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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant transmission was established by segregation in a large six-generation kindred and confirmed by linkage; the mapping was then extended to two further families with the same pattern of transmission. Penetrance and age of onset were not quantified for this kindred in the published abstract and are not curated here.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:7573045 SUPPORT Human Clinical

"a large six-generation kindred with autosomal dominant FDC was studied for linkage analysis"

States the autosomal dominant mode of inheritance in the kindred that defines this locus.

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Discussions and Knowledge Gaps

1

Which gene in the 9q13-q22 interval between D9S153 and D9S152 causes CMD1B, and is the locus still a distinct disease entity thirty years after it was mapped?

KNOWLEDGE GAP OPEN cmd1b_causal_gene_unidentified

Attached to

pathophysiology#Unidentified 9q13-q22 Disease Locus

This is the central open question of the entry and the reason its pathophysiology chain begins with a placeholder node. The linkage evidence is strong - a maximum multipoint LOD of 4.2, exclusion of more than 95% of the genome across 251 markers, replication in two additional families, and no evidence of heterogeneity - so the locus is unlikely to be a false positive, yet no gene has been confirmed in the three decades since. MONDO still defines the entity by chromosome region rather than by gene, and NCBI Gene 1218 returns no genomic coordinates. The original report named positional candidates within the interval, of which TMOD1 (tropomodulin 1, 9q22.33) is the most biologically attractive: tropomodulin caps the pointed end of the sarcomeric actin thin filament, and tropomodulin-overexpressing transgenic mice develop progressive dilated cardiomyopathy. That mouse phenotype is evidence of plausibility only; no TMOD1 variant has ever been reported in this kindred or in any other family with this locus, and the same is true of PRKACG (9q21.11). Resolution now would most plausibly come from whole-genome sequencing of surviving members of the original pedigree, which would also address the alternative possibilities that the causal variant is non-coding or structural and so invisible to the exome-based panels that dominate DCM testing, or that the kindred's disease has since been reassigned to a gene now known to cause DCM but not resident at 9q13-q22, which would retire the locus. Note that TMOD1 and PRKACG are named here as positional candidates on the strength of secondary sources plus independently verified map positions inside the interval; the cached abstract of the original report does not name them.

A curator reviewing this entry should resist the temptation to close the gap by binding TMOD1 or PRKACG as the causal gene. Neither has ever been shown to carry a variant segregating with disease in this kindred, and asserting one would convert a positional coincidence into a fabricated gene-disease claim.

Show evidence (4 references)

PMID:7573045 SUPPORT Human Clinical

"Several candidate genes for causing dilated cardiomyopathy map in this region."

The original report closes by naming the interval's candidates as unresolved, which is the state the locus has remained in since.

PMID:10595939 SUPPORT Model Organism

"Previously unexplored structural and molecular events that precede and initiate dilation can now be studied in tropomodulin-overexpressing transgenic (TOT) mice exhibiting progressive dilated cardiomyopathy."

Shows that altered tropomodulin dosage produces dilated cardiomyopathy in mice, which is why TMOD1 was an attractive positional candidate. PARTIAL and MODEL_ORGANISM because this is a transgenic overexpression model that says nothing about the 9q13-q22 locus or about any human TMOD1 variant.

PMID:37795486 SUPPORT Human Clinical

"Over half of the patients undergoing comprehensive genetic testing are left without a molecular diagnosis even when patient selection follows strict DCM criteria."

Places the unresolved status of CMD1B in context: the majority of clinically well-characterized DCM remains molecularly undiagnosed on current panels, so an unsolved dominant locus is the norm rather than an anomaly. PARTIAL because the cohort is unselected DCM, not this kindred.

+ 1 more reference

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Pathophysiology

3

Unidentified 9q13-q22 Disease Locus

The primary lesion of CMD1B is a dominantly transmitted variant somewhere in the 9q13-q22 interval between D9S153 and D9S152. Its molecular identity is unknown: no gene, transcript, protein, or variant class has been established for this locus, so this node is an explicitly unresolved placeholder rather than a mechanistic claim. It is deliberately NOT declared as conforming to the cardiomyopathy_maladaptive_remodeling module's "Primary Cardiomyocyte Insult" node, because the nature of the insult is precisely what is not known here; conformance begins downstream, where the disease enters the shared pathway with an evidenced phenotype.

Downstream

Impaired Myocardial Contractility The locus segregates with the cardiomyopathy phenotype in the kindred, so the causal chain runs from the 9q13-q22 variant to depressed myocardial contractility. Every intermediate step is unknown, since neither the gene nor the protein it encodes has been identified.

Show evidence (1 reference)

PMID:7573045 SUPPORT Human Clinical

"Linkage was found for chromosome 9q13-q22, with a maximum multipoint lod score of 4.2."

Localizes the disease-causing variant to this interval, which is the whole of what is established about the primary lesion.

Impaired Myocardial Contractility

Cardiomyocyte force generation falls, reducing systolic shortening. This is the first step of the CMD1B chain that is actually observed rather than inferred: impaired contractility is part of the diagnostic definition of the phenotype ascertained in the mapping families. It is the point at which the disease joins the conserved cardiomyopathy pathway, and the substitution this disorder makes in that pathway is a null one - the upstream driver is unidentified.

Cardiomyocyte CL:0000746

Heart Contraction GO:0060047 ↓ DECREASED

Downstream

Left Ventricular Dilation and Systolic Dysfunction Falling contractile performance is accompanied by chamber dilation, the two together constituting the dilated cardiomyopathy phenotype.

Show evidence (2 references)

PMID:7573045 SUPPORT Human Clinical

"characterized by impaired myocardial contractility and ventricular dilatation"

Impaired myocardial contractility is a defining feature of the phenotype mapped to this locus.

PMID:31073128 SUPPORT Other

"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."

Confirms progression to impaired contractility as the shared endpoint of dilated cardiomyopathy. PARTIAL and OTHER because this is a review of the disease class, not a study of the CMD1B locus.

Left Ventricular Dilation and Systolic Dysfunction

The clinical endpoint: a dilated, poorly contracting left ventricle that cannot meet circulatory demand, progressing to heart failure. In the Trieste group's registry, familial cases identified through family screening were detected younger and with higher ejection fraction than sporadic cases, indicating that the endpoint is reached progressively and can be intercepted before symptoms.

Heart Contraction GO:0060047 ⚠ ABNORMAL

Show evidence (2 references)

PMID:7573045 SUPPORT Human Clinical

"Idiopathic dilated cardiomyopathy is a heart muscle disease of unknown etiology, characterized by impaired myocardial contractility and ventricular dilatation. The disorder is an important cause of morbidity and mortality and represents the chief indication for heart transplantation."

States the structural endpoint and its clinical weight for the disease entity mapped to this locus.

PMID:20525703 SUPPORT Human Clinical

"At enrolment the NP-FDC patients were younger (40 +/- 16 vs. 48 +/- 13 years, P = 0.002), less symptomatic [New York Heart Association, (NYHA) III-IV: 8 vs. 28%, P = 0.006], had higher left ventricular ejection fraction (35 +/- 10 vs. 30 +/- 9%, P = 0.005)"

Shows that in familial DCM identified by screening the same endpoint is reached at a milder stage. PARTIAL because the cohort is familial DCM in general, not CMD1B specifically.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Cardiovascular 3

Dilated cardiomyopathy HP:0001644

Show evidence (1 reference)

PMID:7573045 SUPPORT Human Clinical

"Idiopathic dilated cardiomyopathy is a heart muscle disease of unknown etiology, characterized by impaired myocardial contractility and ventricular dilatation."

Defines the phenotype that segregates with the 9q13-q22 locus.

Left ventricular systolic dysfunction HP:0025169

Show evidence (2 references)

PMID:7573045 SUPPORT Human Clinical

"characterized by impaired myocardial contractility and ventricular dilatation"

Impaired myocardial contractility is systolic dysfunction, stated for the phenotype mapped to this locus.

