Restrictive cardiomyopathy
disease diseaseOn this page
Also known as familial restrictive cardiomyopathy
Summary
Restrictive cardiomyopathy (MONDO:0005201) is a disease with 22 cohort genes and 12 clinical trials. The dominant Reactome pathway is Striated Muscle Contraction (6 cohort genes).
At a glance
- Cohort genes: 22
- ClinVar variants: 45
- Clinical trials: 12
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | restrictive cardiomyopathy |
| Mondo ID | MONDO:0005201 |
| EFO | EFO:0002630 |
| MeSH | D002313 |
| Orphanet | 217632 |
| DOID | DOID:397 |
| ICD-11 | 316495940 |
| NCIT | C62798 |
| SNOMED CT | 415295002 |
| UMLS | C0007196 |
| MedGen | 40111 |
| GARD | 0020531 |
| MedDRA | 10038748 |
| Is cancer (heuristic) | no |
Also known as: familial restrictive cardiomyopathy · restrictive cardiomyopathy
Data availability: 45 ClinVar variants · 1 ClinGen variant curation · 4 cell lines.
Disease family
An umbrella term covering 3 Mondo subtypes.
Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › restrictive cardiomyopathy
Related subtypes (5): myocarditis, dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction
Subtypes (3): endomyocardial fibrosis, familial restrictive cardiomyopathy, non-familial restrictive cardiomyopathy
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
45 retrieved; paginated sample, class counts are floors:
11 uncertain significance, 9 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 6 benign/likely benign, 5 likely pathogenic, 5 pathogenic, 1 benign, 1 pathogenic; drug response
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 641618 | NM_001458.5(FLNC):c.6889G>A (p.Val2297Met) | FLNC | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 549664 | NM_001458.5(FLNC):c.7688A>G (p.Tyr2563Cys) | FLNC-AS1 | Pathogenic | criteria provided, single submitter |
| 164337 | NM_000257.4(MYH7):c.2302G>A (p.Gly768Arg) | LOC126861898 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 42910 | NM_000257.4(MYH7):c.2513C>T (p.Pro838Leu) | LOC126861898 | Pathogenic | reviewed by expert panel |
| 9628 | NC_012920.1(MT-RNR1):m.1555A>G | MT-ND1 | Pathogenic; drug response | reviewed by expert panel |
| 12424 | NM_000363.5(TNNI3):c.575G>A (p.Arg192His) | TNNI3 | Pathogenic | reviewed by expert panel |
| 12426 | NM_000363.5(TNNI3):c.433C>T (p.Arg145Trp) | TNNI3 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 165516 | NM_000363.5(TNNI3):c.509G>A (p.Arg170Gln) | TNNI3 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 179285 | NM_000363.5(TNNI3):c.508C>T (p.Arg170Trp) | TNNI3 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 180551 | NM_000363.5(TNNI3):c.522G>C (p.Lys174Asn) | TNNI3 | Pathogenic | no assertion criteria provided |
| 43395 | NM_000363.5(TNNI3):c.557G>A (p.Arg186Gln) | TNNI3 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 165549 | NM_001276345.2(TNNT2):c.310C>T (p.Arg104Cys) | TNNT2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 635051 | NM_001267550.2(TTN):c.29621_29624del (p.Glu9874fs) | TTN | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1027660 | NM_001458.5(FLNC):c.4861A>T (p.Ile1621Phe) | FLNC | Likely pathogenic | no assertion criteria provided |
| 544829 | NM_001458.5(FLNC):c.6892C>T (p.Pro2298Ser) | FLNC-AS1 | Likely pathogenic | criteria provided, single submitter |
| 164378 | NM_000257.4(MYH7):c.1157A>G (p.Tyr386Cys) | MYH7 | Likely pathogenic | reviewed by expert panel |
| 165510 | NM_000363.5(TNNI3):c.574C>T (p.Arg192Cys) | TNNI3 | Likely pathogenic | reviewed by expert panel |
| 2506420 | NM_001267550.2(TTN):c.71866del (p.Ile23956fs) | TTN | Likely pathogenic | no assertion criteria provided |
