Familial thrombocytosis

Summary

Familial thrombocytosis (MONDO:0019111) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide)
• Cohort genes: 3
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0001892	Abnormal bleeding	Very frequent (80-99%)
HP:0001894	Thrombocytosis	Very frequent (80-99%)
HP:0004420	Arterial thrombosis	Very frequent (80-99%)
HP:0004936	Venous thrombosis	Very frequent (80-99%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0000989	Pruritus	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002326	Transient ischemic attack	Frequent (30-79%)
HP:0002637	Cerebral ischemia	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0004950	Peripheral arterial stenosis	Frequent (30-79%)
HP:0100749	Chest pain	Frequent (30-79%)
HP:0001123	Visual field defect	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001279	Syncope	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002321	Vertigo	Occasional (5-29%)
HP:0002863	Myelodysplasia	Occasional (5-29%)
HP:0004808	Acute myeloid leukemia	Occasional (5-29%)
HP:0005268	Spontaneous abortion	Occasional (5-29%)
HP:0005506	Chronic myelogenous leukemia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial thrombocytosis
Mondo ID	MONDO:0019111
OMIM	187950
Orphanet	71493
ICD-11	1695088249
SNOMED CT	720950009
UMLS	C4303761
MedGen	929430
GARD	0016688
Is cancer (heuristic)	no

Also known as: familial thrombocythemia · hereditary thrombocythemia · hereditary thrombocytosis · hereditary thrombocytosis disease · THCYT

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytosis disease › familial thrombocytosis

Related subtypes (2): essential thrombocythemia, reactive thrombocytosis

Subtypes (3): thrombocythemia 1, thrombocythemia 2, thrombocythemia 3

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 15 · 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
JAK2	Supportive	Autosomal dominant	familial thrombocytosis	4
MPL	Supportive	Autosomal dominant	familial thrombocytosis	10
THPO	Supportive	Autosomal dominant	hereditary thrombocytosis with transverse limb defect	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
THPO	Orphanet:329319	Thrombocythemia with distal limb defects
THPO	Orphanet:3319	Congenital amegakaryocytic thrombocytopenia
THPO	Orphanet:397692	Hereditary isolated aplastic anemia
THPO	Orphanet:71493	Familial thrombocytosis
JAK2	Orphanet:131	Budd-Chiari syndrome
JAK2	Orphanet:3318	Essential thrombocythemia
JAK2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
JAK2	Orphanet:71493	Familial thrombocytosis
JAK2	Orphanet:729	Polycythemia vera
JAK2	Orphanet:824	Primary myelofibrosis
MPL	Orphanet:3318	Essential thrombocythemia
MPL	Orphanet:3319	Congenital amegakaryocytic thrombocytopenia
MPL	Orphanet:397692	Hereditary isolated aplastic anemia
MPL	Orphanet:71493	Familial thrombocytosis
MPL	Orphanet:824	Primary myelofibrosis

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
THPO	HGNC:11795	ENSG00000090534	P40225	Thrombopoietin	gencc
JAK2	HGNC:6192	ENSG00000096968	O60674	Tyrosine-protein kinase JAK2	gencc
MPL	HGNC:7217	ENSG00000117400	P40238	Thrombopoietin receptor	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THPO	Thrombopoietin	Lineage-specific cytokine affecting the proliferation and maturation of megakaryocytes from their committed progenitor cells.
JAK2	Tyrosine-protein kinase JAK2	Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications.
MPL	Thrombopoietin receptor	Receptor for thrombopoietin that regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Antibody/Immunoglobulin	1	9.7×	0.157
Kinase	1	9.2×	0.157
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
THPO	Other/Unknown	no		EPO_TPO, Thrombopoietin, 4_helix_cytokine-like_core
JAK2	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
MPL	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Ig-like_fold

Expression context

Cohort genes with no expression data: 0.

