Mitral valve insufficiency

Summary

Mitral valve insufficiency (MONDO:1030008) is a disease with 4 cohort genes and 130 clinical trials. Top therapeutic interventions include isoflurane, captopril, and ertugliflozin.

At a glance

• Cohort genes: 4
• ClinVar variants: 7
• Clinical trials: 130

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitral valve insufficiency
Mondo ID	MONDO:1030008
MeSH	D008944
DOID	DOID:11502
ICD-11	637470326
NCIT	C50888
UMLS	C0026266
MedGen	7670
Is cancer (heuristic)	no

Also known as: congenital insufficiency of mitral valve · congenital mitral insufficiency · congenital mitral regurgitation · insufficiency, mitral · mitral insufficiency · mitral valve incompetence · mitral valve insufficiency/ regurgitation

Data availability: 7 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart valve disorder › mitral valve disorder › mitral valve insufficiency

Related subtypes (6): mitral valve prolapse, mitral valve stenosis, congenital anomaly of the mitral subvalvular apparatus, mitral atresia disorder, inherited mitral valve disease, rheumatic disease of mitral valve

Subtypes (1): congenital mitral valve insufficiency

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

7 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 likely pathogenic, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267941	46;XY;inv(6)(p22q13)dn		Pathogenic	criteria provided, single submitter
374203	NM_000138.5(FBN1):c.478T>C (p.Cys160Arg)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
495227	NM_181486.4(TBX5):c.1221C>G (p.Tyr407Ter)	TBX5	Pathogenic	criteria provided, single submitter
1684630	NC_000017.11:g.8117792_8126946del	TRG-GCC2-6	Pathogenic	criteria provided, single submitter
374081	NM_000138.5(FBN1):c.8016T>G (p.Cys2672Trp)	FBN1	Likely pathogenic	criteria provided, single submitter
374162	NM_002474.3(MYH11):c.4360G>C (p.Asp1454His)	MYH11	Likely pathogenic	criteria provided, single submitter
267889	46;XX;inv(14)(q24.1q32.1)dn		Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 17 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBX5	Orphanet:101016	Romano-Ward syndrome
TBX5	Orphanet:392	Holt-Oram syndrome
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia
MYH11	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYH11	Orphanet:229	Familial aortic dissection
MYH11	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
MYH11	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBX5	HGNC:11604	ENSG00000089225	Q99593	T-box transcription factor TBX5	clinvar
TRG-GCC2-6	HGNC:12273			tRNA-Gly (anticodon GCC) 2-6	clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	clinvar
MYH11	HGNC:7569	ENSG00000133392	P35749	Myosin-11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX5	T-box transcription factor TBX5	DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.
MYH11	Myosin-11	Muscle contraction.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.0

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
Scaffold/PPI	1	4.3×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX5	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TRG-GCC2-6	Other/Unknown	no
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
MYH11	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail

Expression context

Cohort genes with no expression data: 1.

3 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)	3
unknown	1

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cardiac muscle of right atrium	1
tendon of biceps brachii	1
decidua	1
skin of hip	1
synovial joint	1
lower esophagus	1
lower esophagus muscularis layer	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX5	129	broad	marker	tendon of biceps brachii, cardiac muscle of right atrium, buccal mucosa cell
TRG-GCC2-6
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua
MYH11	143	broad	marker	right coronary artery, lower esophagus, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH11	3,818
FBN1	3,640
TBX5	2,250
TRG-GCC2-6	0

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBN1	P35555	11
TBX5	Q99593	4
MYH11	P35749	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. Enrichment computed across 4 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
Muscle contraction	2	51.4×	0.016	TBX5, MYH11
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	253.8×	0.020	TBX5
Sema4D in semaphorin signaling	1	223.9×	0.020	MYH11
Physiological factors	1	223.9×	0.020	TBX5
RHO GTPases activate CIT	1	200.3×	0.020	MYH11
RHO GTPases Activate ROCKs	1	200.3×	0.020	MYH11
Sema4D induced cell migration and growth-cone collapse	1	190.3×	0.020	MYH11
RHO GTPases activate PAKs	1	181.3×	0.020	MYH11
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	181.3×	0.020	MYH11
Cardiogenesis	1	141.0×	0.020	TBX5
Semaphorin interactions	1	131.3×	0.020	MYH11
EPHA-mediated growth cone collapse	1	126.9×	0.020	MYH11
Elastic fibre formation	1	112.0×	0.020	FBN1
TGF-beta receptor signaling activates SMADs	1	108.8×	0.020	FBN1
RHO GTPases activate PKNs	1	105.7×	0.020	MYH11
Molecules associated with elastic fibres	1	102.9×	0.020	FBN1
Smooth Muscle Contraction	1	88.5×	0.022	MYH11
Developmental Biology	2	9.6×	0.025	TBX5, MYH11
EPH-Ephrin signaling	1	55.2×	0.031	MYH11
Integrin cell surface interactions	1	44.8×	0.037	FBN1
Degradation of the extracellular matrix	1	39.2×	0.040	FBN1
Cardiac conduction	1	36.2×	0.041	TBX5
Post-translational protein phosphorylation	1	33.4×	0.043	FBN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.047	FBN1
RHO GTPase Effectors	1	22.7×	0.057	MYH11
Axon guidance	1	15.1×	0.083	MYH11
Nervous system development	1	14.3×	0.083	MYH11
Signaling by Rho GTPases	1	11.4×	0.099	MYH11
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.099	MYH11
RNA Polymerase II Transcription	1	7.5×	0.140	TBX5