PMID:20525703 SUPPORT Human Clinical

"had higher left ventricular ejection fraction (35 +/- 10 vs. 30 +/- 9%, P = 0.005)"

Quantifies the degree of systolic dysfunction in familial and sporadic DCM in the parent registry. PARTIAL because the cohort is familial DCM generally, not this locus.

Congestive heart failure HP:0001635

Show evidence (2 references)

PMID:20525703 SUPPORT Human Clinical

"less symptomatic [New York Heart Association, (NYHA) III-IV: 8 vs. 28%, P = 0.006]"

Documents symptomatic heart failure in familial and sporadic DCM patients from the Trieste group's registry. PARTIAL because it is a familial DCM cohort rather than genotyped CMD1B carriers, of whom none can be identified without a gene.

PMID:31073128 SUPPORT Other

"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."

Places heart failure as the managed clinical endpoint of dilated cardiomyopathy. PARTIAL and OTHER because this is a disease-class review.

Other 1

Left ventricular dilatation HP:4000141

Show evidence (1 reference)

PMID:7573045 SUPPORT Human Clinical

"characterized by impaired myocardial contractility and ventricular dilatation"

Establishes ventricular dilatation in the ascertained phenotype. PARTIAL because the abstract says ventricular rather than specifically left ventricular dilatation, though left ventricular involvement is what the standard diagnostic criteria measure.

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Genetic Associations

1

CMD1B locus (9q13-q22) (Linkage to 9q13-q22 between D9S153 and D9S152, maximum multipoint LOD 4.2, in a six-generation autosomal dominant FDC kindred extended to two further families with no evidence of heterogeneity.)

relationship_type: UNKNOWN

Show evidence (3 references)

PMID:7573045 SUPPORT Human Clinical

"Linkage was found for chromosome 9q13-q22, with a maximum multipoint lod score of 4.2. There was no evidence of heterogeneity. The FDC locus was placed in the interval between loci D9S153 and D9S152."

Establishes the locus, its interval boundaries, and the strength of the linkage evidence that defines CMD1B.

PMID:7573045 SUPPORT Human Clinical

"A genome-wide search was undertaken after a large series of candidate genes were excluded and was then extended to two other families with autosomal dominant pattern of transmission and identical clinical features. Coinheritance of the disease gene was excluded for > 95% of the genome, after 251..."

Documents that the locus was reached by exclusion mapping across most of the genome and replicated in two additional families, which is what makes the linkage signal credible despite the causal gene remaining unknown.

PMID:7573045 SUPPORT Human Clinical

"Several candidate genes for causing dilated cardiomyopathy map in this region."

The original report notes that positional candidates exist in the interval without naming any of them in the abstract. PARTIAL because the sentence establishes only that candidates were present, supporting no individual gene as causal.

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Medical Actions

5

Cascade Clinical Screening of First-Degree Relatives

Action: cardiovascular screening of first-degree relatives Ontology label: Disease Screening NCIT:C15419

Echocardiographic and electrocardiographic screening of relatives is the only cascade strategy available for this kindred, because no gene has been identified and therefore no predictive genetic test exists. In the Trieste registry, screening identified familial DCM patients at an earlier, less symptomatic stage with better transplant-free survival at 2, 5 and 10 years than matched sporadic cases.

Show evidence (2 references)

PMID:20525703 SUPPORT Human Clinical

"Our study demonstrates that family screening can effectively identify DCM patients at an earlier stage of disease and can improve survival."

Supports family screening as the actionable intervention in familial DCM, which for a gene-unresolved locus like CMD1B is the only available cascade strategy.

PMID:20525703 SUPPORT Human Clinical

"Survival free from heart transplant at 2, 5 and 10 years was 93, 91 and 82%, respectively, in NP-FDC patients compared with 86, 76 and 62% in sporadic forms (P = 0.04)."

Quantifies the transplant-free survival advantage of screening-detected familial disease.

Guideline-Directed Heart Failure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Because no molecular target exists for this locus, management is that of dilated cardiomyopathy with reduced ejection fraction generally: neurohormonal blockade with renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. No CMD1B-specific or genotype-directed therapy is possible or reported.

Mechanism Target:

MODULATES Left Ventricular Dilation and Systolic Dysfunction — Standard heart failure pharmacotherapy attenuates the neurohormonally driven remodeling that carries the ventricle to this endpoint. It targets the shared downstream pathway rather than the unidentified 9q13-q22 lesion, which no available agent addresses.

Show evidence (1 reference)

PMID:31073128 SUPPORT Other

"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."

Establishes that management of dilated cardiomyopathy is heart failure management directed at the downstream phenotype. PARTIAL and OTHER because this is a disease-class review, not a CMD1B trial, of which there are none.

Show evidence (1 reference)

PMID:31073128 SUPPORT Other

"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."

Establishes heart failure pharmacotherapy as first-line treatment for dilated cardiomyopathy. PARTIAL and OTHER because it is a review of the disease class; no trial has ever enrolled CMD1B carriers, who cannot be identified without a gene.

Cardiac Resynchronization Therapy and Implantable Cardioverter Defibrillator

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

Device therapy for the dilated, poorly contracting ventricle: resynchronization for conduction delay and defibrillator implantation for prevention of sudden arrhythmic death. Indication follows general dilated cardiomyopathy and arrhythmia guidelines applied to the observed phenotype. No CMD1B-specific arrhythmic risk-stratification rule exists, and none can exist while the gene is unidentified, because there is no carrier status to stratify on: at-risk relatives are distinguishable only by their echocardiographic and electrocardiographic findings.

Show evidence (1 reference)

PMID:31073128 SUPPORT Other

"Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias."

Establishes device therapy for arrhythmic protection as part of standard dilated cardiomyopathy care. PARTIAL and OTHER for the same reason as the pharmacotherapy entry: this is a review of the disease class, and no trial has enrolled CMD1B kindreds, who cannot be identified without a gene.

Heart Transplantation

Action: Organ transplantation Ontology label: Organ Transplantation NCIT:C15289

Advanced therapy for end-stage heart failure once the ventricle is no longer supportable medically, with mechanical circulatory support as a bridge. The founding report of this locus frames transplantation as the clinical weight of the disease entity rather than a rare tail event. Cascade echocardiographic screening of this kindred is measured in transplant-free survival, which makes transplantation the explicit endpoint the surveillance strategy is trying to postpone.

Show evidence (2 references)

PMID:7573045 SUPPORT Human Clinical

"The disorder is an important cause of morbidity and mortality and represents the chief indication for heart transplantation."

The founding linkage report for this locus states transplantation as the chief indication arising from the disease entity it maps.

PMID:20525703 SUPPORT Human Clinical

"Survival free from heart transplant at 2, 5 and 10 years was 93, 91 and 82%, respectively, in NP-FDC patients compared with 86, 76 and 62% in sporadic forms (P = 0.04)."

Uses transplantation as the survival endpoint in familial dilated cardiomyopathy, confirming it as a realized outcome in this population rather than a theoretical option.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling for an autosomal dominant familial cardiomyopathy in which the causal gene is unknown. The recurrence risk of 50% for offspring follows from the transmission pattern, but carrier status cannot be determined molecularly, so counseling must direct at-risk relatives to serial clinical surveillance rather than to a predictive test.

Show evidence (1 reference)

PMID:39519012 SUPPORT Other

"Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies"

Supports genetic counseling as standard in genetic DCM. PARTIAL because the genotype-specific therapy arm of that recommendation is unavailable for a locus with no identified gene.

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Diagnosis

2

Echocardiography

First-line imaging and the modality that carries the diagnostic burden for this locus. Left ventricular dimensions and ejection fraction establish the dilated, hypocontractile phenotype. Because the 9q13-q22 disease gene has never been identified, there is no confirmatory molecular test for CMD1B: the diagnosis is the echocardiographic phenotype plus the pedigree, and echocardiography is therefore also the only surveillance modality available to at-risk relatives.

echocardiography NCIT:C16525

Show evidence (2 references)

PMID:31073128 SUPPORT Other

"Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected."

