Polyvalvular heart disease syndrome

Summary

Polyvalvular heart disease syndrome (MONDO:0016460) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0001634	Mitral valve prolapse	Very frequent (80-99%)
HP:0001654	Abnormal heart valve morphology	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000268	Dolichocephaly	Frequent (30-79%)
HP:0000276	Long face	Frequent (30-79%)
HP:0000322	Short philtrum	Frequent (30-79%)
HP:0000337	Broad forehead	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000377	Abnormal pinna morphology	Frequent (30-79%)
HP:0000448	Prominent nose	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000678	Dental crowding	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0000951	Abnormality of the skin	Occasional (5-29%)
HP:0001642	Pulmonic stenosis	Occasional (5-29%)
HP:0001650	Aortic valve stenosis	Occasional (5-29%)
HP:0001699	Sudden death	Occasional (5-29%)
HP:0005180	Tricuspid regurgitation	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	polyvalvular heart disease syndrome
Mondo ID	MONDO:0016460
Orphanet	228410
SNOMED CT	723448007
UMLS	C4509918
MedGen	1376905
GARD	0020594
Is cancer (heuristic)	no

Also known as: PHD syndrome

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › polyvalvular heart disease syndrome

Related subtypes (33): endocardium disorder, pericardium disorder, cardiac tuberculosis, heart conduction disease, hypertensive heart disease, heart valve disorder, cardiomyopathy, coronary artery disorder, heart failure, congenital heart disease, heart aneurysm, rheumatic heart disease, cardiac rhythm disease, white forelock with malformations, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, microcephaly-cardiac defect-lung malsegmentation syndrome, PHACE syndrome, microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, cardiac anomalies-heterotaxy syndrome, Thomas syndrome, 22q11.2 deletion syndrome, myocardial rupture, heart neoplasm, aortopulmonary window, cor biloculare, inflammation of heart layer, myocardial disorder, carcinoid heart disease, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, coronary microvascular disorder, cardiac ventricle disorder, cardiogenetic disease, cardiogenic shock

Subtypes (2): cardiac anomalies-short stature-joint hypermobility-facial dysmorphism syndrome due to TAB2 mutation, 6q25.1 microdeletion syndrome

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030404	NM_001292034.3(TAB2):c.1764+1G>A	TAB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TAB2	Definitive	Autosomal dominant	congenital heart defects, multiple types, 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TAB2	Orphanet:664401	Cardiac anomalies-short stature-joint hypermobility-facial dysmorphism syndrome due to TAB2 mutation
TAB2	Orphanet:664404	6q25.1 microdeletion syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TAB2	HGNC:17075	ENSG00000055208	Q9NYJ8	TGF-beta-activated kinase 1 and MAP3K7-binding protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TAB2	TGF-beta-activated kinase 1 and MAP3K7-binding protein 2	Adapter required to activate the JNK and NF-kappa-B signaling pathways through the specific recognition of ‘Lys-63’-linked polyubiquitin chains by its RanBP2-type zinc finger (NZF).

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TAB2	Transcription factor	no		Znf_RanBP2, CUE, Znf_RanBP2_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	1
parotid gland	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TAB2	293	ubiquitous	marker	parotid gland, ventricular zone, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TAB2	2,606

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TAB2	Q9NYJ8	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 55. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
IRAK2 mediated activation of TAK1 complex	1	1142.0×	0.010	TAB2
TICAM1,TRAF6-dependent induction of TAK1 complex	1	1038.2×	0.010	TAB2
Alpha-protein kinase 1 signaling pathway	1	1038.2×	0.010	TAB2
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	1	761.3×	0.010	TAB2
TRAF6-mediated induction of TAK1 complex within TLR4 complex	1	713.8×	0.010	TAB2
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	1	519.1×	0.010	TAB2
TCR signaling	1	496.5×	0.010	TAB2
activated TAK1 mediates p38 MAPK activation	1	496.5×	0.010	TAB2
TNF signaling	1	423.0×	0.010	TAB2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	356.9×	0.010	TAB2
Nuclear signaling by ERBB4	1	346.1×	0.010	TAB2
TNFR1-induced NF-kappa-B signaling pathway	1	335.9×	0.010	TAB2
NOD1/2 Signaling Pathway	1	317.2×	0.010	TAB2
MAP kinase activation	1	308.6×	0.010	TAB2
TAK1-dependent IKK and NF-kappa-B activation	1	300.5×	0.010	TAB2
Signaling by ERBB4	1	271.9×	0.010	TAB2
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.010	TAB2
Interleukin-1 family signaling	1	271.9×	0.010	TAB2
Interleukin-17 signaling	1	253.8×	0.010	TAB2
C-type lectin receptors (CLRs)	1	237.9×	0.010	TAB2
Toll Like Receptor 10 (TLR10) Cascade	1	215.5×	0.010	TAB2
Toll Like Receptor 5 (TLR5) Cascade	1	215.5×	0.010	TAB2
MyD88 cascade initiated on plasma membrane	1	203.9×	0.010	TAB2
Toll Like Receptor 3 (TLR3) Cascade	1	193.6×	0.010	TAB2
TRIF (TICAM1)-mediated TLR4 signaling	1	190.3×	0.010	TAB2
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	190.3×	0.010	TAB2
MyD88 dependent cascade initiated on endosome	1	190.3×	0.010	TAB2
MyD88-independent TLR4 cascade	1	184.2×	0.010	TAB2
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	184.2×	0.010	TAB2
Toll Like Receptor 9 (TLR9) Cascade	1	175.7×	0.010	TAB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
non-canonical NF-kappaB signal transduction	1	842.6×	0.006	TAB2
positive regulation of protein kinase activity	1	674.1×	0.006	TAB2
negative regulation of autophagy	1	259.3×	0.010	TAB2
response to lipopolysaccharide	1	124.8×	0.015	TAB2
defense response to bacterium	1	108.0×	0.015	TAB2
heart development	1	78.8×	0.016	TAB2
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	TAB2
inflammatory response	1	37.7×	0.027	TAB2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TAB2	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
TAB2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	TAB2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TAB2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.