Congenital amegakaryocytic thrombocytopenia

Summary

Congenital amegakaryocytic thrombocytopenia (MONDO:0800451) is a disease with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include fludarabine phosphate, alemtuzumab, and treosulfan.

At a glance

• Cohort genes: 1
• ClinVar variants: 841
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital amegakaryocytic thrombocytopenia
Mondo ID	MONDO:0800451
OMIM	604498
ICD-11	801723173
UMLS	C1327915
MedGen	272171
GARD	0026560
Is cancer (heuristic)	no

Also known as: congenital amegakaryocytic thrombocytopenia

Data availability: 841 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytopenia › inherited thrombocytopenia › congenital amegakaryocytic thrombocytopenia

Related subtypes (20): thrombocytopenia 2, thrombocytopenia, cyclic, thrombocytopenia 3, congenital thrombotic thrombocytopenic purpura, thrombocytopenia, X-linked, with or without dyserythropoietic anemia, thrombocytopenia 1, thrombocytopenia 4, thrombocytopenia 5, autosomal dominant macrothrombocytopenia, isolated delta-storage pool disease, syndromic constitutional thrombocytopenia, alpha granule disease, thrombocytopenia 7, macrothrombocytopenia, isolated, congenital autosomal recessive small-platelet thrombocytopenia, thrombocytopenia 9, thrombocytopenia 10, thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, thrombocytopenia 12 with or without myopathy, thrombocytopenia 13, syndromic

Subtypes (1): congenital amegakaryocytic thrombocytopenia 1

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

600 retrieved; paginated sample, class counts are floors:

322 likely benign, 118 uncertain significance, 57 pathogenic, 38 likely pathogenic, 31 pathogenic/likely pathogenic, 20 conflicting classifications of pathogenicity, 9 benign/likely benign, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068628	NM_005373.3(MPL):c.1276C>T (p.Arg426Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
1071039	NM_005373.3(MPL):c.603_606del (p.His201fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072100	NM_005373.3(MPL):c.1042C>T (p.Gln348Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072257	NM_005373.3(MPL):c.1316_1320del (p.Glu439fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072631	NM_005373.3(MPL):c.1563C>A (p.Tyr521Ter)	MPL	Pathogenic	criteria provided, single submitter
1073154	NM_005373.3(MPL):c.1263_1264del (p.Cys422fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073761	NM_005373.3(MPL):c.252del (p.Met84fs)	MPL	Pathogenic	criteria provided, single submitter
1074655	NM_005373.3(MPL):c.1025del (p.Pro342fs)	MPL	Pathogenic	criteria provided, single submitter
1075094	NM_005373.3(MPL):c.308del (p.Leu103fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1236205	NM_005373.3(MPL):c.1670C>A (p.Ser557Ter)	MPL	Pathogenic	criteria provided, single submitter
1301356	NM_005373.3(MPL):c.367C>T (p.Arg123Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1320277	NM_005373.3(MPL):c.1468+1G>C	MPL	Pathogenic	criteria provided, single submitter
1338502	NM_005373.3(MPL):c.313_316del (p.Phe105fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
134819	NM_005373.3(MPL):c.1621C>T (p.Gln541Ter)	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
134831	NM_005373.3(MPL):c.744_747dup (p.Asn250fs)	MPL	Pathogenic/Likely 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
1360846	NM_005373.3(MPL):c.1814_1817del (p.Ser605fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1368759	NM_005373.3(MPL):c.842del (p.Pro281fs)	MPL	Pathogenic	criteria provided, single submitter
1381492	NM_005373.3(MPL):c.605dup (p.Ala203fs)	MPL	Pathogenic	criteria provided, single submitter
1382942	NM_005373.3(MPL):c.1346dup (p.Glu450fs)	MPL	Pathogenic	criteria provided, single submitter
1395269	NM_005373.3(MPL):c.972_973del (p.Asp326fs)	MPL	Pathogenic	criteria provided, single submitter
14154	NM_005373.3(MPL):c.556C>T (p.Gln186Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
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
14163	NM_005373.3(MPL):c.1514G>A (p.Ser505Asn)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1416785	NM_005373.3(MPL):c.478G>T (p.Glu160Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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	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: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	4
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00301834	PHASE2	COMPLETED	Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
NCT00305708	PHASE1/PHASE2	COMPLETED	Busulfan, Antithymocyte Globulin, and Fludarabine Followed By a Donor Stem Cell Transplant in Treating Young Patients With Blood Disorders, Bone Marrow Disorders, Chronic Myelogenous Leukemia in First Chronic Phase, or Acute Myeloid Leukemia in First Remission
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT03333486	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT00295971	PHASE1	COMPLETED	Donor Stem Cell Transplant in Treating Young Patients With Myelodysplastic Syndrome, Leukemia, Bone Marrow Failure Syndrome, or Severe Immunodeficiency Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	6
ALEMTUZUMAB	4	1
TREOSULFAN	4	1