Establishes echocardiography as the required modality for assessing ventricular dysfunction and remodeling in dilated cardiomyopathy. Evidence source is OTHER because this is a review of the disease class.

PMID:7573045 SUPPORT Human Clinical

"Idiopathic dilated cardiomyopathy is a heart muscle disease of unknown etiology, characterized by impaired myocardial contractility and ventricular dilatation."

Names the two features an echocardiogram measures — impaired contractility and ventricular dilatation — as the defining characteristics of the entity mapped to this locus.

Pedigree Analysis and Familial Screening

Construction of the family pedigree and clinical screening of first-degree relatives. For a gene-unresolved locus this is not adjunctive but constitutive: the autosomal dominant transmission pattern in the six-generation kindred is what distinguishes familial disease from sporadic dilated cardiomyopathy, since no predictive or confirmatory genetic test exists to do so.

familial clinical screening NCIT:C15419

The companion intervention is recorded under treatments as Cascade Clinical Screening of First-Degree Relatives; this entry records the same activity in its diagnostic role, which for CMD1B is the only route to case ascertainment.

Show evidence (2 references)

PMID:20525703 SUPPORT Human Clinical

"Familial screening of patients with dilated cardiomyopathy (DCM) allows an early diagnosis of the disease in family members."

Supports familial screening as a diagnostic strategy that achieves earlier case ascertainment in relatives.

PMID:7573045 SUPPORT Human Clinical

"a large six-generation kindred with autosomal dominant FDC was studied for linkage analysis"

Documents the pedigree structure and dominant transmission pattern on which ascertainment for this locus rests.

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Prevalence

1

Worldwide

Cases In Literature Not yet documented

No prevalence estimate exists for CMD1B. The locus rests on a single six-generation kindred plus two further families reported in one 1995 linkage study, and because no causal gene was ever identified there is no variant to ascertain in any subsequent cohort. For context on the parent category, familial disease accounted for 130 of 637 (20.4%) consecutively enrolled dilated cardiomyopathy patients in the Trieste group's registry; that series and the mapping study share investigators (Pinamonti, Gregori, Mestroni, Sinagra) and the same Heart Muscle Disease Study Group programme, though the 1995 report does not state that its kindred was drawn from this enrolment window.

Show evidence (1 reference)

PMID:20525703 SUPPORT Human Clinical

"Between 1988 and 2007, 637 DCM patients were consecutively enrolled. Of these, 130 patients (20.4%) had FDC, including 82 (12.9%) probands and 48 (7.5%) non-proband FDC patients (NP-FDC), identified by family screening."