2 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
monocyte	2
liver	1
right hemisphere of cerebellum	1
right lobe of liver	1
blood vessel layer	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THPO	157	tissue_specific	yes	right lobe of liver, liver, right hemisphere of cerebellum
JAK2	272	ubiquitous	marker	calcaneal tendon, monocyte, blood vessel layer
MPL	166	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, mononuclear cell, monocyte

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JAK2	6,197
THPO	1,375
MPL	1,039

Intra-cohort edges

A	B	Sources
JAK2	MPL	biogrid_interaction, intact, string_interaction
JAK2	THPO	string_interaction
MPL	THPO	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JAK2	O60674	164
THPO	P40225	3
MPL	P40238	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 67. Enrichment computed across 3 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
Platelet Aggregation (Plug Formation)	2	292.8×	0.001	THPO, MPL
Erythropoietin activates Phospholipase C gamma (PLCG)	1	543.8×	0.014	JAK2
Erythropoietin activates STAT5	1	543.8×	0.014	JAK2
Interleukin-6 family signaling	1	475.8×	0.014	JAK2
IFNG signaling activates MAPKs	1	475.8×	0.014	JAK2
Interleukin-23 signaling	1	423.0×	0.014	JAK2
MAPK1 (ERK2) activation	1	380.7×	0.014	JAK2
Signaling by KIT in disease	1	380.7×	0.014	JAK2
MAPK3 (ERK1) activation	1	346.1×	0.014	JAK2
Signaling by Leptin	1	346.1×	0.014	JAK2
Signaling by Erythropoietin	1	346.1×	0.014	JAK2
Interleukin-27 signaling	1	346.1×	0.014	JAK2
Interleukin-6 signaling	1	317.2×	0.014	JAK2
Interleukin-35 Signalling	1	317.2×	0.014	JAK2
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	317.2×	0.014	JAK2
Regulation of IFNG signaling	1	271.9×	0.015	JAK2
Prolactin receptor signaling	1	253.8×	0.015	JAK2
Erythropoietin activates RAS	1	253.8×	0.015	JAK2
RAF-independent MAPK1/3 activation	1	211.5×	0.015	JAK2
Interleukin-2 family signaling	1	211.5×	0.015	JAK2
IL-6-type cytokine receptor ligand interactions	1	211.5×	0.015	JAK2
Signaling by CSF3 (G-CSF)	1	190.3×	0.016	JAK2
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	173.0×	0.016	JAK2
Interleukin-12 family signaling	1	158.6×	0.016	JAK2
Growth hormone receptor signaling	1	158.6×	0.016	JAK2
Inactivation of CSF3 (G-CSF) signaling	1	146.4×	0.016	JAK2
Signaling by RAS mutants	1	141.0×	0.016	JAK2
Interleukin-20 family signaling	1	141.0×	0.016	JAK2
Interleukin-12 signaling	1	135.9×	0.016	JAK2
Interleukin receptor SHC signaling	1	135.9×	0.016	JAK2

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
thrombopoietin-mediated signaling pathway	3	2106.5×	8e-09	THPO, JAK2, MPL
nuclear receptor-mediated mineralocorticoid signaling pathway	1	5617.3×	0.004	JAK2
symbiont-induced defense-related programmed cell death	1	5617.3×	0.004	JAK2
interleukin-35-mediated signaling pathway	1	5617.3×	0.004	JAK2
basophil homeostasis	1	5617.3×	0.004	MPL
response to interleukin-12	1	2808.7×	0.004	JAK2
positive regulation of growth factor dependent skeletal muscle satellite cell proliferation	1	2808.7×	0.004	JAK2
positive regulation of platelet formation	1	2808.7×	0.004	MPL
regulation of postsynapse to nucleus signaling pathway	1	2808.7×	0.004	JAK2
monocyte homeostasis	1	1872.4×	0.004	MPL
positive regulation of growth hormone receptor signaling pathway	1	1872.4×	0.004	JAK2
eosinophil homeostasis	1	1872.4×	0.004	MPL
positive regulation of MAPK cascade	2	53.8×	0.004	THPO, JAK2
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	52.2×	0.004	THPO, JAK2
collagen-activated signaling pathway	1	1404.3×	0.005	JAK2
granulocyte-macrophage colony-stimulating factor signaling pathway	1	1404.3×	0.005	JAK2
activation of Janus kinase activity	1	1404.3×	0.005	JAK2
post-embryonic hemopoiesis	1	936.2×	0.005	JAK2
cellular response to interleukin-3	1	936.2×	0.005	JAK2
interleukin-5-mediated signaling pathway	1	936.2×	0.005	JAK2
interleukin-23-mediated signaling pathway	1	936.2×	0.005	JAK2
erythropoietin-mediated signaling pathway	1	936.2×	0.005	JAK2
positive regulation of NK T cell proliferation	1	936.2×	0.005	JAK2
positive regulation of leukocyte proliferation	1	936.2×	0.005	JAK2
interleukin-3-mediated signaling pathway	1	802.5×	0.005	JAK2
interleukin-12-mediated signaling pathway	1	624.1×	0.006	JAK2
positive regulation of lymphocyte proliferation	1	624.1×	0.006	MPL
mammary gland epithelium development	1	624.1×	0.006	JAK2
positive regulation of hematopoietic stem cell proliferation	1	624.1×	0.006	THPO
response to hydroperoxide	1	561.7×	0.006	JAK2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
THPO	PROGESTERONE
JAK2	FEDRATINIB
MPL	LUSUTROMBOPAG