| 93411 | NM_000719.7(CACNA1C):c.5150C>G (p.Ala1717Gly) | CACNA1C | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 44910 | NM_004415.4(DSP):c.4489C>T (p.Arg1497Trp) | DSP | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 496250 | NM_004415.4(DSP):c.8117A>T (p.Lys2706Met) | DSP | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 287943 | NM_001130987.2(DYSF):c.1255C>T (p.Arg419Trp) | DYSF | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 472122 | NM_001458.5(FLNC):c.6031G>A (p.Gly2011Arg) | FLNC | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 549663 | NM_001458.5(FLNC):c.6893C>T (p.Pro2298Leu) | FLNC-AS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 691765 | NM_014476.6(PDLIM3):c.365G>A (p.Arg122Gln) | LOC126807246 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 45784 | NM_016599.5(MYOZ2):c.488T>C (p.Leu163Ser) | MYOZ2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 444869 | NM_032578.4(MYPN):c.802C>T (p.Pro268Ser) | MYPN | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 691670 | NM_145046.5(CALR3):c.772_777delinsGCCAGG (p.Lys258_Pro259delinsAlaArg) | CALR3 | Uncertain significance | criteria provided, single submitter |
| 180341 | NM_004415.4(DSP):c.4385_4386delinsTT (p.Ser1462Ile) | DSP | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 1722580 | NM_001458.5(FLNC):c.3551G>T (p.Gly1184Val) | FLNC | Uncertain significance | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 0 · Orphanet: 77 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| SLC25A4 | Orphanet:1369 | Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome |
| SLC25A4 | Orphanet:254892 | Autosomal dominant progressive external ophthalmoplegia |
| TNNI3 | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| TNNI3 | Orphanet:75249 | Familial isolated restrictive cardiomyopathy |
| 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 |
| CACNA1C | Orphanet:101016 | Romano-Ward syndrome |
| CACNA1C | Orphanet:130 | Brugada syndrome |
| CACNA1C | Orphanet:528084 | Non-specific syndromic intellectual disability |
| CACNA1C | Orphanet:595098 | Timothy syndrome type 1 |
| CACNA1C | Orphanet:595105 | Timothy syndrome type 2 |
| CACNA1C | Orphanet:595109 | Atypical Timothy syndrome |
| SYNE2 | Orphanet:98853 | Autosomal dominant Emery-Dreifuss muscular dystrophy |
| TRPM4 | Orphanet:130 | Brugada syndrome |
| TRPM4 | Orphanet:316 | Progressive symmetric erythrokeratodermia |
| TRPM4 | Orphanet:871 | Hereditary progressive cardiac conduction defect |
| MYPN | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| MYPN | Orphanet:171439 | Childhood-onset nemaline myopathy |
| MYPN | Orphanet:171881 | Cap myopathy |
| MYPN | Orphanet:75249 | Familial isolated restrictive cardiomyopathy |
| DMD | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| DMD | Orphanet:206546 | Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers |
| DMD | Orphanet:777 | X-linked non-syndromic intellectual disability |
| DMD | Orphanet:98895 | Becker muscular dystrophy |
| DMD | Orphanet:98896 | Duchenne muscular dystrophy |
| 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 |
| DSP | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| DSP | Orphanet:158687 | Lethal acantholytic erosive disorder |
| DSP | Orphanet:2032 | Idiopathic pulmonary fibrosis |
| DSP | Orphanet:293165 | Skin fragility-woolly hair-palmoplantar keratoderma syndrome |
| DSP | Orphanet:293888 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant |
| DSP | Orphanet:293899 | Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant |
| DSP | Orphanet:293910 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant |
Cohort genes → proteins
22 cohort genes, 20 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 22 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| SLC25A4 | HGNC:10990 | ENSG00000151729 | P12235 | ADP/ATP translocase 1 | clinvar |
| TNNI3 | HGNC:11947 | ENSG00000129991 | P19429 | Troponin I, cardiac muscle | clinvar |
| TNNT2 | HGNC:11949 | ENSG00000118194 | P45379 | Troponin T, cardiac muscle | clinvar |
| TTN | HGNC:12403 | ENSG00000155657 | Q8WZ42 | Titin | clinvar |