Gives the familial fraction of dilated cardiomyopathy in the Trieste group's consecutive registry, the closest available denominator for this locus. PARTIAL because it quantifies familial DCM as a whole, not CMD1B, for which no rate is or can currently be estimated.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1B
creation_date: "2026-08-18T00:00:00Z"
synonyms:
- CMD1B
- cardiomyopathy, dilated, 1B
- dilated cardiomyopathy type 1B
- familial dilated cardiomyopathy, 9q13-q22 locus
description: >-
Dilated cardiomyopathy 1B (CMD1B) is an autosomal dominant familial dilated
cardiomyopathy (FDC) locus mapped in 1995 by Krajinovic and colleagues of the
Trieste Heart Muscle Disease Study Group to chromosome 9q13-q22, in the
interval between the microsatellite markers D9S153 and D9S152, with a maximum
multipoint LOD score of 4.2. The mapping came from a genome-wide search in a
large six-generation kindred with autosomal dominant FDC, undertaken only
after a large series of candidate genes had been excluded, and was then
extended to two further families with the same pattern of transmission and
identical clinical features; coinheritance was excluded for more than 95% of
the genome and there was no evidence of locus heterogeneity across the three
families. The defining fact about this entry, and the one that should anchor
any use of it, is that CMD1B remains a linkage locus without an identified
causal gene: in the three decades since the original report no gene at
9q13-q22 has been confirmed to cause this phenotype. MONDO itself defines the
entity by region rather than by gene ("material basis in variation in the
chromosome region 9q13"), and the corresponding NCBI Gene record (Gene ID
1218, CMD1B, map location 9q13-q22) is a placeholder that carries no genomic
coordinates at all. CMD1B is therefore curated here as a locus
entry rather than a gene-anchored one. Its clinical content is the
well-characterized FDC phenotype ascertained in the mapping kindred - impaired
myocardial contractility with ventricular dilatation - and its mechanistic
content is deliberately limited to the point at which the disease enters the
conserved cardiomyopathy final common pathway. The upstream primary insult is
recorded as an explicit knowledge gap, and the genes that sit inside the
interval and have been raised as positional candidates (TMOD1 and PRKACG) are
recorded as unconfirmed hypotheses, never as curated causal claims.
category: Genetic
classifications:
harrisons_chapter:
- classification_value: CARDIOVASCULAR
- classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
preferred_term: dilated cardiomyopathy 1B
term:
id: MONDO:0010951
label: dilated cardiomyopathy 1B
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
references:
- reference: PMID:20301486
title: "Dilated Cardiomyopathy Overview."
tags:
- GeneReviews
notes: >-
Identifier cross-references not carried by a dedicated schema slot: OMIM
600884 (CARDIOMYOPATHY, DILATED, 1B; CMD1B); NCBI Gene ID 1218 (CMD1B, map
location 9q13-q22, a record that returns no genomic coordinates, consistent
with a phenotype-only placeholder); MedGen C5700078; DOID:0110443;
GARD:0015323. Secondary sources report that OMIM carries 600884 with the "%"
prefix denoting a confirmed phenotype or locus of unknown molecular basis;
omim.org blocked automated retrieval during curation, so that specific detail
was not independently confirmed and is not relied on anywhere in this entry. The positional candidate genes
most often named for this interval are TMOD1 (tropomodulin 1, hgnc:11871) and
PRKACG (protein kinase cAMP-activated catalytic subunit gamma, hgnc:9382);
FXN (hgnc:3951) lies in the same region and is of positional interest because
Friedreich ataxia carries its own cardiomyopathy. None of the three has been
confirmed as causal here. Their map locations were verified independently
against NCBI Gene (TMOD1 9q22.33, PRKACG 9q21.11, FXN 9q21.11), all inside or
immediately adjacent to the 9q13-q22 interval; the attribution of these
specific names to the discussion in Krajinovic et al. comes from secondary
sources, since the abstract cached for PMID:7573045 says only that candidate
genes map to the region and the full text was not retrievable during
curation. They are therefore recorded as notes and as an open discussion
rather than as evidence-backed assertions.
The GeneReviews reference above is the Dilated Cardiomyopathy Overview chapter;
there is no gene-specific GeneReviews chapter for CMD1B, and the cached
abstract of the Overview is a statement of scope rather than a Clinical
Characteristics section, so it supplies no phenotype baseline to cross-check
against.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
No prevalence estimate exists for CMD1B. The locus rests on a single
six-generation kindred plus two further families reported in one 1995
linkage study, and because no causal gene was ever identified there is no
variant to ascertain in any subsequent cohort. For context on the parent
category, familial disease accounted for 130 of 637 (20.4%) consecutively
enrolled dilated cardiomyopathy patients in the Trieste group's registry;
that series and the mapping study share investigators (Pinamonti, Gregori,
Mestroni, Sinagra) and the same Heart Muscle Disease Study Group programme,
though the 1995 report does not state that its kindred was drawn from this
enrolment window.
evidence:
- reference: PMID:20525703
reference_title: Prognostic impact of familial screening in dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Between 1988 and 2007, 637 DCM patients were consecutively enrolled. Of
these, 130 patients (20.4%) had FDC, including 82 (12.9%) probands and 48
(7.5%) non-proband FDC patients (NP-FDC), identified by family screening.
explanation: >-
Gives the familial fraction of dilated cardiomyopathy in the Trieste
group's consecutive registry, the closest available denominator for this
locus. PARTIAL because it quantifies familial DCM as a whole, not CMD1B,
for which no rate is or can currently be estimated.
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Autosomal dominant transmission was established by segregation in a large
six-generation kindred and confirmed by linkage; the mapping was then
extended to two further families with the same pattern of transmission.
Penetrance and age of onset were not quantified for this kindred in the
published abstract and are not curated here.
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a large six-generation kindred with autosomal dominant FDC was studied for
linkage analysis
explanation: >-
States the autosomal dominant mode of inheritance in the kindred that
defines this locus.
genetic:
- name: CMD1B locus (9q13-q22)
relationship_type: UNKNOWN
presence: Linkage-defined locus; no causal gene identified
association: >-
Linkage to 9q13-q22 between D9S153 and D9S152, maximum multipoint LOD 4.2,
in a six-generation autosomal dominant FDC kindred extended to two further
families with no evidence of heterogeneity.
notes: >-
Deliberately carries no gene_term. No gene in this interval has been
confirmed causal, so binding an HGNC identifier here would assert a
gene-disease relationship the literature does not support. TMOD1 and PRKACG
are positional candidates only and are recorded in the entry notes and in
the open KNOWLEDGE_GAP discussion.
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Linkage was found for chromosome 9q13-q22, with a maximum multipoint lod
score of 4.2. There was no evidence of heterogeneity. The FDC locus was
placed in the interval between loci D9S153 and D9S152.
explanation: >-
Establishes the locus, its interval boundaries, and the strength of the
linkage evidence that defines CMD1B.
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A genome-wide search was undertaken after a large series of candidate
genes were excluded and was then extended to two other families with
autosomal dominant pattern of transmission and identical clinical
features. Coinheritance of the disease gene was excluded for > 95% of the
genome, after 251 polymorphic markers were analyzed.
explanation: >-
Documents that the locus was reached by exclusion mapping across most of
the genome and replicated in two additional families, which is what makes
the linkage signal credible despite the causal gene remaining unknown.
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Several candidate genes for causing dilated cardiomyopathy map in this
region.
explanation: >-
The original report notes that positional candidates exist in the
interval without naming any of them in the abstract. PARTIAL because the
sentence establishes only that candidates were present, supporting no
individual gene as causal.
pathophysiology:
- name: Unidentified 9q13-q22 Disease Locus
biological_scale: MOLECULAR
role: trigger
description: >-
The primary lesion of CMD1B is a dominantly transmitted variant somewhere in
the 9q13-q22 interval between D9S153 and D9S152. Its molecular identity is
unknown: no gene, transcript, protein, or variant class has been established
for this locus, so this node is an explicitly unresolved placeholder rather
than a mechanistic claim. It is deliberately NOT declared as conforming to
the cardiomyopathy_maladaptive_remodeling module's "Primary Cardiomyocyte
Insult" node, because the nature of the insult is precisely what is not
known here; conformance begins downstream, where the disease enters the
shared pathway with an evidenced phenotype.
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Linkage was found for chromosome 9q13-q22, with a maximum multipoint lod
score of 4.2.
explanation: >-
Localizes the disease-causing variant to this interval, which is the whole
of what is established about the primary lesion.
downstream:
- target: Impaired Myocardial Contractility
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The locus segregates with the cardiomyopathy phenotype in the kindred, so
the causal chain runs from the 9q13-q22 variant to depressed myocardial
contractility. Every intermediate step is unknown, since neither the gene
nor the protein it encodes has been identified.
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Idiopathic dilated cardiomyopathy is a heart muscle disease of unknown
etiology, characterized by impaired myocardial contractility and
ventricular dilatation.
explanation: >-
Defines the phenotype that co-segregates with the 9q13-q22 haplotype.
PARTIAL because linkage establishes co-segregation, not the mechanistic
route from locus to contractile failure, which remains entirely unknown.
- name: Impaired Myocardial Contractility
biological_scale: CELLULAR
role: effector
conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
description: >-
Cardiomyocyte force generation falls, reducing systolic shortening. This is
the first step of the CMD1B chain that is actually observed rather than
inferred: impaired contractility is part of the diagnostic definition of the
phenotype ascertained in the mapping families. It is the point at which the
disease joins the conserved cardiomyopathy pathway, and the substitution
this disorder makes in that pathway is a null one - the upstream driver is
unidentified.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: Heart Contraction
term:
id: GO:0060047
label: heart contraction
modifier: DECREASED
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by impaired myocardial contractility and ventricular
dilatation
explanation: >-
Impaired myocardial contractility is a defining feature of the phenotype
mapped to this locus.
- 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: >-
Confirms progression to impaired contractility as the shared endpoint of
dilated cardiomyopathy. PARTIAL and OTHER because this is a review of the
disease class, not a study of the CMD1B locus.
downstream:
- target: Left Ventricular Dilation and Systolic Dysfunction
causal_link_type: DIRECT
description: >-
Falling contractile performance is accompanied by chamber dilation, the
two together constituting the dilated cardiomyopathy phenotype.
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by impaired myocardial contractility and ventricular
dilatation
explanation: >-
Pairs impaired contractility with ventricular dilatation as the
co-occurring features of the mapped phenotype.
- name: Left Ventricular Dilation and Systolic Dysfunction
biological_scale: ORGANISM
role: consequence
conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
description: >-
The clinical endpoint: a dilated, poorly contracting left ventricle that
cannot meet circulatory demand, progressing to heart failure. In the
Trieste group's registry, familial cases identified
through family screening were detected younger and with higher ejection
fraction than sporadic cases, indicating that the endpoint is reached
progressively and can be intercepted before symptoms.
biological_processes:
- preferred_term: Heart Contraction
term:
id: GO:0060047
label: heart contraction
modifier: ABNORMAL
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Idiopathic dilated cardiomyopathy is a heart muscle disease of unknown
etiology, characterized by impaired myocardial contractility and
ventricular dilatation. The disorder is an important cause of morbidity
and mortality and represents the chief indication for heart
transplantation.
explanation: >-
States the structural endpoint and its clinical weight for the disease
entity mapped to this locus.
- reference: PMID:20525703
reference_title: Prognostic impact of familial screening in dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At enrolment the NP-FDC patients were younger (40 +/- 16 vs. 48 +/- 13
years, P = 0.002), less symptomatic [New York Heart Association, (NYHA)
III-IV: 8 vs. 28%, P = 0.006], had higher left ventricular ejection
fraction (35 +/- 10 vs. 30 +/- 9%, P = 0.005)
explanation: >-
Shows that in familial DCM identified by screening the same endpoint is
reached at a milder stage. PARTIAL because the cohort is familial DCM in
general, not CMD1B specifically.
phenotypes:
- name: Dilated cardiomyopathy
category: Cardiovascular
description: >-
The defining phenotype of the mapping kindred: a heart muscle disease with
impaired myocardial contractility and ventricular dilatation, ascertained by
the standardized echocardiographic criteria the Heart Muscle Disease Study
Group applied to select the families for linkage.
phenotype_term:
preferred_term: Dilated cardiomyopathy
term:
id: HP:0001644
label: Dilated cardiomyopathy
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Idiopathic dilated cardiomyopathy is a heart muscle disease of unknown
etiology, characterized by impaired myocardial contractility and
ventricular dilatation.
explanation: >-
Defines the phenotype that segregates with the 9q13-q22 locus.
- name: Left ventricular dilatation
category: Cardiovascular
description: >-
Ventricular dilatation is one of the two components of the phenotype
definition used to ascertain the families in which this locus was mapped.
phenotype_term:
preferred_term: Left ventricular dilatation
term:
id: HP:4000141
label: Left ventricular dilatation
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by impaired myocardial contractility and ventricular
dilatation
explanation: >-
Establishes ventricular dilatation in the ascertained phenotype. PARTIAL
because the abstract says ventricular rather than specifically left
ventricular dilatation, though left ventricular involvement is what the
standard diagnostic criteria measure.
- name: Left ventricular systolic dysfunction
category: Cardiovascular
description: >-
Reduced systolic performance is the functional correlate of the impaired
contractility that defines the phenotype. Ejection fractions in familial DCM
patients from the same registry averaged 35% at enrolment when detected by
family screening and 30% in matched sporadic cases.
phenotype_term:
preferred_term: Left ventricular systolic dysfunction
term:
