinguished by two allele classes acting differently (dominant missense
      disrupting filament assembly; recessive truncating abolishing desmin), by
      desmin-positive sarcoplasmic aggregates, and by being the cardiac-predominant
      pole of a spectrum whose skeletal-predominant pole this KB curates separately
      as myofibrillar myopathy.
    gene:
      preferred_term: DES
      term:
        id: hgnc:2770
        label: DES
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 1S
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1S
    term:
      id: MONDO:0013262
      label: dilated cardiomyopathy 1S
  differentiating_mechanisms:
  - description: >-
      Beta-cardiac myosin heavy chain (MYH7), the thick-filament motor - the same
      protein whose other alleles cause hypertrophic cardiomyopathy 1. This member
      exists to carry the group's cleanest allelic contrast: the dilated alleles
      (Ser532Pro, Phe764Leu) diminish contractile function and the ventricle
      dilates, where the hypertrophic alleles increase it and the ventricle
      thickens. The founding study states the principle directly - distinct
      mutations in one sarcomere protein trigger two different remodelling
      programmes - and affected individuals show neither antecedent hypertrophy nor
      hypertrophic histopathology.
    gene:
      preferred_term: MYH7
      term:
        id: hgnc:7577
        label: MYH7
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 1Z
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 1Z
    term:
      id: MONDO:0012745
      label: dilated cardiomyopathy 1Z
  differentiating_mechanisms:
  - description: >-
      Cardiac troponin C (TNNC1), the calcium sensor of the thin filament. It is the
      member where the route from lesion to dilated phenotype is least settled, and
      the entry preserves that: three competing mechanistic models are curated -
      thin-filament calcium desensitization, phosphorylation-uncoupling derived from
      explanted human myocardium, and a kinetic model of halved force-activation rate
      - rather than a single asserted chain. TNNC1 is also pleiotropic in the same
      way TNNI3 is, causing hypertrophic (CMH13) and restrictive cardiomyopathy from
      different substitutions in one small protein.
    gene:
      preferred_term: TNNC1
      term:
        id: hgnc:11943
        label: TNNC1
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 2A
  member_type: DISEASE
  disease_term:
    preferred_term: dilated cardiomyopathy 2A
    term:
      id: MONDO:0012746
      label: dilated cardiomyopathy 2A
  differentiating_mechanisms:
  - description: >-
      Cardiac troponin I (TNNI3), the inhibitory subunit of the troponin complex,
      and the group's only recessive member: CMD2A is caused by biallelic
      loss-of-function genotypes, mechanistically distinct from the far commoner
      heterozygous TNNI3 missense disease that produces hypertrophic (CMH7) and
      restrictive cardiomyopathy. Its distinguishing feature is a developmentally
      timed onset found nowhere else in the group - the fetal and neonatal heart
      expresses slow skeletal troponin I instead of cTnI, so a cTnI-null heart is
      protected until the perinatal isoform switch withdraws that substitute, and
      affected children are typically well at birth before decompensating in the
      first months of life.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
- member: Dilated Cardiomyopathy 2G
  member_type: DISEASE
  disease_term:
    preferred_term: cardiomyopathy, dilated, 2G
    term:
      id: MONDO:0030887
      label: cardiomyopathy, dilated, 2G
  differentiating_mechanisms:
  - description: >-
      Leiomodin-2 (LMOD2), which nucleates and elongates actin at the pointed end of
      the thin filament and thereby sets its length - a *geometric* lesion unique in
      the group, in which motor, calcium regulation, Z-disc scaffold and
      quality-control machinery are all intact but the filament is built to the
      wrong specification, degrading thin-thick overlap. It is also the group's most
      severe member and its second recessive one: biallelic loss means the neonatal
      heart never has functional leiomodin-2, so there is no compensated phase and
      presentation is at birth, frequently lethal.
    gene:
      preferred_term: LMOD2
      term:
        id: hgnc:6648
        label: LMOD2
    module: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
notes: >-
  Scope decision. This entity was curated as a `kb/groupings/` union rather than as
  a Disease entry, for the same reason as the Familial Hypertrophic Cardiomyopathy
  grouping: DisMech already covers general dilated cardiomyopathy at MONDO:0005021
  and the individual familial forms as separate entries, so MONDO:0700335's
  curatable content is exactly the membership boundary and the per-member
  differentiators.