| MYOZ2 | HGNC:1330 | ENSG00000172399 | Q9NPC6 | Myozenin-2 | clinvar |
| CACNA1C | HGNC:1390 | ENSG00000151067 | Q13936 | Voltage-dependent L-type calcium channel subunit alpha-1C | clinvar |
| SYNE2 | HGNC:17084 | ENSG00000054654 | Q8WXH0 | Nesprin-2 | clinvar |
| TRPM4 | HGNC:17993 | ENSG00000130529 | Q8TD43 | Transient receptor potential cation channel subfamily M member 4 | clinvar |
| CALR3 | HGNC:20407 | ENSG00000269058 | Q96L12 | Calreticulin-3 | clinvar |
| MYPN | HGNC:23246 | ENSG00000138347 | Q86TC9 | Myopalladin | clinvar |
| DMD | HGNC:2928 | ENSG00000198947 | P11532 | Dystrophin | clinvar |
| DSG2 | HGNC:3049 | ENSG00000046604 | Q14126 | Desmoglein-2 | clinvar |
| DSP | HGNC:3052 | ENSG00000096696 | P15924 | Desmoplakin | clinvar |
| DYSF | HGNC:3097 | ENSG00000135636 | O75923 | Dysferlin | clinvar |
| FLNC | HGNC:3756 | ENSG00000128591 | Q14315 | Filamin-C | clinvar |
| AKAP9 | HGNC:379 | ENSG00000127914 | Q99996 | A-kinase anchor protein 9 | clinvar |
| MHRT | HGNC:51291 | myosin heavy chain associated RNA transcript | clinvar | ||
| FLNC-AS1 | HGNC:53474 | ENSG00000242902 | FLNC antisense RNA 1 | clinvar | |
| MT-ND1 | HGNC:7455 | ENSG00000198888 | P03886 | NADH-ubiquinone oxidoreductase chain 1 | clinvar |
| MYH6 | HGNC:7576 | ENSG00000197616 | P13533 | Myosin-6 | clinvar |
| MYH7 | HGNC:7577 | ENSG00000092054 | P12883 | Myosin-7 | clinvar |
| MYL3 | HGNC:7584 | ENSG00000160808 | P08590 | Myosin light chain 3 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| SLC25A4 | ADP/ATP translocase 1 | ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell. |
| TNNI3 | Troponin I, cardiac muscle | Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. |
| 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. |
| MYOZ2 | Myozenin-2 | Myozenins may serve as intracellular binding proteins involved in linking Z line proteins such as alpha-actinin, gamma-filamin, TCAP/telethonin, LDB3/ZASP and localizing calcineurin signaling to the sarcomere. |
| CACNA1C | Voltage-dependent L-type calcium channel subunit alpha-1C | Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents. |
| SYNE2 | Nesprin-2 | Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization. |
| TRPM4 | Transient receptor potential cation channel subfamily M member 4 | Calcium-activated selective cation channel that mediates membrane depolarization. |
| CALR3 | Calreticulin-3 | During spermatogenesis, may act as a lectin-independent chaperone for specific client proteins such as ADAM3. |
| MYPN | Myopalladin | Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines. |
| DMD | Dystrophin | Anchors the extracellular matrix to the cytoskeleton via F-actin. |
| DSG2 | Desmoglein-2 | A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. |
| DSP | Desmoplakin | A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. |
| DYSF | Dysferlin | Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion. |
| FLNC | Filamin-C | Muscle-specific filamin, which plays a central role in sarcomere assembly and organization. |
| AKAP9 | A-kinase anchor protein 9 | Scaffolding protein that assembles several protein kinases and phosphatases on the centrosome and Golgi apparatus. |
| MT-ND1 | NADH-ubiquinone oxidoreductase chain 1 | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. |
| MYH6 | Myosin-6 | Muscle contraction. |
| MYH7 | Myosin-7 | Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. |
| MYL3 | Myosin light chain 3 | Regulatory light chain of myosin. |
Protein-family classification
Druggable: 5 · Difficult: 4 · Unknown: 13 · Druggable fraction: 0.23
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 |
|---|---|---|---|
| Ion channel | 2 | 10.1× | 0.098 |
| Antibody/Immunoglobulin | 2 | 2.6× | 0.346 |
| Scaffold/PPI | 3 | 2.4× | 0.346 |
| Kinase | 1 | 1.3× | 0.665 |
| Other/Unknown | 13 | 1.1× | 0.665 |
