Platelet-type bleeding disorder 8

Summary

Platelet-type bleeding disorder 8 (MONDO:0012354) is a disease caused by P2RY12 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: P2RY12 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	platelet-type bleeding disorder 8
Mondo ID	MONDO:0012354
MeSH	C565220
OMIM	609821
Orphanet	36355
DOID	DOID:0060692
SNOMED CT	725291001
UMLS	C1853278
MedGen	344008
GARD	0012478
Is cancer (heuristic)	no

Also known as: BDPLT8 · bleeding disorder, platelet-type 8 · bleeding disorder, platelet-type, 8 · platelet-type bleeding disorder 8

Data availability: 11 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › hemorrhagic disease › inherited bleeding disorder, platelet-type › platelet-type bleeding disorder 8

Related subtypes (27): gray platelet syndrome, primary release disorder of platelets, platelet-type von Willebrand disease, platelet-type bleeding disorder 16, platelet-type bleeding disorder 17, Ehlers-Danlos syndrome, fibronectinemic type, Bernard-Soulier syndrome, Scott syndrome, congenital thrombotic thrombocytopenic purpura, Quebec platelet disorder, platelet-type bleeding disorder 12, platelet-type bleeding disorder 10, platelet-type bleeding disorder 14, platelet-type bleeding disorder 9, platelet-type bleeding disorder 11, platelet-type bleeding disorder 15, platelet-type bleeding disorder 18, platelet-type bleeding disorder 19, platelet-type bleeding disorder 20, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder, bleeding disorder, platelet-type, 24, bleeding disorder, platelet-type, 22, bleeding disorder, platelet-type, 21, Glanzmann thrombasthenia, bleeding diathesis due to thromboxane synthesis deficiency, bleeding disorder, platelet-type, 25

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

11 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 1 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 benign, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
9081	NM_022788.5(P2RY12):c.717_718del (p.Ile240fs)	MED12L	Pathogenic	no assertion criteria provided
548443	NM_022788.5(P2RY12):c.794G>C (p.Arg265Pro)	P2RY12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572656	NM_022788.5(P2RY12):c.662dup (p.Arg222fs)	P2RY12	Likely pathogenic	criteria provided, single submitter
2572166	NM_022788.5(P2RY12):c.469_470del (p.Leu157fs)	MED12L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2434536	NM_022788.5(P2RY12):c.160C>T (p.Arg54Trp)	MED12L	Uncertain significance	criteria provided, multiple submitters, no conflicts
4075415	NM_022788.5(P2RY12):c.326A>T (p.Tyr109Phe)	MED12L	Uncertain significance	criteria provided, single submitter
9082	NM_022788.5(P2RY12):c.767G>A (p.Arg256Gln)	MED12L	Uncertain significance	criteria provided, multiple submitters, no conflicts
988856	NM_022788.5(P2RY12):c.772C>A (p.Pro258Thr)	MED12L	Uncertain significance	criteria provided, single submitter
8750	NM_002558.4(P2RX1):c.1053GCT[2] (p.Leu354del)	P2RX1	Uncertain significance	no assertion criteria provided
9083	NM_022788.5(P2RY12):c.793C>T (p.Arg265Trp)	P2RY12	Uncertain significance	criteria provided, multiple submitters, no conflicts
261633	NM_022788.5(P2RY12):c.36T>G (p.Gly12=)	P2RY12	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
P2RY12	Strong	Autosomal recessive	platelet-type bleeding disorder 8	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
P2RY12	Orphanet:36355	Bleeding disorder due to P2Y12 defect
MED12L	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
P2RY12	HGNC:18124	ENSG00000169313	Q9H244	P2Y purinoceptor 12	gencc,clinvar
MED12L	HGNC:16050	ENSG00000144893	Q86YW9	Mediator of RNA polymerase II transcription subunit 12-like protein	clinvar
P2RX1	HGNC:8533	ENSG00000108405	P51575	P2X purinoceptor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
P2RY12	P2Y purinoceptor 12	Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system.
MED12L	Mediator of RNA polymerase II transcription subunit 12-like protein	May be a component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
P2RX1	P2X purinoceptor 1	ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and with relatively high calcium permeability.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
GPCR	1	8.0×	0.240
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
P2RY12	GPCR	yes		GPCR_Rhodpsn, P2Y12_rcpt, GPCR_Rhodpsn_7TM
MED12L	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
P2RX1	Other/Unknown	no		P2X_purnocptor, P2X1_purnocptor, P2X_extracellular_dom_sf

Expression context

Cohort genes with no expression data: 0.

