Familial isolated dilated cardiomyopathy

Summary

Familial isolated dilated cardiomyopathy (MONDO:0700335) is a disease (an umbrella term covering 45 Mondo subtypes) with 5 cohort genes.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Umbrella term: 45 Mondo subtypes
• Cohort genes: 5
• ClinVar variants: 6
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	2.91	Europe	Validated
Point prevalence	1-5 / 10 000	17.5	Europe	Validated
Annual incidence	1-9 / 100 000	6	United States	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0001644	Dilated cardiomyopathy	Very frequent (80-99%)
HP:0025169	Left ventricular systolic dysfunction	Very frequent (80-99%)
HP:0000969	Edema	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0002875	Exertional dyspnea	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012764	Orthopnea	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0001727	Thromboembolic stroke	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0003457	EMG abnormality	Occasional (5-29%)
HP:0100578	Lipoatrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial isolated dilated cardiomyopathy
Mondo ID	MONDO:0700335
Orphanet	154
ICD-11	949016860
UMLS	C5679590
MedGen	1826005
GARD	0027293
Is cancer (heuristic)	no

Also known as: familial isolated dilated cardiomyopathy · familial or idiopathic dilated cardiomyopathy

Data availability: 6 ClinVar variants · 46 cell lines.

Disease family

An umbrella term covering 45 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › dilated cardiomyopathy › familial dilated cardiomyopathy › familial isolated dilated cardiomyopathy

Related subtypes (28): autosomal recessive limb-girdle muscular dystrophy type 2C, Barth syndrome, histiocytoid cardiomyopathy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, autosomal recessive limb-girdle muscular dystrophy type 2F, myofibrillar myopathy 1, autosomal recessive limb-girdle muscular dystrophy type 2E, dilated cardiomyopathy 1J, hypertrophic cardiomyopathy 25, autosomal recessive limb-girdle muscular dystrophy type 2D, DK1-congenital disorder of glycosylation, autosomal recessive limb-girdle muscular dystrophy type 2M, early-onset myopathy with fatal cardiomyopathy, PGM1-congenital disorder of glycosylation, autosomal recessive limb-girdle muscular dystrophy type 2W, symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers, Emery-Dreifuss muscular dystrophy, cardiomyopathy, dilated, 1LL, cardiomyopathy, dilated, 1MM, cardiomyopathy, dilated, 100, cardiomyopathy, dilated, 2I, cardiomyopathy, dilated, 2j, cardiomyopathy, dilated, 2K, cardiomyopathy, dilated, 2l, cardiomyopathy, dilated, 1QQ, cardiomyopathy, dilated, 2M, cardiomyopathy, dilated, 3C

Subtypes (45): dilated cardiomyopathy 1A, dilated cardiomyopathy 3B, dilated cardiomyopathy 1B, dilated cardiomyopathy 1E, dilated cardiomyopathy 1C, dilated cardiomyopathy 1D, dilated cardiomyopathy 1G, dilated cardiomyopathy 1H, dilated cardiomyopathy 1I, dilated cardiomyopathy 1K, dilated cardiomyopathy 1L, dilated cardiomyopathy 1M, dilated cardiomyopathy 1O, dilated cardiomyopathy 1P, dilated cardiomyopathy 1Q, dilated cardiomyopathy 1W, dilated cardiomyopathy 1X, dilated cardiomyopathy 1Y, dilated cardiomyopathy 1Z, dilated cardiomyopathy 2A, dilated cardiomyopathy 1AA, dilated cardiomyopathy 1BB, dilated cardiomyopathy 1CC, dilated cardiomyopathy 1DD, dilated cardiomyopathy 1EE, dilated cardiomyopathy 1FF, dilated cardiomyopathy 1R, dilated cardiomyopathy 1S, dilated cardiomyopathy 1GG, dilated cardiomyopathy 1U, dilated cardiomyopathy 1V, dilated cardiomyopathy 1HH, dilated cardiomyopathy 2B, dilated cardiomyopathy 1II, dilated cardiomyopathy 1JJ, dilated cardiomyopathy 1KK, left ventricular noncompaction 8, left ventricular noncompaction 10, dilated cardiomyopathy 1NN, cardiomyopathy, dilated, 2D, cardiomyopathy, dilated, 2E, cardiomyopathy, dilated, 2F, cardiomyopathy, dilated, 2G, cardiomyopathy, dilated, 2c, cardiomyopathy, dilated, 2H

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 pathogenic/likely pathogenic, 1 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1328520	NM_207163.3(LMOD2):c.273+1G>A	LMOD2	Pathogenic	no assertion criteria provided
12414	NM_001276345.2(TNNT2):c.451C>T (p.Arg151Trp)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4823944	NM_001267550.2(TTN):c.49564del (p.Arg16522fs)	TTN	Likely pathogenic	criteria provided, single submitter
201852	NM_007078.3(LDB3):c.1594G>C (p.Ala532Pro)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
585295	NM_001943.5(DSG2):c.1361A>C (p.Asp454Ala)	DSG2	Uncertain significance	criteria provided, single submitter
640656	NM_007078.3(LDB3):c.1633A>G (p.Ser545Gly)	LDB3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 27 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNT2	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:54260	Left ventricular noncompaction
TNNT2	Orphanet:75249	Familial isolated restrictive cardiomyopathy
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
LDB3	Orphanet:154	Familial isolated dilated cardiomyopathy
LDB3	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LDB3	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LDB3	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LDB3	Orphanet:54260	Left ventricular noncompaction
LDB3	Orphanet:98912	Late-onset distal myopathy, Markesbery-Griggs type
DSG2	Orphanet:154	Familial isolated dilated cardiomyopathy
DSG2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSG2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSG2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMOD2	Orphanet:154	Familial isolated dilated cardiomyopathy