| Transcription factor | 1 | 0.4× | 0.942 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| SLC25A4 | Other/Unknown | no | MCP, ADT_euk_type, MCP_transmembrane | |
| TNNI3 | Other/Unknown | no | Troponin, Troponin-I_N, Troponin_sf | |
| TNNT2 | Other/Unknown | no | Troponin, TNNT, Troponin_sf | |
| TTN | Kinase | yes | 2.7.11.1 | Prot_kinase_dom, Ig_sub2, Ig_sub |
| MYOZ2 | Other/Unknown | no | MYOZ | |
| CACNA1C | Ion channel | yes | VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu | |
| SYNE2 | Other/Unknown | no | Actinin_actin-bd_CS, CH_dom, Spectrin_repeat | |
| TRPM4 | Ion channel | yes | Ion_trans_dom, TRPM_SLOG, TRPM | |
| CALR3 | Other/Unknown | no | Calret/calnex, Calreticulin/calnexin_P_dom_sf, Calreticulin | |
| MYPN | Antibody/Immunoglobulin | yes | Ig_sub2, Ig_sub, Ig-like_dom | |
| DMD | Transcription factor | no | Znf_ZZ, WW_dom, Actinin_actin-bd_CS | |
| DSG2 | Other/Unknown | no | Cadherin-like_dom, Desmosomal_cadherin, Cadherin-like_sf | |
| DSP | Scaffold/PPI | no | Plectin_repeat, SH3_domain, Spectrin/alpha-actinin | |
| DYSF | Other/Unknown | no | C2_dom, Peroxin/Ferlin, Ferlin_A-domain | |
| FLNC | Antibody/Immunoglobulin | yes | Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom | |
| AKAP9 | Other/Unknown | no | ELK_dom, PACT_domain, AKAP9/Pericentrin | |
| MHRT | Other/Unknown | no | ||
| FLNC-AS1 | Other/Unknown | no | ||
| MT-ND1 | Other/Unknown | no | NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS | |
| MYH6 | Scaffold/PPI | no | Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin | |
| MYH7 | Scaffold/PPI | no | IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail | |
| MYL3 | Other/Unknown | no | EF_hand_dom, EF-hand-dom_pair, CALM/Myosin/TropC-like |
Expression context
Cohort genes with no expression data: 1.
18 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) | 21 |
| unknown | 1 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| apex of heart | 8 |
| hindlimb stylopod muscle | 6 |
| heart right ventricle | 3 |
| left ventricle myocardium | 3 |
| skeletal muscle tissue of biceps brachii | 3 |
| gastrocnemius | 3 |
| right atrium auricular region | 2 |
| cardiac atrium | 2 |
| skeletal muscle tissue of rectus abdominis | 2 |
| jejunal mucosa | 2 |
| biceps brachii | 1 |
| gluteal muscle | 1 |
| myocardium | 1 |
| muscle layer of sigmoid colon | 1 |
| right coronary artery | 1 |
| ganglionic eminence | 1 |
| ventricular zone | 1 |
| mucosa of transverse colon | 1 |
| rectum | 1 |
| left testis | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| SLC25A4 | 292 | ubiquitous | marker | left ventricle myocardium, heart right ventricle, apex of heart |
| TNNI3 | 169 | broad | marker | apex of heart, left ventricle myocardium, right atrium auricular region |
| 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 |
| MYOZ2 | 179 | broad | marker | heart right ventricle, left ventricle myocardium, myocardium |
| CACNA1C | 134 | broad | marker | apex of heart, right coronary artery, muscle layer of sigmoid colon |
| SYNE2 | 284 | ubiquitous | marker | ventricular zone, skeletal muscle tissue of biceps brachii, ganglionic eminence |
| TRPM4 | 201 | ubiquitous | marker | mucosa of transverse colon, rectum, apex of heart |
| CALR3 | 57 | broad | yes | right testis, left testis, testis |
| MYPN | 116 | broad | marker | hindlimb stylopod muscle, gastrocnemius, vastus lateralis |
| DMD | 295 | ubiquitous | marker | trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion |
| DSG2 | 238 | ubiquitous | marker | mucosa of sigmoid colon, colonic mucosa, jejunal mucosa |
| DSP | 253 | ubiquitous | marker | skin of hip, upper leg skin, hair follicle |
| DYSF | 257 | ubiquitous | marker | blood, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis |
| FLNC | 255 | ubiquitous | marker | gastrocnemius, hindlimb stylopod muscle, tibialis anterior |