  Deliberately excluded, with reasons. (1) `Dilated Cardiomyopathy` (MONDO:0005021)
  - the superclass of this grouping, not a member; a grouping points down at its
  members, and the umbrella additionally covers acquired and secondary causes.
  (2) `DSP Cardiomyopathy`, `PKP2 Cardiomyopathy`, `Naxos disease`, `Carvajal
  Syndrome` and `Arrhythmogenic Right Ventricular Cardiomyopathy` - desmosomal
  arrhythmogenic cardiomyopathies, a distinct nosologic class, even though the
  left-dominant forms dilate. (3) The left ventricular noncompaction entries -
  a distinct morphological entity. (4) Syndromic and neuromuscular entries in which
  dilated cardiomyopathy is one feature of a multisystem disease (Barth syndrome,
  Emery-Dreifuss muscular dystrophy, myofibrillar myopathy,
  Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome) - excluded on the "isolated"
  clause of the class definition. (5) Acquired dilated cardiomyopathies (Takotsubo,
  peripartum, Chagas) - not heritable.

  How the advisory evaluator reads these criteria. Both criteria blocks are
  NECESSARY and both are single leaves, and every listed member satisfies both on
  the annotations the entries actually carry: all eight carry HP:0001644 and all
  eight declare `conforms_to` edges to cardiomyopathy_maladaptive_remodeling, which
  was verified before the criteria were written rather than assumed. No SUFFICIENT
  block is asserted; the three entries such a block would wrongly capture are named
  in the grouping_rationale.

  Mechanistic spread is the substantive content here. The thirteen members span
  seven classes of cardiomyocyte lesion - sarcomeric thin-filament regulation
  (TNNC1, TNNI3, TNNT2), sarcomeric motor (MYH7), sarcomeric spring and scaffold
  (TTN), thin-filament length specification (LMOD2), Z-disc structural (ACTN2),
  cytoskeletal intermediate filament (DES), nuclear envelope (LMNA), protein
  quality control (BAG3), post-transcriptional (RBM20) and ion channel (SCN5A) -
  plus one locus-only entity (CMD1B). This is the group's principal contrast with the
  Familial Hypertrophic Cardiomyopathy grouping, whose members are overwhelmingly
  sarcomeric, and it is why `grouping_basis` records SHARED_MECHANISM and
  SHARED_PHENOTYPE but deliberately not SHARED_GENE_FAMILY.

  Curation gaps. Ten of the eleven genes with ClinGen Definitive validity for
  dilated cardiomyopathy are now represented as members: TTN, LMNA, MYH7, TNNT2,
  TNNC1, DES, SCN5A, BAG3, RBM20 and LMOD2 (ACTN2 is a member on MONDO's split of
  the ACTN2 spectrum; TNNI3 is represented by the recessive CMD2A entity).

  FLNC is the one Definitive gene curated but deliberately NOT admitted as a member.
  `FLNC-Related Dilated Cardiomyopathy` exists as a DisMech entry, named after the
  ClinGen gene-disease pair and covering the truncating allele class. It is held out
  of this grouping for two reasons. First, its phenotype is an overlapping dilated
  and left-dominant *arrhythmogenic* cardiomyopathy rather than an isolated dilated
  one, so it falls outside the "isolated" clause of the class definition. Second,
  it carries no MONDO mapping - there is no numbered CMD class for FLNC-related
  dilated cardiomyopathy, and the alternatives are each wrong in a different way
  (MONDO:0016189, qualitative or quantitative defects of filamin C, is a
  filaminopathy class spanning the myopathies; MONDO:0005021 is the general
  umbrella) - so it cannot satisfy the verified relationship this grouping's
  mapping records, in which every member is a direct MONDO child of MONDO:0700335.
  Admitting it would weaken a claim the grouping currently makes honestly. The
  non-truncating FLNC allele class is curated separately again, as
  `Hypertrophic Cardiomyopathy 26` and `Myofibrillar Myopathy`.

  Numerous further numbered CMD entities exist in MONDO with limited or disputed
  gene-disease validity; those are lower-value.