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell migration involved in coronary vasculogenesis	1	5617.3×	0.003	TBX5
positive regulation of cardiac conduction	1	5617.3×	0.003	TBX5
cardiac left ventricle formation	1	2808.7×	0.003	TBX5
atrioventricular node cell fate commitment	1	2808.7×	0.003	TBX5
bundle of His cell to Purkinje myocyte communication by electrical coupling	1	2808.7×	0.003	TBX5
positive regulation of cell communication by electrical coupling involved in cardiac conduction	1	2808.7×	0.003	TBX5
atrioventricular bundle cell differentiation	1	1872.4×	0.003	TBX5
skeletal muscle myosin thick filament assembly	1	1872.4×	0.003	MYH11
post-embryonic eye morphogenesis	1	1872.4×	0.003	FBN1
positive regulation of secondary heart field cardioblast proliferation	1	1872.4×	0.003	TBX5
bundle of His development	1	1404.3×	0.003	TBX5
obsolete sequestering of BMP in extracellular matrix	1	1404.3×	0.003	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	1404.3×	0.003	FBN1
positive regulation of cardioblast differentiation	1	1404.3×	0.003	TBX5
atrioventricular node cell development	1	1404.3×	0.003	TBX5
heart development	2	52.5×	0.003	TBX5, FBN1
negative regulation of osteoclast development	1	1123.5×	0.003	FBN1
positive regulation of gap junction assembly	1	802.5×	0.004	TBX5
sinoatrial node development	1	702.2×	0.004	TBX5
forelimb morphogenesis	1	702.2×	0.004	TBX5
pericardium development	1	624.1×	0.004	TBX5
negative regulation of cardiac muscle cell proliferation	1	624.1×	0.004	TBX5
regulation of atrial cardiac muscle cell membrane depolarization	1	624.1×	0.004	TBX5
embryonic eye morphogenesis	1	510.7×	0.005	FBN1
elastic fiber assembly	1	510.7×	0.005	MYH11
endocardial cushion development	1	468.1×	0.005	TBX5
atrial septum morphogenesis	1	432.1×	0.005	TBX5
cellular response to insulin-like growth factor stimulus	1	432.1×	0.005	FBN1
atrioventricular valve morphogenesis	1	401.2×	0.005	TBX5
smooth muscle contraction	1	267.5×	0.007	MYH11

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Ertugliflozin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Cyproheptadine.

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TBX5	0	0
TRG-GCC2-6	0	0
FBN1	0	0
MYH11	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TBX5	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	TBX5, TRG-GCC2-6, FBN1, MYH11