| AKAP9 | 292 | ubiquitous | marker | jejunal mucosa, bronchial epithelial cell, cortical plate |
| MHRT | ||||
| FLNC-AS1 | 114 | yes | hindlimb stylopod muscle, apex of heart, muscle of leg | |
| MT-ND1 | 134 | ubiquitous | marker | adipose tissue, gastrocnemius, frontal cortex |
| MYH6 | 154 | tissue_specific | yes | cardiac muscle of right atrium, cardiac atrium, vena cava |
| MYH7 | 167 | tissue_specific | marker | apex of heart, hindlimb stylopod muscle, skeletal muscle tissue of biceps brachii |
| MYL3 | 198 | broad | marker | apex of heart, heart right ventricle, hindlimb stylopod muscle |
Protein interactions among cohort
Intra-cohort edges: 27.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| TTN | 4,237 |
| AKAP9 | 3,537 |
| MT-ND1 | 3,537 |
| FLNC | 3,174 |
| CACNA1C | 3,145 |
| MYH6 | 3,119 |
| SLC25A4 | 3,085 |
| DSP | 2,897 |
| MYH7 | 2,744 |
| DMD | 2,479 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| CALR3 | MYL3 | string_interaction |
| CALR3 | MYOZ2 | string_interaction |
| CALR3 | MYPN | string_interaction |
| DMD | DYSF | string_interaction |
| DMD | FLNC | string_interaction |
| DSG2 | DSP | string_interaction |
| DYSF | FLNC | intact |
| DYSF | TTN | biogrid_interaction, intact |
| FLNC | MYOZ2 | biogrid_interaction, string_interaction |
| MYH6 | MYL3 | string_interaction |
| MYH6 | TNNI3 | string_interaction |
| MYH6 | TNNT2 | string_interaction |
| MYH6 | TTN | string_interaction |
| MYH7 | MYL3 | string_interaction |
| MYH7 | MYOZ2 | string_interaction |
| MYH7 | TNNI3 | string_interaction |
| MYH7 | TNNT2 | string_interaction |
| MYH7 | TTN | string_interaction |
| MYL3 | MYOZ2 | string_interaction |
| MYL3 | SLC25A4 | string_interaction |
| MYL3 | TNNI3 | string_interaction |
| MYL3 | TNNT2 | string_interaction |
| MYL3 | TTN | string_interaction |
| MYOZ2 | MYPN | string_interaction |
| MYPN | TTN | biogrid_interaction, string_interaction |
| TNNI3 | TNNT2 | biogrid_interaction, string_interaction |
| TNNI3 | TTN | string_interaction |
Structural data
PDB: 14 · AlphaFold-only: 6 · No structure: 2
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| TTN | Q8WZ42 | 64 |
| MYH7 | P12883 | 43 |
| TNNI3 | P19429 | 39 |
| CACNA1C | Q13936 | 33 |
| TRPM4 | Q8TD43 | 29 |
| TNNT2 | P45379 | 25 |
| FLNC | Q14315 | 14 |
| DSG2 | Q14126 | 12 |
| DYSF | O75923 | 11 |
| DMD | P11532 | 6 |
| MT-ND1 | P03886 | 5 |
| DSP | P15924 | 4 |
| SYNE2 | Q8WXH0 | 3 |
| MYL3 | P08590 | 3 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| SLC25A4 | P12235 | 92.07 |
| CALR3 | Q96L12 | 77.43 |
| MYH6 | P13533 | 74.91 |
| MYOZ2 | Q9NPC6 | 65.51 |
| MYPN | Q86TC9 | 52.71 |
| AKAP9 | Q99996 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 73. Enrichment computed across 22 evidence-associated genes (16 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 16 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 | 6 | 115.7× | 4e-10 | TNNI3, TNNT2, TTN, DMD, MYH6, MYL3 |
| Muscle contraction | 4 | 19.3× | 0.002 | CACNA1C, AKAP9, MYH6, MYL3 |
| Apoptotic cleavage of cell adhesion proteins | 2 | 129.8× | 0.002 | DSG2, DSP |
| Phase 2 - plateau phase | 2 | 95.2× | 0.003 | CACNA1C, AKAP9 |
| Mitochondrial Uncoupling | 1 | 356.9× | 0.041 | SLC25A4 |
| Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization | 1 | 237.9× | 0.051 | SLC25A4 |
| Cardiac conduction | 2 | 13.6× | 0.096 | CACNA1C, AKAP9 |
| Interactions of Vpr with host cellular proteins | 1 | 89.2× | 0.102 | SLC25A4 |
| Phase 3 - rapid repolarisation | 1 | 71.4× | 0.102 | AKAP9 |
| Formation of the cornified envelope | 2 | 11.0× | 0.102 | DSG2, DSP |
| Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane | 1 | 59.5× | 0.111 | SLC25A4 |
| Cell-extracellular matrix interactions | 1 | 42.0× | 0.143 | FLNC |
| TRP channels | 1 | 25.5× | 0.163 | TRPM4 |
| Adrenaline,noradrenaline inhibits insulin secretion | 1 | 24.6× | 0.163 | CACNA1C |