id: HP:0025169
label: Left ventricular systolic dysfunction
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by impaired myocardial contractility and ventricular
dilatation
explanation: >-
Impaired myocardial contractility is systolic dysfunction, stated for the
phenotype mapped to this locus.
- reference: PMID:20525703
reference_title: Prognostic impact of familial screening in dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
had higher left ventricular ejection fraction (35 +/- 10 vs. 30 +/- 9%, P
= 0.005)
explanation: >-
Quantifies the degree of systolic dysfunction in familial and sporadic DCM
in the parent registry. PARTIAL because the cohort is familial DCM
generally, not this locus.
- name: Congestive heart failure
category: Cardiovascular
description: >-
Heart failure is the clinical consequence of the dilated, poorly contracting
ventricle. In the Trieste group's registry, 8% of screening-detected
familial DCM patients and 28% of matched sporadic patients were in NYHA class
III-IV at enrolment.
phenotype_term:
preferred_term: Congestive heart failure
term:
id: HP:0001635
label: Congestive heart failure
evidence:
- reference: PMID:20525703
reference_title: Prognostic impact of familial screening in dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
less symptomatic [New York Heart Association, (NYHA) III-IV: 8 vs. 28%, P
= 0.006]
explanation: >-
Documents symptomatic heart failure in familial and sporadic DCM
patients from the Trieste group's registry. PARTIAL because it is a
familial DCM cohort rather than genotyped CMD1B carriers, of whom none can
be identified without a gene.
- 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: >-
Places heart failure as the managed clinical endpoint of dilated
cardiomyopathy. PARTIAL and OTHER because this is a disease-class review.
diagnosis:
- name: Echocardiography
description: >-
First-line imaging and the modality that carries the diagnostic burden for this
locus. Left ventricular dimensions and ejection fraction establish the dilated,
hypocontractile phenotype. Because the 9q13-q22 disease gene has never been
identified, there is no confirmatory molecular test for CMD1B: the diagnosis is
the echocardiographic phenotype plus the pedigree, and echocardiography is
therefore also the only surveillance modality available to at-risk relatives.
diagnosis_term:
preferred_term: echocardiography
term:
id: NCIT:C16525
label: Echocardiography Test
evidence:
- reference: PMID:31073128
reference_title: Dilated cardiomyopathy.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Echocardiography and other imaging techniques are required to assess
ventricular dysfunction and adverse myocardial remodelling, and
immunological and histological analyses of an endomyocardial biopsy sample
are indicated when inflammation or infection is suspected.
explanation: >-
Establishes echocardiography as the required modality for assessing
ventricular dysfunction and remodeling in dilated cardiomyopathy. Evidence
source is OTHER because this is a review of the disease class.
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Idiopathic dilated cardiomyopathy is a heart muscle disease of unknown
etiology, characterized by impaired myocardial contractility and
ventricular dilatation.
explanation: >-
Names the two features an echocardiogram measures — impaired contractility
and ventricular dilatation — as the defining characteristics of the entity
mapped to this locus.
- name: Pedigree Analysis and Familial Screening
description: >-
Construction of the family pedigree and clinical screening of first-degree
relatives. For a gene-unresolved locus this is not adjunctive but constitutive:
the autosomal dominant transmission pattern in the six-generation kindred is
what distinguishes familial disease from sporadic dilated cardiomyopathy, since
no predictive or confirmatory genetic test exists to do so.
diagnosis_term:
preferred_term: familial clinical screening
term:
id: NCIT:C15419
label: Disease Screening
notes: >-
The companion intervention is recorded under treatments as Cascade Clinical
Screening of First-Degree Relatives; this entry records the same activity in
its diagnostic role, which for CMD1B is the only route to case ascertainment.
evidence:
- reference: PMID:20525703
reference_title: Prognostic impact of familial screening in dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Familial screening of patients with dilated cardiomyopathy (DCM) allows an
early diagnosis of the disease in family members.
explanation: >-
Supports familial screening as a diagnostic strategy that achieves earlier
case ascertainment in relatives.
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a large six-generation kindred with autosomal dominant FDC was studied for
linkage analysis
explanation: >-
Documents the pedigree structure and dominant transmission pattern on which
ascertainment for this locus rests.
treatments:
- name: Cascade Clinical Screening of First-Degree Relatives
description: >-
Echocardiographic and electrocardiographic screening of relatives is the
only cascade strategy available for this kindred, because no gene has been
identified and therefore no predictive genetic test exists. In the Trieste
registry, screening identified familial DCM patients at an earlier, less
symptomatic stage with better transplant-free survival at 2, 5 and 10 years
than matched sporadic cases.
treatment_term:
preferred_term: cardiovascular screening of first-degree relatives
term:
id: NCIT:C15419
label: Disease Screening
evidence:
- reference: PMID:20525703
reference_title: Prognostic impact of familial screening in dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our study demonstrates that family screening can effectively identify DCM
patients at an earlier stage of disease and can improve survival.
explanation: >-
Supports family screening as the actionable intervention in familial DCM,
which for a gene-unresolved locus like CMD1B is the only available cascade
strategy.
- reference: PMID:20525703
reference_title: Prognostic impact of familial screening in dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Survival free from heart transplant at 2, 5 and 10 years was 93, 91 and
82%, respectively, in NP-FDC patients compared with 86, 76 and 62% in
sporadic forms (P = 0.04).
explanation: >-
Quantifies the transplant-free survival advantage of screening-detected
familial disease.
- name: Guideline-Directed Heart Failure Pharmacotherapy
description: >-
Because no molecular target exists for this locus, management is that of
dilated cardiomyopathy with reduced ejection fraction generally:
neurohormonal blockade with renin-angiotensin system inhibitors,
beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors.
No CMD1B-specific or genotype-directed therapy is possible or reported.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- 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: >-
Establishes heart failure pharmacotherapy as first-line treatment for
dilated cardiomyopathy. PARTIAL and OTHER because it is a review of the
disease class; no trial has ever enrolled CMD1B carriers, who cannot be
identified without a gene.
target_mechanisms:
- target: Left Ventricular Dilation and Systolic Dysfunction
treatment_effect: MODULATES
description: >-
Standard heart failure pharmacotherapy attenuates the neurohormonally
driven remodeling that carries the ventricle to this endpoint. It targets
the shared downstream pathway rather than the unidentified 9q13-q22
lesion, which no available agent addresses.
evidence:
- 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: >-
Establishes that management of dilated cardiomyopathy is heart failure
management directed at the downstream phenotype. PARTIAL and OTHER
because this is a disease-class review, not a CMD1B trial, of which
there are none.
- name: Cardiac Resynchronization Therapy and Implantable Cardioverter Defibrillator
description: >-
Device therapy for the dilated, poorly contracting ventricle: resynchronization
for conduction delay and defibrillator implantation for prevention of sudden
arrhythmic death. Indication follows general dilated cardiomyopathy and
arrhythmia guidelines applied to the observed phenotype. No CMD1B-specific
arrhythmic risk-stratification rule exists, and none can exist while the gene
is unidentified, because there is no carrier status to stratify on: at-risk
relatives are distinguishable only by their echocardiographic and
electrocardiographic findings.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: implantable cardioverter-defibrillator placement
term:
id: NCIT:C80435
label: Implantable Cardioverter-Defibrillator Placement
evidence:
- reference: PMID:31073128
reference_title: Dilated cardiomyopathy.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Cardiac resynchronization therapy and implantable cardioverter-defibrillators
may be required to prevent life-threatening arrhythmias.
explanation: >-
Establishes device therapy for arrhythmic protection as part of standard
dilated cardiomyopathy care. PARTIAL and OTHER for the same reason as the
pharmacotherapy entry: this is a review of the disease class, and no trial
has enrolled CMD1B kindreds, who cannot be identified without a gene.
- name: Heart Transplantation
description: >-
Advanced therapy for end-stage heart failure once the ventricle is no longer
supportable medically, with mechanical circulatory support as a bridge. The
founding report of this locus frames transplantation as the clinical weight of
the disease entity rather than a rare tail event. Cascade echocardiographic
screening of this kindred is measured in transplant-free survival, which makes
transplantation the explicit endpoint the surveillance strategy is trying to
postpone.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Organ transplantation
term:
id: NCIT:C15289
label: Organ Transplantation
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The disorder is an important cause of morbidity and mortality and represents
the chief indication for heart transplantation.
explanation: >-
The founding linkage report for this locus states transplantation as the
chief indication arising from the disease entity it maps.
- reference: PMID:20525703
reference_title: Prognostic impact of familial screening in dilated cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Survival free from heart transplant at 2, 5 and 10 years was 93, 91 and
82%, respectively, in NP-FDC patients compared with 86, 76 and 62% in
sporadic forms (P = 0.04).
explanation: >-
Uses transplantation as the survival endpoint in familial dilated
cardiomyopathy, confirming it as a realized outcome in this population
rather than a theoretical option.
- name: Genetic Counseling
description: >-
Counseling for an autosomal dominant familial cardiomyopathy in which the
causal gene is unknown. The recurrence risk of 50% for offspring follows
from the transmission pattern, but carrier status cannot be determined
molecularly, so counseling must direct at-risk relatives to serial clinical
surveillance rather than to a predictive test.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:39519012
reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Current guidelines recommend genetic counseling and screening, as well as
endorsing a handful of genotype-specific therapies
explanation: >-
Supports genetic counseling as standard in genetic DCM. PARTIAL because
the genotype-specific therapy arm of that recommendation is unavailable
for a locus with no identified gene.
discussions:
- discussion_id: cmd1b_causal_gene_unidentified
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Which gene in the 9q13-q22 interval between D9S153 and D9S152 causes CMD1B,
and is the locus still a distinct disease entity thirty years after it was
mapped?
attaches_to:
- "pathophysiology#Unidentified 9q13-q22 Disease Locus"
rationale: >-
This is the central open question of the entry and the reason its
pathophysiology chain begins with a placeholder node. The linkage evidence
is strong - a maximum multipoint LOD of 4.2, exclusion of more than 95% of
the genome across 251 markers, replication in two additional families, and
no evidence of heterogeneity - so the locus is unlikely to be a false
positive, yet no gene has been confirmed in the three decades since. MONDO
still defines the entity by chromosome region rather than by gene, and NCBI
Gene 1218 returns no genomic coordinates. The original report
named positional candidates within the interval, of which TMOD1
(tropomodulin 1, 9q22.33) is the most biologically attractive: tropomodulin
caps the pointed end of the sarcomeric actin thin filament, and
tropomodulin-overexpressing transgenic mice develop progressive dilated
cardiomyopathy. That mouse phenotype is evidence of plausibility only; no
TMOD1 variant has ever been reported in this kindred or in any other family
with this locus, and the same is true of PRKACG (9q21.11). Resolution now
would most plausibly come from whole-genome sequencing of surviving members
of the original pedigree, which would also address the alternative
possibilities that the causal variant is non-coding or structural and so
invisible to the exome-based panels that dominate DCM testing, or that the
kindred's disease has since been reassigned to a gene now known to cause DCM
but not resident at 9q13-q22, which would retire the locus. Note that TMOD1
and PRKACG are named here as positional candidates on the strength of
secondary sources plus independently verified map positions inside the
interval; the cached abstract of the original report does not name them.
evidence:
- reference: PMID:7573045
reference_title: Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Several candidate genes for causing dilated cardiomyopathy map in this
region.
explanation: >-
The original report closes by naming the interval's candidates as
unresolved, which is the state the locus has remained in since.
- reference: PMID:10595939
reference_title: "Pathogenesis of dilated cardiomyopathy: molecular, structural, and population analyses in tropomodulin-overexpressing transgenic mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Previously unexplored structural and molecular events that precede and
initiate dilation can now be studied in tropomodulin-overexpressing
transgenic (TOT) mice exhibiting progressive dilated cardiomyopathy.
explanation: >-
Shows that altered tropomodulin dosage produces dilated cardiomyopathy in
mice, which is why TMOD1 was an attractive positional candidate. PARTIAL
and MODEL_ORGANISM because this is a transgenic overexpression model that
says nothing about the 9q13-q22 locus or about any human TMOD1 variant.
- reference: PMID:37795486
reference_title: Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Over half of the patients undergoing comprehensive genetic testing are
left without a molecular diagnosis even when patient selection follows
strict DCM criteria.
explanation: >-
Places the unresolved status of CMD1B in context: the majority of
clinically well-characterized DCM remains molecularly undiagnosed on
current panels, so an unsolved dominant locus is the norm rather than an
anomaly. PARTIAL because the cohort is unselected DCM, not this kindred.
- reference: PMID:33983834
reference_title: The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The foundations of DCM genetics rest on marked locus and allelic
heterogeneity.
explanation: >-
Frames why a large number of independently mapped DCM loci exist and why
several, including this one, remain without an assigned gene. PARTIAL and
OTHER because it is a review of the disease class.
notes: >-
A curator reviewing this entry should resist the temptation to close the gap
by binding TMOD1 or PRKACG as the causal gene. Neither has ever been shown
to carry a variant segregating with disease in this kindred, and asserting
one would convert a positional coincidence into a fabricated gene-disease
claim.

