Congenital thrombotic thrombocytopenic purpura

Summary

Congenital thrombotic thrombocytopenic purpura (MONDO:0010122) is a disease caused by ADAMTS13 (GenCC Strong), with 1 cohort gene and 6 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ADAMTS13 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 401
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000		Worldwide	Validated
Cases/families		123	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital thrombotic thrombocytopenic purpura
Mondo ID	MONDO:0010122
OMIM	274150
Orphanet	93583
NCIT	C131657
SNOMED CT	373420004
UMLS	C1268935
MedGen	224783
GARD	0009430
Is cancer (heuristic)	no

Also known as: congenital ADAMTS-13 deficiency · congenital ADAMTS13 deficiency · congenital thrombotic thrombocytopenic purpura · congenital TTP · familial TTP · hereditary thrombotic thrombocytopenic purpura · Microangiopathic hemolytic Anaemia · thrombotic thrombocytopenic purpura, congenital · thrombotic thrombocytopenic purpura, hereditary · TTP · TTP, congenital · Upshaw-Schulman syndrome · USS

Data availability: 401 ClinVar variants · 4 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 › congenital thrombotic thrombocytopenic purpura

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, Quebec platelet disorder, platelet-type bleeding disorder 12, platelet-type bleeding disorder 10, platelet-type bleeding disorder 8, 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

401 retrieved; paginated sample, class counts are floors:

225 uncertain significance, 78 conflicting classifications of pathogenicity, 34 likely pathogenic, 29 pathogenic, 15 benign/likely benign, 9 pathogenic/likely pathogenic, 6 benign, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
5813	NM_139025.3(ADAMTS13):c.[1342C>G;1523G>A]		Pathogenic	no assertion criteria provided
1343360	NM_139027.6(ADAMTS13):c.3482T>C (p.Ile1161Thr)	ADAMTS13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705385	NM_139027.6(ADAMTS13):c.3242G>A (p.Trp1081Ter)	ADAMTS13	Pathogenic	criteria provided, single submitter
1705645	NM_139027.6(ADAMTS13):c.85G>T (p.Gly29Ter)	ADAMTS13	Pathogenic	criteria provided, single submitter
1804165	NM_139027.6(ADAMTS13):c.1169G>A (p.Trp390Ter)	ADAMTS13	Pathogenic	criteria provided, multiple submitters, no conflicts
2136834	NM_139027.6(ADAMTS13):c.3198_3199del (p.Cys1067fs)	ADAMTS13	Pathogenic	criteria provided, multiple submitters, no conflicts
2636095	NM_139027.6(ADAMTS13):c.1456_1457del (p.Met486fs)	ADAMTS13	Pathogenic	criteria provided, multiple submitters, no conflicts
2912892	NM_139027.6(ADAMTS13):c.781del (p.Ala261fs)	ADAMTS13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065326	NM_139027.6(ADAMTS13):c.3547G>A (p.Gly1183Arg)	ADAMTS13	Pathogenic	criteria provided, single submitter
3362787	NM_139027.6(ADAMTS13):c.722del (p.Gly241fs)	ADAMTS13	Pathogenic	no assertion criteria provided
3362788	NM_139027.6(ADAMTS13):c.2865G>A (p.Trp955Ter)	ADAMTS13	Pathogenic	no assertion criteria provided
3894581	NM_139027.6(ADAMTS13):c.2153T>A (p.Leu718Ter)	ADAMTS13	Pathogenic	criteria provided, single submitter
4291762	NM_139027.6(ADAMTS13):c.2883del (p.Cys962fs)	ADAMTS13	Pathogenic	criteria provided, single submitter
4849209	NM_139027.6(ADAMTS13):c.1094G>A (p.Trp365Ter)	ADAMTS13	Pathogenic	criteria provided, single submitter
5798	NM_139027.6(ADAMTS13):c.286C>G (p.His96Asp)	ADAMTS13	Pathogenic	no assertion criteria provided
5799	NM_139027.6(ADAMTS13):c.2851T>G (p.Cys951Gly)	ADAMTS13	Pathogenic	no assertion criteria provided
5800	NM_139027.6(ADAMTS13):c.304C>T (p.Arg102Cys)	ADAMTS13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5801	NM_139027.6(ADAMTS13):c.587C>T (p.Thr196Ile)	ADAMTS13	Pathogenic	criteria provided, multiple submitters, no conflicts
5803	NM_139027.6(ADAMTS13):c.3070T>G (p.Cys1024Gly)	ADAMTS13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5805	NM_139027.6(ADAMTS13):c.3602dup (p.Leu1202fs)	ADAMTS13	Pathogenic	no assertion criteria provided
5806	NM_139027.6(ADAMTS13):c.2376_2401del (p.Ala793fs)	ADAMTS13	Pathogenic	no assertion criteria provided
5807	NM_139027.6(ADAMTS13):c.3975dup (p.Glu1326fs)	ADAMTS13	Pathogenic	criteria provided, multiple submitters, no conflicts
5808	NM_139027.6(ADAMTS13):c.3470G>A (p.Cys1157Tyr)	ADAMTS13	Pathogenic	no assertion criteria provided
5809	NM_139027.6(ADAMTS13):c.2074C>T (p.Arg692Cys)	ADAMTS13	Pathogenic	criteria provided, multiple submitters, no conflicts
5811	NM_139027.6(ADAMTS13):c.1345C>T (p.Gln449Ter)	ADAMTS13	Pathogenic	no assertion criteria provided
5815	NM_139027.6(ADAMTS13):c.1783_1784del (p.Leu595fs)	ADAMTS13	Pathogenic	no assertion criteria provided
5817	NM_139027.6(ADAMTS13):c.414+1G>A	ADAMTS13	Pathogenic	no assertion criteria provided
5818	NM_139027.6(ADAMTS13):c.749C>T (p.Ala250Val)	ADAMTS13	Pathogenic	no assertion criteria provided
5819	NM_139027.6(ADAMTS13):c.331-1G>A	ADAMTS13	Pathogenic	no assertion criteria provided
5820	NM_139027.6(ADAMTS13):c.291_319del (p.Glu98fs)	ADAMTS13	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
ADAMTS13	Strong	Autosomal recessive	congenital thrombotic thrombocytopenic purpura	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAMTS13	Orphanet:93583	Congenital thrombotic thrombocytopenic purpura

