Congenital amegakaryocytic thrombocytopenia 1

Summary

Congenital amegakaryocytic thrombocytopenia 1 (MONDO:0800452) is a disease caused by MPL (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: MPL (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 69
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Prevalence at birth	1-9 / 1 000 000	0.15	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0001873	Thrombocytopenia	Very frequent (80-99%)
HP:0011902	Abnormal hemoglobin	Very frequent (80-99%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000995	Melanocytic nevus	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003312	Abnormal form of the vertebral bodies	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0001671	Abnormal cardiac septum morphology	Occasional (5-29%)
HP:0004331	Decreased skull ossification	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital amegakaryocytic thrombocytopenia 1
Mondo ID	MONDO:0800452
MeSH	C535982
OMIM	604498
Orphanet	3319
DOID	DOID:0061005, DOID:0090118
NCIT	C115207
SNOMED CT	716336002
UMLS	C5882667
MedGen	1845022
GARD	0000640
Is cancer (heuristic)	no

Also known as: amegakaryocytic thrombocytopenia, congenital 1 · CAMT1 · thrombocytopenia congenital amegakaryocytic · thrombocytopenia, congenital amegakaryocytic

Data availability: 69 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › congenital hematological disorder › congenital amegakaryocytic thrombocytopenia 1

Related subtypes (20): congenital anemia, congenital agammaglobulinemia, sulfhemoglobinemia, congenital, congenital factor XII deficiency, leukocyte adhesion deficiency type II, thrombocytopenia-absent radius syndrome, congenital thrombotic thrombocytopenic purpura, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, GNE myopathy, hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency, congenital factor XI deficiency, congenital plasminogen activator inhibitor type 1 deficiency, congenital analbuminemia, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, constitutional neutropenia, congenital vitamin K-dependent coagulation factors deficiency, congenital secondary polycythemia, hereditary thrombocytosis with transverse limb defect, congenital factor XIII deficiency, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia 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

69 retrieved; paginated sample, class counts are floors:

22 likely pathogenic, 16 pathogenic/likely pathogenic, 9 pathogenic, 9 conflicting classifications of pathogenicity, 5 benign/likely benign, 5 uncertain significance, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069689	NM_005373.3(MPL):c.273C>A (p.Tyr91Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069872	NM_005373.3(MPL):c.230del (p.Cys77fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075094	NM_005373.3(MPL):c.308del (p.Leu103fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
134822	NM_005373.3(MPL):c.235_236del (p.Leu79fs)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
135563	NM_005373.3(MPL):c.79+2T>A	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14154	NM_005373.3(MPL):c.556C>T (p.Gln186Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
14155	NM_005373.3(MPL):c.1499del (p.Leu500fs)	MPL	Pathogenic	no assertion criteria provided
14156	NM_005373.3(MPL):c.769C>T (p.Arg257Cys)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14157	NM_005373.3(MPL):c.1904C>T (p.Pro635Leu)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14158	NM_005373.3(MPL):c.305G>C (p.Arg102Pro)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
14159	NM_005373.3(MPL):c.1473G>A (p.Trp491Ter)	MPL	Pathogenic	no assertion criteria provided
14160	NM_005373.3(MPL):c.1566-1G>T	MPL	Pathogenic	no assertion criteria provided
1416785	NM_005373.3(MPL):c.478G>T (p.Glu160Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2025217	NM_005373.3(MPL):c.209del (p.Pro70fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265248	NM_005373.3(MPL):c.317C>T (p.Pro106Leu)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265249	NM_005373.3(MPL):c.378del (p.Phe126fs)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
2928056	NM_005373.3(MPL):c.1033C>T (p.Gln345Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3340285	NM_005373.3(MPL):c.1545G>A (p.Trp515Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371574	NM_005373.3(MPL):c.127C>T (p.Arg43Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
435886	NM_005373.3(MPL):c.972del (p.Arg325fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
458369	NM_005373.3(MPL):c.1744_1745del (p.Leu582fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631607	NM_005373.3(MPL):c.1774C>T (p.Arg592Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632897	NM_005373.3(MPL):c.1653+1del	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
644406	NM_005373.3(MPL):c.304C>T (p.Arg102Cys)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956954	NM_005373.3(MPL):c.268C>T (p.Arg90Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1379348	NM_005373.3(MPL):c.407C>A (p.Pro136His)	MPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1523230	NM_005373.3(MPL):c.1166-1G>C	MPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445438	NM_005373.3(MPL):c.407C>G (p.Pro136Arg)	MPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3367097	NM_005373.3(MPL):c.391G>C (p.Gly131Arg)	MPL	Likely pathogenic	criteria provided, single submitter
3584214	NM_005373.3(MPL):c.256del (p.His86fs)	MPL	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
MPL	Definitive	Autosomal recessive	congenital amegakaryocytic thrombocytopenia	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MPL	HGNC:7217	ENSG00000117400	P40238	Thrombopoietin receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MPL	Thrombopoietin receptor	Receptor for thrombopoietin that regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MPL	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Ig-like_fold

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
male germ line stem cell (sensu Vertebrata) in testis	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MPL	166	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, mononuclear cell, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MPL	1,039

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MPL	P40238	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Platelet Aggregation (Plug Formation)	1	439.2×	0.002	MPL

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
basophil homeostasis	1	16852.0×	4e-04	MPL
positive regulation of platelet formation	1	8426.0×	4e-04	MPL
monocyte homeostasis	1	5617.3×	4e-04	MPL
eosinophil homeostasis	1	5617.3×	4e-04	MPL
thrombopoietin-mediated signaling pathway	1	2106.5×	8e-04	MPL
positive regulation of lymphocyte proliferation	1	1872.4×	8e-04	MPL
neutrophil homeostasis	1	1532.0×	8e-04	MPL
platelet formation	1	702.2×	0.002	MPL
cellular response to hypoxia	1	121.2×	0.008	MPL

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
MPL	LUSUTROMBOPAG

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MPL	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LUSUTROMBOPAG	4	MPL
ELTROMBOPAG	4	MPL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MPL	23	Functional:15, Binding:7, ADMET: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

2 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)
LUSUTROMBOPAG	4	MPL
ELTROMBOPAG	4	MPL

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	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.