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBX5	1	—
TRG-GCC2-6	0	—
FBN1	0	—
MYH11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 130.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	111
PHASE4	7
PHASE2	4
PHASE1	4
PHASE3	3
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01074671	PHASE4	COMPLETED	CG Future® Annuloplasty Ring/Band Clinical Trial
NCT01201070	PHASE4	UNKNOWN	Study of Administration Of Antithrombin in Patients With Low Plasmatic Levels of Antithrombin After Cardiac Surgery
NCT01368575	PHASE4	UNKNOWN	Surgical Treatment of Ischemic Mitral Regurgitation
NCT01641614	PHASE4	COMPLETED	Beating Versus Arrested Heart for Mitral Valve Replacement
NCT02180893	PHASE4	COMPLETED	The Use of Paravertebral Block for Cardiac Surgery
NCT02534155	PHASE4	TERMINATED	High and Intermediate Risk Degenerative Mitral Regurgitation Treatment: A Trial Comparing MitraClip® to Surgical Therapy
NCT02687932	PHASE4	COMPLETED	Pharmacological Reduction of Functional, Ischemic Mitral REgurgitation
NCT00608140	PHASE3	TERMINATED	Effectiveness of Surgical Mitral Valve Repair Versus Medical Treatment for People With Significant Mitral Regurgitation and Non-ischemic Congestive Heart Failure
NCT04231331	PHASE3	COMPLETED	Ertugliflozin for Functional Mitral Regurgitation
NCT05696509	PHASE3	COMPLETED	Influence of Anesthetics on Clinical Outcome in Mitral and Aortic Valve Replacement in Adults
NCT00082121	PHASE2	COMPLETED	Safety and Efficacy of TP10, a Complement Inhibitor, in Adult Women Undergoing Cardiopulmonary Bypass Surgery
NCT00209339	PHASE1/PHASE2	COMPLETED	Feasibility Study of a Percutaneous Mitral Valve Repair System.
NCT00348829	PHASE2	TERMINATED	Mitral Valve Reconstruction in Chronic Heart Failure (CHF): Identification of Predictors for a Successful Therapy
NCT00807040	PHASE2	COMPLETED	Comparing the Effectiveness of Repairing Versus Replacing the Heart’s Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation
NCT00903370	PHASE2	COMPLETED	Surgical Ablation Versus No Surgical Ablation for Patients With Atrial Fibrillation Undergoing Mitral Valve Surgery
NCT00512005	PHASE1	UNKNOWN	VIVID - Valvular and Ventricular Improvement Via iCoapsys Delivery - Feasibility Study
NCT00700947	PHASE1	TERMINATED	Using Beta Blockers to Treat Mitral Regurgitation
NCT05695287	PHASE1	COMPLETED	The Effects of Sevoflurane, Isoflurane and Propofol During Cardiac Surgery
NCT05742789	PHASE1	COMPLETED	Effect of Anesthetics on Troponin I and С-reactive Protein
NCT02322840	Not specified	ACTIVE_NOT_RECRUITING	Transcatheter Mitral Valve Replacement System (TMVR) Pilot Study and The Early Feasibility Study of the TMVR Transseptal System
NCT02803957	Not specified	ACTIVE_NOT_RECRUITING	Randomized Trial of the Neochord DS1000 System Versus Open Surgical Repair
NCT03066050	Not specified	ACTIVE_NOT_RECRUITING	Long Term Follow Up for CTSN Mitral Valve Repair Studies
NCT03142152	Not specified	RECRUITING	The EMPOWER Trial - The Carillon Mitral Contour System® in Treating Heart Failure With FMR
NCT03193801	Not specified	ACTIVE_NOT_RECRUITING	PARTNER 3 Trial - Mitral Valve in Valve
NCT03433274	Not specified	ACTIVE_NOT_RECRUITING	Clinical Trial to Evaluate the Safety and Effectiveness of Using the Tendyne Transcatheter Mitral Valve System for the Treatment of Symptomatic Mitral Regurgitation
NCT03470246	Not specified	RECRUITING	Personalized Activity Intervention in Rehabilitation After Cardiac Operations (the PACO Trial)
NCT03706833	Not specified	ACTIVE_NOT_RECRUITING	Edwards PASCAL CLASP IID/IIF Pivotal Clinical Trial
NCT03962023	Not specified	RECRUITING	Prognostic Impact of Imaging Parameters in Patients With Primary Mitral Insufficiency by Prolapse (COHORTE-IM)
NCT04153292	Not specified	RECRUITING	The ENCIRCLE Trial
NCT04190602	Not specified	RECRUITING	Multicenter Post-Market Observational Registry of the NeoChord Artificial Chordae Delivery System
NCT04343313	Not specified	RECRUITING	The Half Moon Transcatheter Mitral Valve Repair (TMVr) Pilot Study
NCT04430075	Not specified	RECRUITING	MiCLASP Post Market Clinical Follow-Up (PMCF) Study
NCT04822675	Not specified	ACTIVE_NOT_RECRUITING	REvascularization and Valve Intervention for Ischemic Valve diseasE: REVIVE Trial
NCT05508438	Not specified	NOT_YET_RECRUITING	To Evaluate the Efficacy and Safety of the Transfemoral Mitral Valve Repair System in the Treatment of Patients With Moderately Severe and Severe Functional Mitral Regurgitation(FMR) Who Remained Clinically Symptomatic After Guideline-directed Medical Treatment
NCT05526560	Not specified	ACTIVE_NOT_RECRUITING	Real-world Clinical Outcomes of the MITRIS RESILIA Mitral Valve
NCT05625607	Not specified	RECRUITING	Polish Transcatheter Transfemoral Mitral Valve-in-Valve Implantation (Mitral ViV) Registry
NCT05927441	Not specified	RECRUITING	DragonFly EU Pivotal Study
NCT06235385	Not specified	RECRUITING	European Association of Cardiovascular Imaging Multiple and Mixed Valvular Disease Study
NCT06377449	Not specified	RECRUITING	Influence of Lung Ultrasonography on the Prognosis and Postoperative Outcomes in Cardiac Surgical Patients
NCT06465745	Not specified	RECRUITING	AltaValve Pivotal Trial

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ISOFLURANE	4	3
CAPTOPRIL	4	2
ERTUGLIFLOZIN	4	2
TORSEMIDE	4	2
VALSARTAN	4	1
ANTITHROMBIN III HUMAN	3	1
CHEMBL115622	0	1