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
ADAMTS13	HGNC:1366	ENSG00000160323	Q76LX8	A disintegrin and metalloproteinase with thrombospondin motifs 13	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADAMTS13	A disintegrin and metalloproteinase with thrombospondin motifs 13	Cleaves the vWF multimers in plasma into smaller forms thereby controlling vWF-mediated platelet thrombus 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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAMTS13	Protease	yes	3.4.24.87	TSP1_rpt, Peptidase_M12B, ADAM_Cys-rich

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
liver	1
right hemisphere of cerebellum	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADAMTS13	132	tissue_specific	marker	right lobe of liver, liver, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADAMTS13	1,125

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADAMTS13	Q76LX8	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Defects of platelet adhesion to exposed collagen	1	11420.0×	0.001	ADAMTS13
Diseases of hemostasis	1	2855.0×	0.001	ADAMTS13
Enhanced cleavage of VWF variant by ADAMTS13	1	2855.0×	0.001	ADAMTS13
Defective VWF cleavage by ADAMTS13 variant	1	2855.0×	0.001	ADAMTS13
Platelet Adhesion to exposed collagen	1	671.8×	0.005	ADAMTS13
Defective B3GALTL causes PpS	1	308.6×	0.008	ADAMTS13
O-glycosylation of TSR domain-containing proteins	1	300.5×	0.008	ADAMTS13
Regulation of clotting cascade	1	233.1×	0.008	ADAMTS13
Diseases associated with O-glycosylation of proteins	1	215.5×	0.008	ADAMTS13
O-linked glycosylation	1	144.6×	0.011	ADAMTS13
Diseases of glycosylation	1	131.3×	0.011	ADAMTS13
Diseases of metabolism	1	80.4×	0.017	ADAMTS13
Hemostasis	1	36.0×	0.034	ADAMTS13
Post-translational protein modification	1	19.2×	0.060	ADAMTS13
Disease	1	13.1×	0.081	ADAMTS13
Metabolism of proteins	1	12.4×	0.081	ADAMTS13

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
response to potassium ion	1	2106.5×	0.004	ADAMTS13
response to amine	1	1872.4×	0.004	ADAMTS13
glycoprotein metabolic process	1	1123.5×	0.004	ADAMTS13
peptide catabolic process	1	1053.2×	0.004	ADAMTS13
cellular response to interleukin-4	1	648.1×	0.005	ADAMTS13
platelet activation	1	267.5×	0.008	ADAMTS13
protein catabolic process	1	237.3×	0.008	ADAMTS13
response to toxic substance	1	210.7×	0.008	ADAMTS13
cellular response to type II interferon	1	208.1×	0.008	ADAMTS13
blood coagulation	1	173.7×	0.008	ADAMTS13
protein processing	1	170.2×	0.008	ADAMTS13
cell-matrix adhesion	1	163.6×	0.008	ADAMTS13
cellular response to tumor necrosis factor	1	163.6×	0.008	ADAMTS13
integrin-mediated signaling pathway	1	160.5×	0.008	ADAMTS13
extracellular matrix organization	1	122.1×	0.009	ADAMTS13
cellular response to lipopolysaccharide	1	98.0×	0.011	ADAMTS13
proteolysis	1	34.2×	0.029	ADAMTS13

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
ADAMTS13	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADAMTS13	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADAMTS13	3.4.24.87	ADAMTS13 endopeptidase

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	1	ADAMTS13
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
ADAMTS13	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE4	1
EARLY_PHASE1	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04767828	PHASE4	UNKNOWN	A Single Arm Study of Brain Metastasis in Patients With HER2-positive Breast Cancer
NCT02216084	PHASE1	COMPLETED	Phase 1 Dose Escalation, Single Dose Study to Assess Safety and Pharmacokinetics of BAX930 in Hereditary Thrombotic Thrombocytopenic Purpura (TTP)
NCT01808521	EARLY_PHASE1	COMPLETED	A Pilot Study of N-acetylcysteine in Thrombotic Thrombocytopenia Purpura
NCT01257269	Not specified	RECRUITING	Genotype and Phenotype Correlation in Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)
NCT05004493	Not specified	RECRUITING	Biorepository and Registry for Plasma Exchange Patients
NCT03519672	Not specified	COMPLETED	Prospective Psychometric Evaluation Study of a Patient-reported Outcomes (PRO) Instrument for Congenital Thrombotic Thrombocytopenic Purpura (cTTP, Upshaw-Schulman Syndrome [USS], Hereditary Thrombotic Thrombocytopenic Purpura [hTTP]

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHEMBL5435500	0	1