| Phase 0 - rapid depolarisation | 1 | 21.6× | 0.163 | CACNA1C |
| Host Interactions of HIV factors | 1 | 21.0× | 0.163 | SLC25A4 |
| Formation of the dystrophin-glycoprotein complex (DGC) | 1 | 19.3× | 0.163 | DMD |
| Meiosis | 1 | 17.8× | 0.163 | SYNE2 |
| Sensory perception of sweet, bitter, and umami (glutamate) taste | 1 | 17.4× | 0.163 | TRPM4 |
| NCAM signaling for neurite out-growth | 1 | 17.0× | 0.163 | CACNA1C |
| Transport of vitamins, nucleosides, and related molecules | 1 | 17.0× | 0.163 | SLC25A4 |
| Smooth Muscle Contraction | 1 | 16.6× | 0.163 | DYSF |
| RND1 GTPase cycle | 1 | 16.6× | 0.163 | DSP |
| RND3 GTPase cycle | 1 | 16.2× | 0.163 | DSP |
| Centrosome maturation | 1 | 15.9× | 0.163 | AKAP9 |
| NCAM1 interactions | 1 | 15.5× | 0.163 | CACNA1C |
| Oncogenic MAPK signaling | 1 | 15.5× | 0.163 | AKAP9 |
| Keratinization | 2 | 7.0× | 0.163 | DSG2, DSP |
| Regulation of insulin secretion | 1 | 13.7× | 0.174 | CACNA1C |
| Cell Cycle | 2 | 4.5× | 0.174 | SYNE2, AKAP9 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 20 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| cardiac muscle contraction | 7 | 140.4× | 5e-12 | TNNI3, TNNT2, TTN, DMD, MYH6, MYH7, MYL3 |
| muscle filament sliding | 5 | 263.3× | 5e-10 | TNNI3, TNNT2, TTN, MYH6, MYH7 |
| sarcomere organization | 6 | 114.9× | 5e-10 | TNNT2, TTN, MYOZ2, MYPN, FLNC, MYH6 |
| ventricular cardiac muscle tissue morphogenesis | 5 | 175.5× | 3e-09 | TNNI3, TNNT2, MYH6, MYH7, MYL3 |
| regulation of ventricular cardiac muscle cell action potential | 4 | 280.9× | 3e-08 | CACNA1C, TRPM4, DSG2, DSP |
| regulation of heart rate by cardiac conduction | 5 | 93.6× | 5e-08 | CACNA1C, TRPM4, DSG2, DSP, AKAP9 |
| regulation of the force of heart contraction | 3 | 148.7× | 3e-05 | MYH6, MYH7, MYL3 |
| striated muscle contraction | 3 | 126.4× | 4e-05 | TTN, MYH6, MYH7 |
| muscle contraction | 4 | 41.6× | 5e-05 | TTN, MYH6, MYH7, MYL3 |
| skeletal muscle contraction | 3 | 76.6× | 1e-04 | TNNI3, TTN, MYH7 |
| regulation of heart rate | 3 | 70.2× | 2e-04 | DMD, MYH6, MYH7 |
| membrane depolarization during AV node cell action potential | 2 | 337.0× | 2e-04 | CACNA1C, TRPM4 |
| bundle of His cell-Purkinje myocyte adhesion involved in cell communication | 2 | 240.7× | 4e-04 | DSG2, DSP |
| desmosome organization | 2 | 210.7× | 5e-04 | DSG2, DSP |
| skeletal muscle tissue development | 3 | 43.6× | 5e-04 | MYOZ2, DMD, MYL3 |
| negative regulation of ATP-dependent activity | 2 | 168.5× | 7e-04 | TNNI3, TNNT2 |
| adult heart development | 2 | 120.4× | 0.001 | MYH6, MYH7 |
| cardiac muscle hypertrophy in response to stress | 2 | 105.3× | 0.002 | MYH6, MYH7 |
| regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | 2 | 67.4× | 0.004 | CACNA1C, DMD |
| cardiac muscle cell development | 2 | 62.4× | 0.004 | TTN, MYH6 |
| regulation of heart contraction | 2 | 49.6× | 0.007 | TNNT2, MYH6 |
| ATP metabolic process | 2 | 46.8× | 0.007 | MYH6, MYH7 |
| monocyte activation involved in immune response | 1 | 842.6× | 0.008 | DYSF |
| visceral muscle development | 1 | 842.6× | 0.008 | MYH6 |
| regulation of muscle system process | 1 | 842.6× | 0.008 | DMD |
| regulation of cellular response to growth factor stimulus | 1 | 842.6× | 0.008 | DMD |
| positive regulation of atrial cardiac muscle cell action potential | 1 | 842.6× | 0.008 | TRPM4 |
| positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization | 1 | 842.6× | 0.008 | TRPM4 |
| response to calcium ion | 2 | 31.8× | 0.012 | TNNT2, TTN |
| regulation of systemic arterial blood pressure by ischemic conditions | 1 | 421.3× | 0.013 | TNNI3 |
Therapeutics
Drug target analysis
Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 21
Druggability breadth: 12 of 22 evidence-associated genes (55%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Genes with an approved drug
The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.