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
LDB3	HGNC:15710	ENSG00000122367	O75112	LIM domain-binding protein 3	clinvar
DSG2	HGNC:3049	ENSG00000046604	Q14126	Desmoglein-2	clinvar
LMOD2	HGNC:6648	ENSG00000170807	Q6P5Q4	Leiomodin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNNT2	Troponin T, cardiac muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
LDB3	LIM domain-binding protein 3	May function as an adapter in striated muscle to couple protein kinase C-mediated signaling via its LIM domains to the cytoskeleton.
DSG2	Desmoglein-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
LMOD2	Leiomodin-2	Mediates nucleation of actin filaments and thereby promotes actin polymerization.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	5.5×	0.503
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
LDB3	Transcription factor	no		PDZ, Znf_LIM, Zasp-like_motif
DSG2	Other/Unknown	no		Cadherin-like_dom, Desmosomal_cadherin, Cadherin-like_sf
LMOD2	Other/Unknown	no		WH2_dom, TMOD, LRR_dom_sf

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
biceps brachii	2
skeletal muscle tissue of biceps brachii	2
cardiac atrium	1
right atrium auricular region	1
gluteal muscle	1
hindlimb stylopod muscle	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
cardiac muscle of right atrium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNT2	154	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
LDB3	247	broad	marker	skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle, apex of heart
DSG2	238	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, jejunal mucosa
LMOD2	153	tissue_specific	marker	left ventricle myocardium, cardiac muscle of right atrium, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
DSG2	2,033
TNNT2	1,944
LDB3	1,275
LMOD2	755

Intra-cohort edges

A	B	Sources
LDB3	TNNT2	string_interaction
LDB3	TTN	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
TNNT2	P45379	25
DSG2	Q14126	12
LMOD2	Q6P5Q4	3
LDB3	O75112	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 5 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	2	205.8×	2e-04	TNNT2, TTN
Apoptotic cleavage of cell adhesion proteins	1	346.1×	0.012	DSG2
RHOG GTPase cycle	1	49.4×	0.039	DSG2
RAC2 GTPase cycle	1	42.3×	0.039	DSG2
RAC3 GTPase cycle	1	39.6×	0.039	DSG2
Platelet degranulation	1	29.3×	0.039	TTN
Formation of the cornified envelope	1	29.3×	0.039	DSG2
Keratinization	1	18.6×	0.053	DSG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sarcomere organization	4	306.4×	1e-08	TNNT2, TTN, LDB3, LMOD2
muscle filament sliding	2	421.3×	2e-04	TNNT2, TTN
cardiac muscle contraction	2	160.5×	0.001	TNNT2, TTN
response to calcium ion	2	127.2×	0.001	TNNT2, TTN
muscle contraction	2	83.2×	0.002	TTN, LMOD2
Purkinje myocyte development	1	1685.2×	0.005	DSG2
skeletal muscle myosin thick filament assembly	1	1123.5×	0.005	TTN
sarcomerogenesis	1	1123.5×	0.005	TTN
positive regulation of protein localization to cell-cell junction	1	1123.5×	0.005	DSG2
negative regulation of endothelial cell differentiation	1	674.1×	0.007	DSG2
skeletal muscle thin filament assembly	1	561.7×	0.007	TTN
detection of muscle stretch	1	481.5×	0.007	TTN
pointed-end actin filament capping	1	481.5×	0.007	LMOD2
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	1	481.5×	0.007	DSG2
desmosome organization	1	421.3×	0.007	DSG2
actin nucleation	1	374.5×	0.007	LMOD2
cardiac muscle hypertrophy	1	337.0×	0.007	TTN
regulation of muscle contraction	1	337.0×	0.007	TNNT2
negative regulation of ATP-dependent activity	1	337.0×	0.007	TNNT2
negative regulation of inflammatory response to wounding	1	337.0×	0.007	DSG2
mesenchymal to epithelial transition	1	306.4×	0.007	DSG2
obsolete protein kinase A signaling	1	280.9×	0.007	TTN
positive regulation of ATP-dependent activity	1	280.9×	0.007	TNNT2
cardiac muscle tissue morphogenesis	1	280.9×	0.007	TTN
muscle structure development	1	280.9×	0.007	LDB3
regulation of ventricular cardiac muscle cell action potential	1	280.9×	0.007	DSG2
cardiac myofibril assembly	1	259.3×	0.008	TTN
myofibril assembly	1	224.7×	0.008	LMOD2
mitotic chromosome condensation	1	198.3×	0.009	TTN
maternal process involved in female pregnancy	1	187.2×	0.009	DSG2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNNT2	0	0
TTN	0	0
LDB3	0	0
DSG2	0	0
LMOD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TNNT2	2	Binding:2
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TTN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	TNNT2, LDB3, DSG2, LMOD2

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TNNT2	2	—
TTN	1	—
LDB3	0	—
DSG2	0	—
LMOD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.