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.

Table (click to expand)

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