| Symbol | Example approved molecule |
|---|---|
| CACNA1C | REMIFENTANIL |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| CACNA1C | 85 | 4 |
| SLC25A4 | 0 | 0 |
| TNNI3 | 0 | 0 |
| TNNT2 | 0 | 0 |
| TTN | 0 | 0 |
| MYOZ2 | 0 | 0 |
| SYNE2 | 0 | 0 |
| TRPM4 | 0 | 0 |
| CALR3 | 0 | 0 |
| MYPN | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| REMIFENTANIL | 4 | CACNA1C |
| BEPRIDIL | 4 | CACNA1C |
| CLOTRIMAZOLE | 4 | CACNA1C |
| PROPIVERINE | 4 | CACNA1C |
| DIBUCAINE | 4 | CACNA1C |
| IMIPRAMINE | 4 | CACNA1C |
| DULOXETINE | 4 | CACNA1C |
| QUINIDINE | 4 | CACNA1C |
| ESTRADIOL | 4 | CACNA1C |
| TOLTERODINE | 4 | CACNA1C |
| PIMOZIDE | 4 | CACNA1C |
| NIMODIPINE | 4 | CACNA1C |
| NICARDIPINE | 4 | CACNA1C |
| AMLODIPINE | 4 | CACNA1C |
| VARDENAFIL | 4 | CACNA1C |
| CLEMASTINE | 4 | CACNA1C |
| ISRADIPINE | 4 | CACNA1C |
| TERFENADINE | 4 | CACNA1C |
| NISOLDIPINE | 4 | CACNA1C |
| SOLIFENACIN | 4 | CACNA1C |
| PINAVERIUM | 4 | CACNA1C |
| SILDENAFIL | 4 | CACNA1C |
| NIFEDIPINE | 4 | CACNA1C |
| XANOMELINE | 4 | CACNA1C |
| DILTIAZEM | 4 | CACNA1C |
| PRENYLAMINE | 4 | CACNA1C |
| OLICERIDINE | 4 | CACNA1C |
| PROPRANOLOL | 4 | CACNA1C |
| ALVIMOPAN | 4 | CACNA1C |
| ASTEMIZOLE | 4 | CACNA1C |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 1.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| CACNA1C | 575 | Binding:319, Functional:211, Toxicity:26, ADMET:19 |
| TRPM4 | 14 | Binding:13, Functional:1 |
| MT-ND1 | 5 | Binding:5 |
| TNNI3 | 2 | Binding:2 |
| TNNT2 | 2 | Binding:2 |
| DSP | 2 | Binding:2 |
| SLC25A4 | 1 | Binding:1 |
| TTN | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| TTN | 2.7.11.1 | non-specific serine/threonine protein kinase |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| CACNA1C | 575 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 20; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
30 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.