📚

References & Deep Research

References

1

PMID:20301486

Dilated Cardiomyopathy Overview.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Dilated Cardiomyopathy 1B (CMD1B) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 13 citations 2026-08-18T05:07:23.508436

Dilated Cardiomyopathy 1B (CMD1B) — Comprehensive Research Report

Executive Summary

Dilated Cardiomyopathy 1B (CMD1B) is a historical genetic-linkage designation for one form of autosomal dominant familial dilated cardiomyopathy (FDC), mapped in 1995 to chromosome 9q13–q22 by a genome-wide linkage study in a single large six-generation kindred (Krajinovic et al., Am J Hum Genet 1995;57(4):846–852, PMID: 7573045). The single most important characteristic of this entry, and the fact that should anchor any knowledge-base curation of it, is that CMD1B remains a locus without a confirmed causative gene. Unlike sibling entries in the OMIM dilated-cardiomyopathy phenotypic series that were later resolved to specific genes (CMD1A→LMNA, CMD1D→TNNT2, etc.), no gene at 9q13–q22 has ever been confirmed as causal for this family's phenotype in the ~30 years since the original report. OMIM's entry for CMD1B (600884) carries the "%" symbol designation — "a confirmed Mendelian phenotype or phenotypic locus for which the underlying molecular basis is not known" — and NCBI Gene's corresponding record (Gene ID 1218) is explicitly listed as "phenotype only," i.e., a mapped locus placeholder rather than a characterized gene.

1. Disease Information

Overview: CMD1B denotes one of several genetically distinct forms of monogenic autosomal dominant familial dilated cardiomyopathy (FDC/DCM) catalogued in OMIM's dilated cardiomyopathy phenotypic series (headed by reference entry CMD1A, OMIM #115200). Dilated cardiomyopathy as a clinical entity is a myocardial disease defined by left ventricular (or biventricular) dilatation and systolic dysfunction (impaired contractility) in the absence of coronary artery disease, hypertension, valvular disease, or congenital heart disease sufficient to explain the degree of dysfunction.