Top cohort targets by molecule count

Symbol	Molecules	Max phase
THPO	103	4
JAK2	100	4
MPL	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROGESTERONE	4	THPO
CLOTRIMAZOLE	4	THPO
COLCHICINE	4	THPO
SALMETEROL XINAFOATE	4	THPO
BRETYLIUM TOSYLATE	4	THPO
SULFAPHENAZOLE	4	THPO
AMOXAPINE	4	THPO
DICYCLOMINE	4	THPO
NICARDIPINE HYDROCHLORIDE	4	THPO
CARBIDOPA ANHYDROUS	4	THPO
EPINEPHRINE BITARTRATE	4	THPO
BUDESONIDE	4	THPO
CHLORZOXAZONE	4	THPO
PIMOZIDE	4	THPO
NICLOSAMIDE	4	JAK2, THPO
AZACITIDINE	4	THPO
TRIFLUPERIDOL	4	THPO
CAPTOPRIL	4	THPO
KETOCONAZOLE	4	THPO
PSEUDOEPHEDRINE	4	THPO
CLEMASTINE	4	THPO
RIBAVIRIN	4	THPO
SERTRALINE HYDROCHLORIDE	4	THPO
TERFENADINE	4	THPO
FLUOROURACIL	4	THPO
NIFEDIPINE	4	THPO
PRAZOSIN	4	THPO
MAPROTILINE	4	THPO
MECAMYLAMINE	4	THPO
HYDRALAZINE	4	THPO

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
JAK2	2,018	Binding:1911, Functional:51, ADMET:48, Unclassified:4, Toxicity:4
MPL	23	Functional:15, Binding:7, ADMET:1
THPO	2	Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
JAK2	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
JAK2	2,018

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

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)
PROGESTERONE	4	THPO
CLOTRIMAZOLE	4	THPO
COLCHICINE	4	THPO
SALMETEROL XINAFOATE	4	THPO
BRETYLIUM TOSYLATE	4	THPO
SULFAPHENAZOLE	4	THPO
AMOXAPINE	4	THPO
DICYCLOMINE	4	THPO
NICARDIPINE HYDROCHLORIDE	4	THPO
CARBIDOPA ANHYDROUS	4	THPO
EPINEPHRINE BITARTRATE	4	THPO
BUDESONIDE	4	THPO
CHLORZOXAZONE	4	THPO
PIMOZIDE	4	THPO
NICLOSAMIDE	4	JAK2, THPO
AZACITIDINE	4	THPO
TRIFLUPERIDOL	4	THPO
CAPTOPRIL	4	THPO
KETOCONAZOLE	4	THPO
PSEUDOEPHEDRINE	4	THPO
CLEMASTINE	4	THPO
RIBAVIRIN	4	THPO
SERTRALINE HYDROCHLORIDE	4	THPO
TERFENADINE	4	THPO
FLUOROURACIL	4	THPO
NIFEDIPINE	4	THPO
PRAZOSIN	4	THPO
MAPROTILINE	4	THPO
MECAMYLAMINE	4	THPO
HYDRALAZINE	4	THPO

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	THPO, JAK2, MPL
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.