| Compound | Max phase | Cohort target (bioactivity) |
|---|---|---|
| REMIFENTANIL | 4 | CACNA1C |
| BEPRIDIL | 4 | CACNA1C |
| CLOTRIMAZOLE | 4 | CACNA1C |
| PROPIVERINE | 4 | CACNA1C |
| DIBUCAINE | 4 | CACNA1C |
| IMIPRAMINE | 4 | CACNA1C |
| DULOXETINE | 4 | CACNA1C |
| QUINIDINE | 4 | CACNA1C |
| ESTRADIOL | 4 | CACNA1C |
| TOLTERODINE | 4 | CACNA1C |
| PIMOZIDE | 4 | CACNA1C |
| NIMODIPINE | 4 | CACNA1C |
| NICARDIPINE | 4 | CACNA1C |
| AMLODIPINE | 4 | CACNA1C |
| VARDENAFIL | 4 | CACNA1C |
| CLEMASTINE | 4 | CACNA1C |
| ISRADIPINE | 4 | CACNA1C |
| TERFENADINE | 4 | CACNA1C |
| NISOLDIPINE | 4 | CACNA1C |
| SOLIFENACIN | 4 | CACNA1C |
| PINAVERIUM | 4 | CACNA1C |
| SILDENAFIL | 4 | CACNA1C |
| NIFEDIPINE | 4 | CACNA1C |
| XANOMELINE | 4 | CACNA1C |
| DILTIAZEM | 4 | CACNA1C |
| PRENYLAMINE | 4 | CACNA1C |
| OLICERIDINE | 4 | CACNA1C |
| PROPRANOLOL | 4 | CACNA1C |
| ALVIMOPAN | 4 | CACNA1C |
| ASTEMIZOLE | 4 | CACNA1C |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 1 | CACNA1C |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 3 | TTN, TRPM4, FLNC |
| D | Druggable family + AlphaFold only, no drug | 1 | MYPN |
| E | Difficult family or no structure, no drug | 17 | SLC25A4, TNNI3, TNNT2, MYOZ2, SYNE2, CALR3, DMD, DSG2, DSP, DYSF (+7 more) |
Undrugged target profiles
21 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| SLC25A4 | 1 | — |
| TNNI3 | 2 | — |
| TNNT2 | 2 | — |
| TTN | 1 | — |
| MYOZ2 | 0 | — |
| SYNE2 | 0 | — |
| TRPM4 | 14 | — |
| CALR3 | 0 | — |
| MYPN | 0 | — |
| DMD | 0 | — |
| DSG2 | 0 | — |
| DSP | 2 | — |
| DYSF | 0 | — |
| FLNC | 0 | — |
| AKAP9 | 0 | — |
| MHRT | 0 | — |
| FLNC-AS1 | 0 | — |
| MT-ND1 | 5 | — |
| MYH6 | 0 | — |
| MYH7 | 0 | — |
| MYL3 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 12.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 12 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT02432092 | Not specified | RECRUITING | Pediatric Cardiomyopathy Mutation Analysis |
| NCT03479580 | Not specified | RECRUITING | Coronary Artery Disease and Coronary Microvascular Disease in Cardiomyopathies Registry |
| NCT03527342 | Not specified | ENROLLING_BY_INVITATION | Sahlgrenska Cardiomyopathy Project |
| NCT06607471 | Not specified | RECRUITING | Multimodal and Multidisciplinary Approach to Optimize Diagnostic, Prognostic, and Therapeutic Management of Patients with Non-ischemic Cardiomyopathies and Arrhythmogenic-inflammatory Phenotypes: a Multicenter, Observational, Retrospective and Prospective Registry Study. |
| NCT06748261 | Not specified | NOT_YET_RECRUITING | AI-enabled Screening and Diagnosis of Cardiomyopathies Using Coronary CTA |
| NCT06794710 | Not specified | NOT_YET_RECRUITING | Early Identification and Treatment of Rare Cardiomyopathy Cohorts |
| NCT00703443 | Not specified | WITHDRAWN | The Genetics of Cardiomyopathy and Heart Failure |
| NCT01873963 | Not specified | COMPLETED | Genotype-Phenotype Associations in Pediatric Cardiomyopathy (PCM GENES) |
| NCT03061994 | Not specified | UNKNOWN | Metabolomic Study of All-age Cardiomyopathy |
| NCT03076580 | Not specified | UNKNOWN | An Integrative-Omics Study of Cardiomyopathy Patients for Diagnosis and Prognosis in China |
| NCT03572569 | Not specified | UNKNOWN | Risk Stratification in Children and Adolescents With Primary Cardiomyopathy |
| NCT04712136 | Not specified | COMPLETED | Healthy-related Quality of Life and Physical Activity of Children With Cardiac Malformations |