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	0

Top tissues across cohort

Tissue	Cohort genes
inferior vagus X ganglion	1
superior vestibular nucleus	1
ventral tegmental area	1
adrenal tissue	1
leukocyte	1
monocyte	1
popliteal artery	1
saphenous vein	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
P2RY12	204	broad	marker	inferior vagus X ganglion, superior vestibular nucleus, ventral tegmental area
MED12L	160	broad	marker	monocyte, leukocyte, adrenal tissue
P2RX1	171	broad	marker	popliteal artery, tibial artery, saphenous vein

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
P2RY12	1,834
P2RX1	1,613
MED12L	1,199

Intra-cohort edges

A	B	Sources
P2RX1	P2RY12	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
P2RX1	P51575	7
P2RY12	Q9H244	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MED12L	Q86YW9	66.04

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
P2Y receptors	1	475.8×	0.008	P2RY12
Elevation of cytosolic Ca2+ levels	1	356.9×	0.008	P2RX1
ADP signalling through P2Y purinoceptor 12	1	248.3×	0.008	P2RY12
Platelet homeostasis	1	139.3×	0.011	P2RX1
G alpha (i) signalling events	1	19.5×	0.061	P2RY12
Neutrophil degranulation	1	11.5×	0.085	P2RX1

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
platelet activation	2	178.3×	0.002	P2RY12, P2RX1
visual system development	1	5617.3×	0.002	P2RY12
monoatomic ion transport	2	104.0×	0.002	P2RY12, P2RX1
positive regulation of integrin activation by cell surface receptor linked signal transduction	1	2808.7×	0.003	P2RY12
regulation of microglial cell migration	1	2808.7×	0.003	P2RY12
serotonin secretion by platelet	1	1872.4×	0.004	P2RX1
insemination	1	1404.3×	0.004	P2RX1
cerebral cortex radial glia-guided migration	1	1404.3×	0.004	P2RY12
regulation of vascular associated smooth muscle contraction	1	1123.5×	0.004	P2RX1
positive regulation of monoatomic ion transport	1	1123.5×	0.004	P2RY12
regulation of chemotaxis	1	936.2×	0.004	P2RY12
positive regulation of microglial cell migration	1	936.2×	0.004	P2RY12
regulation of presynaptic cytosolic calcium ion concentration	1	624.1×	0.005	P2RX1
hemostasis	1	561.7×	0.005	P2RY12
positive regulation of calcium ion import across plasma membrane	1	561.7×	0.005	P2RX1
substrate-dependent cell migration, cell extension	1	510.7×	0.005	P2RY12
positive regulation of cell adhesion mediated by integrin	1	351.1×	0.006	P2RY12
response to ATP	1	330.4×	0.006	P2RX1
positive regulation of ruffle assembly	1	330.4×	0.006	P2RY12
cellular response to ATP	1	295.6×	0.007	P2RY12
positive regulation of chemotaxis	1	280.9×	0.007	P2RY12
response to axon injury	1	170.2×	0.011	P2RY12
neuronal action potential	1	160.5×	0.011	P2RX1
regulation of synaptic vesicle exocytosis	1	151.8×	0.011	P2RX1
lamellipodium assembly	1	147.8×	0.011	P2RY12
ceramide biosynthetic process	1	140.4×	0.011	P2RX1
cell projection organization	1	124.8×	0.012	P2RY12
synaptic transmission, glutamatergic	1	119.5×	0.012	P2RX1
platelet aggregation	1	112.3×	0.012	P2RY12
regulation of blood pressure	1	73.9×	0.018	P2RX1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
P2RY12	CANGRELOR TETRASODIUM

Top cohort targets by molecule count

Symbol	Molecules	Max phase
P2RY12	11	4
P2RX1	5	3
MED12L	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANGRELOR TETRASODIUM	4	P2RY12
PRASUGREL	4	P2RY12
CLOPIDOGREL	4	P2RY12
CANGRELOR	4	P2RY12
TICAGRELOR	4	P2RY12
ANAGRELIDE	4	P2RY12
SELATOGREL	3	P2RY12
SURAMIN	3	P2RX1
PYRIDOXAL PHOSPHATE ANHYDROUS	3	P2RX1
REGRELOR	2	P2RY12
ELINOGREL	2	P2RY12
REGRELOR DISODIUM	2	P2RY12
LIXAZINONE	2	P2RY12
ADENOSINE TRIPHOSPHATE	2	P2RX1
SALFLUVERINE	2	P2RX1
IMD-0354	1	P2RX1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
P2RY12	160	Binding:102, Functional:58
P2RX1	55	Binding:47, Functional:8

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
P2RY12	160

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

16 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)
CANGRELOR TETRASODIUM	4	P2RY12
PRASUGREL	4	P2RY12
CLOPIDOGREL	4	P2RY12
CANGRELOR	4	P2RY12
TICAGRELOR	4	P2RY12
ANAGRELIDE	4	P2RY12
SELATOGREL	3	P2RY12
SURAMIN	3	P2RX1
PYRIDOXAL PHOSPHATE ANHYDROUS	3	P2RX1
REGRELOR	2	P2RY12
ELINOGREL	2	P2RY12
REGRELOR DISODIUM	2	P2RY12
LIXAZINONE	2	P2RY12
ADENOSINE TRIPHOSPHATE	2	P2RX1
SALFLUVERINE	2	P2RX1
IMD-0354	1	P2RX1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	P2RY12
B	Phased (≥1) drug, not yet approved	1	P2RX1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MED12L

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)
MED12L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.