Key identifiers: | Resource | ID | Notes | |---|---|---| | OMIM | %600884 — "CARDIOMYOPATHY, DILATED, 1B; CMD1B" | Symbol "%" = confirmed phenotype/locus, molecular basis unknown | | NCBI Gene | 1218 | Listed as "phenotype only" record | | Cytogenetic locus | 9q13–q22 | Interval between markers D9S153 and D9S152 | | Alternative names | FDC (familial dilated cardiomyopathy, as used for this family), CMPD1 | | | Parent phenotype (general DCM) | OMIM #115200 (CMD1A used as descriptive reference), HP:0001644 (Dilated cardiomyopathy) | | | Suggested MONDO | MONDO:0011486 (verify locally against your OAK adapter before curating — search results were inconsistent on this mapping and it warrants direct confirmation) | |

Source of information: This entry is derived from a single-family gene-mapping study (aggregated linkage/pedigree data across a six-generation kindred, augmented by two additional families sharing the diagnostic criteria), not from an EHR-derived or large aggregated cohort resource. This is important for evidence-source classification: the founding evidence is HUMAN_CLINICAL (a linkage/pedigree study), not a population database.

Sources: - OMIM Entry %600884 — CARDIOMYOPATHY, DILATED, 1B; CMD1B - CMD1B — NCBI Gene ID 1218 - OMIM Entry #115200 — CARDIOMYOPATHY, DILATED, 1A; CMD1A

2. Etiology

Disease Causal Factors: Purely genetic/mechanistic in the classic sense used by OMIM — an autosomal dominant transmission pattern was demonstrated by segregation analysis in the index six-generation kindred. No specific causal gene, variant, or protein has been identified or validated at the 9q13–q22 interval; the "cause" recorded in the literature is a statistical linkage signal, not a molecular lesion.

Genetic risk factors: - Linkage was established with a maximum multipoint LOD score of 4.2 (highly significant), placing the FDC locus in the interval between microsatellite markers D9S153 and D9S152 on 9q13–q22. - "There was no evidence of heterogeneity" reported when the original family's data were combined with two additional families selected on the same stringent diagnostic criteria — i.e., the locus appeared consistent across the cohort studied, but this cohort was small and specific to European (predominantly French-Canadian/European ancestry, per the Heart Muscle Disease Study Group's typical recruitment) pedigrees; broader population generalizability was never established. - Candidate genes proposed but never confirmed at this locus (Krajinovic et al. 1995 and subsequent reviews): - TMOD1 (tropomodulin), HGNC-mapped to 9q22 — flagged as "a particularly attractive candidate gene" given its role in actin filament capping in the sarcomere. - PRKACG (cAMP-dependent protein kinase, catalytic gamma subunit), mapping to the same interval, noted for its role in regulating cardiac calcium-channel ion conductance. - The FXN (Friedreich ataxia) gene region was also noted as nearby, since Friedreich ataxia is frequently associated with (a distinct, non-familial) cardiomyopathy phenotype — raised as a positional/biological point of interest rather than a formally tested candidate causing this family's DCM. - No subsequent publication has been identified confirming any of these candidates, or any other gene at 9q13–q22, as causal. This should be treated as an open negative/unresolved finding rather than omitted.

Environmental/lifestyle risk factors: Not applicable to this monogenic-linkage entry specifically; for dilated cardiomyopathy broadly (general background, not CMD1B-specific), recognized modifiers include alcohol use, peripartum status, myocarditis, and chemotherapy exposure — none of which were reported as contributing factors in the original CMD1B kindred.

Protective factors: None reported for this locus specifically.

Gene-environment interactions: Not established for CMD1B.

Sources: - Linkage of familial dilated cardiomyopathy to chromosome 9 — PubMed - OMIM Entry %600884

3. Phenotypes

CMD1B does not have its own distinct phenotype description in OMIM — as is typical for entries in this phenotypic series, the clinical/phenotypic description is referenced to the series' descriptive entry, CMD1A (#115200), and the family-specific clinical criteria used were the standardized echocardiographic diagnostic criteria for familial dilated cardiomyopathy (Mestroni et al., used broadly by the Heart Muscle Disease Study Group consortium that produced the Krajinovic paper).

General DCM phenotype (applicable to the CMD1B kindred as ascertained): | Phenotype | HPO suggestion | Notes | |---|---|---| | Dilated cardiomyopathy | HP:0001644 | Core diagnostic feature | | Left ventricular dilatation | HP:4000141 (or generic left ventricular dilation term — verify local HPO version) | Primary echocardiographic criterion | | Reduced left ventricular ejection fraction / impaired myocardial contractility | HP:0005110 (arrhythmia) not applicable; use "left ventricular systolic dysfunction" HPO term if present locally | Impaired contractility is the functional correlate of dilatation | | Congestive heart failure | HP:0001635 | Frequent presenting/complicating feature | | Ventricular arrhythmia | HP:0004308 or related | Reported general feature of the DCM series | | Sudden cardiac death | HP:0001645 | Documented cause of mortality in DCM kindreds generally; not explicitly quantified for this specific family in available search results |

Onset/severity/progression: The original linkage study does not report detailed per-individual age-of-onset or penetrance statistics in the material retrievable via search (the PubMed abstract for PMID:7573045 was not fully accessible during this research pass due to access restrictions — this should be independently verified by fetching the full abstract/paper text before citing specific quantitative penetrance/age-of-onset figures for CMD1B). General FDC literature (Mestroni et al., Michels et al.) indicates adult-onset in most autosomal dominant FDC kindreds, with age-dependent (incomplete at young ages) penetrance typical of this disease class — this generalization should not be attributed specifically to the CMD1B family without confirming it in the primary source.

Quality of life impact: Not specifically reported for this locus; generic DCM QOL impact (heart-failure-related functional limitation) applies.

Caveat for curation: Because CMD1B has no confirmed gene, phenotype curation should rely on the general FDC/DCM phenotype description (shared with CMD1A) rather than inventing locus-specific phenotype detail not present in the primary literature.

Sources: - OMIM Entry #115200 — CARDIOMYOPATHY, DILATED, 1A - Linkage of familial dilated cardiomyopathy to chromosome 9 — PubMed

4. Genetic/Molecular Information

Causal genes: None confirmed. This is the defining molecular fact of the entry.

Locus: 9q13–q22 (linkage interval D9S153–D9S152)

Candidate genes evaluated but not confirmed: - TMOD1 — HGNC:11874, 9q22 - PRKACG — HGNC:9382, 9q13 - (positional note only) FXN — HGNC:3951, 9q21.11

Variant classification: Not applicable — no pathogenic variant has been reported at this locus for DCM.

Allele frequency / population data: Not applicable (no variant identified).

Modifier genes: None reported.

Epigenetic information: None reported specific to this locus.

Chromosomal abnormalities: None reported (this is a linkage locus from sequence-level normal chromosome 9, not a structural variant/CNV disorder).

Curation guidance: In a schema requiring a genetic: block with a specific gene, CMD1B cannot be populated with a causal gene the way CMD1A (LMNA) or CMD1D (TNNT2) can. If your knowledge base requires disorders to have a defined causal gene for pathophysiology modeling, CMD1B may not be curatable as a standard gene-anchored Disease entry — it may be more appropriate to represent it as a historical/superseded linkage finding (e.g., in notes, or omitted in favor of one of the resolved DCM subtypes) rather than force a genetic_context block onto an unconfirmed locus. This is a judgment call for project scope, consistent with dismech's general practice of not fabricating molecular specificity that the literature does not support.

Sources: - OMIM Entry %600884 - CMD1B — NCBI Gene ID 1218 ("phenotype only")

5. Environmental Information

Not applicable/not reported for this specific locus. No environmental, lifestyle, or infectious triggers were described in the founding linkage study or subsequent literature identified.

6. Mechanism / Pathophysiology

No locus-specific mechanism can be described, since no causal gene or protein has been identified. Any pathophysiological narrative would necessarily be speculative (based on candidate gene biology never confirmed) and should not be presented as established mechanism.

If a knowledge base entry is created, the appropriate framing is: - Candidate mechanistic hypotheses only (flagged clearly as unconfirmed/KNOWLEDGE_GAP in a modules/hypothesis framework), e.g.: - TMOD1-mediated hypothesis: tropomodulin caps the pointed end of actin thin filaments in the sarcomere; dysregulation could theoretically impair sarcomeric contractile function (GO:0051694 pointed-end actin filament capping) — but this was never demonstrated for the CMD1B family. - PRKACG-mediated hypothesis: altered cAMP-PKA signaling could affect L-type calcium channel conductance and excitation-contraction coupling (GO:0005267 potassium channel activity is not relevant; more appropriate would be GO:0086036 regulation of cardiac muscle cell membrane potential) — again, never confirmed. - General DCM final-common-pathway mechanism (applicable at the disease-class level, not specific to CMD1B): sarcomeric/cytoskeletal/nuclear-envelope protein dysfunction → impaired force generation or transmission → compensatory ventricular remodeling and dilatation → progressive systolic dysfunction → neurohormonal activation → heart failure. This maps to dismech's existing cardiomyopathy_maladaptive_remodeling module pattern (cardiomyocyte insult → neurohormonal activation → ventricular remodeling → contractile dysfunction → heart failure), but conformance to that module for CMD1B specifically cannot be evidence-supported absent a confirmed causal gene/protein.

Sources: - OMIM Entry %600884

7. Anatomical Structures Affected

Organ level: Heart (primary); secondary systemic complications from heart failure (pulmonary congestion, hepatic congestion, renal hypoperfusion) as in any DCM.
Chamber-level: Left ventricle primarily; biventricular involvement possible, consistent with general DCM phenotype criteria.
UBERON suggestions: UBERON:0002082 (cardiac ventricle), UBERON:0002084 (heart left ventricle), UBERON:0000948 (heart)
Cell/tissue level: Cardiomyocytes (CL:0000746) — presumed target cell type by analogy to other DCM-causing loci, not specifically demonstrated for this locus.
Subcellular: Not established (would depend on the unconfirmed candidate gene — sarcomere for TMOD1, plasma membrane/cAMP signaling complex for PRKACG).

8. Temporal Development

Not specifically documented for this locus beyond the fact that it is an adult-onset autosomal dominant familial cardiomyopathy consistent with the general FDC pattern. Detailed age-of-onset, progression rate, and disease-stage data specific to the Krajinovic kindred were not retrievable in this research pass (full-text access to PMID:7573045 was blocked) — flag as a gap requiring direct full-text retrieval before curation rather than inferring generic DCM natural history onto this specific family.

9. Inheritance and Population

Inheritance pattern: Autosomal dominant (established by segregation analysis and confirmed by the LOD score of 4.2 across a six-generation pedigree plus two additional families).

Penetrance/expressivity: Not quantified in materials retrieved; general FDC literature (not CMD1B-specific) describes age-dependent, often incomplete penetrance.

Genetic anticipation, mosaicism, founder effects, consanguinity: Not reported for this locus.

Epidemiology of general DCM (context, not CMD1B-specific): - Overall DCM prevalence is estimated at approximately 1 in 250–500 in the general population. - Familial DCM accounts for an estimated 20–50% of cases, predominantly autosomal dominant. - DCM is more prevalent in men; males show higher all-cause mortality, sudden cardiac death, and cardiovascular mortality than females, while women more often present with more severe heart-failure symptoms at diagnosis despite smaller LV volumes and higher ejection fraction. - CMD1B-specific prevalence/incidence: not established — this remains a single-kindred (plus two additional families) linkage finding, not a population-level entity with its own epidemiological statistics.

Sources: - Sex- and age-based differences in the natural history and outcome of dilated cardiomyopathy — PMC - Epidemiology — Dilated Cardiomyopathy — NCBI Bookshelf - Comprehensive review on gene mutations contributing to dilated cardiomyopathy — Frontiers 2023

10. Diagnostics

Locus-specific genetic testing: Not applicable/not available — there is no commercially or clinically validated gene test for "CMD1B" because no gene has been confirmed. Modern DCM genetic testing panels do not include a CMD1B-specific gene (they are built around the 12 genes with definitive/strong evidence per current expert consensus: BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN, plus other candidates).

General DCM diagnosis (context): - Echocardiography (primary imaging modality) and cardiac MRI (increasingly emphasized per 2023 ESC guidelines for scar/fibrosis assessment via late gadolinium enhancement) are the key diagnostic tools. - 2023 ESC Guidelines for the management of cardiomyopathies recommend genetic testing in DCM patients, particularly those under age 50 with atrioventricular conduction delay, or with a family history of DCM or sudden cardiac death in a first-degree relative, with priority testing of LMNA, PLN, RBM20, and FLNC. - Cascade clinical and genetic screening of relatives is recommended when a familial pattern is present — directly relevant to how the original CMD1B kindred would have been managed today, though no gene-based cascade test exists for this specific locus.

Sources: - 2023 ESC Guidelines for the management of cardiomyopathies — Eur Heart J - 2023 ESC Guidelines Key Points — ACC - Genetic counselling implementation in dilated cardiomyopathy — ESC consensus statement

11. Outcome/Prognosis

No family-specific survival/mortality data for the CMD1B kindred were retrieved. General DCM prognosis context: DCM is a leading cause of heart failure globally and the most common indication for heart transplantation; approximately 16.9% mortality has been reported in longitudinal DCM cohorts (with ~4.7% sudden death), with better outcomes generally in women than men after adjustment.

12. Treatment

No CMD1B-specific (locus-targeted) therapy exists, since no molecular target has been identified. Management would follow standard heart-failure-with-reduced-ejection-fraction pharmacotherapy per current guidelines (ACEi/ARB/ARNI, beta-blockers, mineralocorticoid receptor antagonists, SGLT2 inhibitors), device therapy (ICD/CRT) per risk stratification, and heart transplantation for end-stage disease — the 2023 ESC guidelines explicitly state that "pharmacological treatment of dilated cardiomyopathy patients does not differ from those recommended in chronic heart failure." Suggested NCIT terms for generic management: NCIT:C15986 (Pharmacotherapy), NCIT:C15289 (Organ Transplantation), NCIT:C15329 (Surgical Procedure, for device implantation).

13. Prevention

Family cascade screening (clinical echocardiographic screening of first-degree relatives) is the applicable preventive/early-detection strategy for any FDC kindred, including historically this one, though gene-based cascade testing is not possible for this unresolved locus.

14–15. Other Species / Model Organisms

No animal or cellular models exist specifically for CMD1B, since there is no confirmed gene to model. This is a critical curation constraint: sections of a knowledge-base template requiring animal_models or experimental_models with modeled_mechanisms targeting a CMD1B-specific node cannot be populated without fabricating a gene-target link the literature does not support.

Curation Recommendation

Given dismech's strict anti-hallucination and evidence-discipline requirements (exact PMID quotes, no fabricated gene links, no invented ontology terms), CMD1B is a poor candidate for a fully gene-anchored Disease entry in its current, unresolved state. Recommended options, consistent with the project's general practices: 1. Do not curate a genetic: block with any of the candidate genes (TMOD1, PRKACG) unless a primary source explicitly confirms causality (none was found). 2. If curated at all, frame the entry around the linkage locus and its unresolved status as the core content, citing PMID:7573045 for the linkage finding, and explicitly note in notes (not as an evidence-backed causal claim) that no gene has been confirmed. 3. Consider whether this entry duplicates/should defer to the general FDC/DCM entry (CMD1A-equivalent) rather than standing alone, given it contributes no distinguishing molecular content beyond the chromosome 9 linkage interval. 4. Before any curation proceeds, obtain full-text access to Krajinovic et al. 1995 (PMID:7573045) — this research pass was blocked from the full abstract by a cookie-consent wall — to extract exact, quotable clinical/pedigree details (family size, penetrance, age of onset, exact LOD score context) rather than relying on secondarily-reported summaries.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	4
Resolved	3
Unresolved (possible confabulation)	1
Unverifiable	0
References weighed for topical relevance	3
On topic	2
Off topic	0

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

DOI:10.1093/eurheartj/ehag159/8529603 (3 mentions) - Identifier did not resolve to a record

Dilated Cardiomyopathy 1B

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Dilated Cardiomyopathy 1B (CMD1B) — Comprehensive Research Report

Executive Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14–15. Other Species / Model Organisms

Curation Recommendation

Sources

Reference Validation

Unresolved references