Bernard-Soulier syndrome

Summary

Bernard-Soulier syndrome (MONDO:0009276) is a disease caused by variants in GP1BA, GP1BB, and GP9, with 3 cohort genes. The dominant Reactome pathway is Defective F9 activation (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: GP1BA (GenCC Definitive), GP1BB (GenCC Definitive), GP9 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 221
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0011871	Impaired ristocetin-induced platelet aggregation	Obligate (100%)
HP:0001892	Abnormal bleeding	Very frequent (80-99%)
HP:0001902	Giant platelets	Very frequent (80-99%)
HP:0011879	Decreased platelet glycoprotein Ib-IX-V	Very frequent (80-99%)
HP:0040185	Macrothrombocytopenia	Very frequent (80-99%)
HP:0000132	Menorrhagia	Frequent (30-79%)
HP:0000967	Petechiae	Frequent (30-79%)
HP:0002239	Gastrointestinal hemorrhage	Frequent (30-79%)
HP:0004406	Spontaneous, recurrent epistaxis	Frequent (30-79%)
HP:0006298	Prolonged bleeding after dental extraction	Frequent (30-79%)
HP:0007420	Spontaneous hematomas	Frequent (30-79%)
HP:0000225	Gingival bleeding	Occasional (5-29%)
HP:0000978	Bruising susceptibility	Occasional (5-29%)
HP:0002248	Hematemesis	Occasional (5-29%)
HP:0004846	Prolonged bleeding after surgery	Occasional (5-29%)
HP:0012143	Abnormal megakaryocyte morphology	Occasional (5-29%)
HP:0012587	Macroscopic hematuria	Occasional (5-29%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0002076	Migraine	Very rare (<1-4%)
HP:0002099	Asthma	Very rare (<1-4%)
HP:0008738	Partially duplicated kidney	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Bernard-Soulier syndrome
Mondo ID	MONDO:0009276
MeSH	D001606
OMIM	231200
Orphanet	274
DOID	DOID:2217
ICD-11	507309898
NCIT	C84595
SNOMED CT	234478007
UMLS	C0005129
MedGen	2212
GARD	0002470
MedDRA	10057473
NORD	851
Is cancer (heuristic)	no

Also known as: Bernard-Soulier syndrome · Bernard-Soulier syndrome, type A1 (recessive) · BSS · deficiency of platelet glycoprotein 1b · giant platelet disease · giant platelet disorder, isolated · giant platelet syndrome · Hemorrhagiparous thrombocytic dystrophy · macrothrombocytopenia, familial Bernard-Soulier type · Platelet glycoprotein 1b, deficiency of

Data availability: 221 ClinVar variants · 137 ClinGen variant curations · 13 GenCC gene-disease records · 7 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

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

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, Scott syndrome, congenital thrombotic thrombocytopenic purpura, 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

Subtypes (1): Bernard-Soulier syndrome, type A2, autosomal dominant

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

221 retrieved; paginated sample, class counts are floors:

93 likely pathogenic, 62 uncertain significance, 27 pathogenic, 20 benign, 7 conflicting classifications of pathogenicity, 6 likely benign, 4 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1677212	NM_000173.7(GP1BA):c.241T>C (p.Cys81Arg)	GP1BA	Pathogenic	reviewed by expert panel
1679419	NM_000173.7(GP1BA):c.499G>T (p.Glu167Ter)	GP1BA	Pathogenic	no assertion criteria provided
1691251	NM_000173.7(GP1BA):c.1480del (p.Thr494fs)	GP1BA	Pathogenic	reviewed by expert panel
1691252	NM_000173.7(GP1BA):c.674G>C (p.Cys225Ser)	GP1BA	Pathogenic	no assertion criteria provided
1695379	NM_000173.7(GP1BA):c.97T>C (p.Cys33Arg)	GP1BA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1703858	NM_000173.7(GP1BA):c.1846_1852del (p.Asn616fs)	GP1BA	Pathogenic	criteria provided, single submitter
2137887	NM_000173.7(GP1BA):c.1454dup (p.Ser486fs)	GP1BA	Pathogenic	reviewed by expert panel
2572131	NM_000173.7(GP1BA):c.1408del (p.Ser470fs)	GP1BA	Pathogenic	criteria provided, single submitter
4156	NM_000173.7(GP1BA):c.515C>T (p.Ala172Val)	GP1BA	Pathogenic	criteria provided, multiple submitters, no conflicts
4157	NM_000173.7(GP1BA):c.1620G>A (p.Trp540Ter)	GP1BA	Pathogenic	reviewed by expert panel
435347	NM_000173.7(GP1BA):c.673T>A (p.Cys225Ser)	GP1BA	Pathogenic	reviewed by expert panel
4539007	NM_000173.7(GP1BA):c.1562_1563del (p.Leu521fs)	GP1BA	Pathogenic	reviewed by expert panel
872581	NM_000173.7(GP1BA):c.1601_1602del (p.Tyr534fs)	GP1BA	Pathogenic	reviewed by expert panel
1691232	NM_000407.5(GP1BB):c.443G>A (p.Trp148Ter)	GP1BB	Pathogenic	reviewed by expert panel
1691255	NM_000407.5(GP1BB):c.317_320dup (p.Glu109fs)	GP1BB	Pathogenic	no assertion criteria provided
1701430	NM_000407.5(GP1BB):c.281A>G (p.Asp94Gly)	GP1BB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1703862	NM_000407.5(GP1BB):c.22dup (p.Ala8fs)	GP1BB	Pathogenic	criteria provided, single submitter
2572122	NM_000407.5(GP1BB):c.124_145del (p.Arg42fs)	GP1BB	Pathogenic	criteria provided, single submitter
3380918	NM_000407.5(GP1BB):c.315del (p.Gly106fs)	GP1BB	Pathogenic	reviewed by expert panel
4687727	NC_000022.10:g.(?19711061)(19712295_?)del	GP1BB	Pathogenic	criteria provided, single submitter
627237	NM_000407.5(GP1BB):c.143C>A (p.Ser48Ter)	GP1BB	Pathogenic	criteria provided, multiple submitters, no conflicts
1333009	NC_000003.12:g.129058767_129062425del	GP9	Pathogenic	criteria provided, single submitter
1338739	NM_000174.5(GP9):c.-210_*133del (p.Met1fs)	GP9	Pathogenic	criteria provided, single submitter
13529	NM_000174.5(GP9):c.182A>G (p.Asn61Ser)	GP9	Pathogenic	reviewed by expert panel
13531	NM_000174.5(GP9):c.212T>C (p.Phe71Ser)	GP9	Pathogenic	reviewed by expert panel
2573379	NM_000174.5(GP9):c.8_11dup (p.Trp4fs)	GP9	Pathogenic	criteria provided, single submitter
3366941	NM_000174.5(GP9):c.46dup (p.Ala16fs)	GP9	Pathogenic	criteria provided, single submitter
3775050	NM_000174.5(GP9):c.266G>A (p.Cys89Tyr)	GP9	Pathogenic	reviewed by expert panel
1324499	NM_000407.5(GP1BB):c.423C>A (p.Cys141Ter)	SEPT5-GP1BB	Pathogenic	reviewed by expert panel
1031446	NM_000173.7(GP1BA):c.673T>C (p.Cys225Arg)	GP1BA	Likely pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 9 · 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
GP1BA	Definitive	Autosomal recessive	Bernard-Soulier syndrome	12
GP1BB	Definitive	Autosomal recessive	Bernard-Soulier syndrome	6
GP9	Definitive	Autosomal recessive	Bernard-Soulier syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GP1BA	Orphanet:140957	Autosomal dominant macrothrombocytopenia
GP1BA	Orphanet:274	Bernard-Soulier syndrome
GP1BA	Orphanet:52530	Pseudo-von Willebrand disease
GP1BA	Orphanet:853	Fetal and neonatal alloimmune thrombocytopenia
GP1BB	Orphanet:140957	Autosomal dominant macrothrombocytopenia
GP1BB	Orphanet:274	Bernard-Soulier syndrome
GP1BB	Orphanet:567	22q11.2 deletion syndrome
GP1BB	Orphanet:853	Fetal and neonatal alloimmune thrombocytopenia
GP9	Orphanet:274	Bernard-Soulier syndrome

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
GP1BA	HGNC:4439	ENSG00000185245	P07359	Platelet glycoprotein Ib alpha chain	gencc,clinvar
GP1BB	HGNC:4440	ENSG00000203618	P13224	Platelet glycoprotein Ib beta chain	gencc,clinvar
GP9	HGNC:4444	ENSG00000169704	P14770	Platelet glycoprotein IX	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GP1BA	Platelet glycoprotein Ib alpha chain	GP-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to the A1 domain of vWF, which is already bound to the subendothelium.
GP1BB	Platelet glycoprotein Ib beta chain	Gp-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to von Willebrand factor, which is already bound to the subendothelium.
GP9	Platelet glycoprotein IX	The GPIb-V-IX complex functions as the vWF receptor and mediates vWF-dependent platelet adhesion to blood vessels.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GP1BA	Other/Unknown	no		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt
GP1BB	Other/Unknown	no		LRRNT, Cys-rich_flank_reg_C, LRR_dom_sf
GP9	Other/Unknown	no		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt

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
leukocyte	3
monocyte	3
mononuclear cell	2
granulocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GP1BA	186	tissue_specific	marker	monocyte, mononuclear cell, leukocyte
GP1BB	121	broad	marker	monocyte, leukocyte, granulocyte
GP9	88	tissue_specific	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GP1BA	1,703
GP9	1,331
GP1BB	1,280

Intra-cohort edges

A	B	Sources
GP1BA	GP1BB	biogrid_interaction, intact, string_interaction
GP1BA	GP9	biogrid_interaction, intact, string_interaction
GP1BB	GP9	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GP1BA	P07359	22
GP1BB	P13224	3
GP9	P14770	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Defective F9 activation	3	1903.3×	5e-10	GP1BA, GP1BB, GP9
Enhanced binding of GP1BA variant to VWF multimer:collagen	3	1631.4×	5e-10	GP1BA, GP1BB, GP9
Defective binding of VWF variant to GPIb:IX:V	3	1631.4×	5e-10	GP1BA, GP1BB, GP9
FXIIa, PKa-dependent activation of coagulation pathway	3	1142.0×	1e-09	GP1BA, GP1BB, GP9
GP1b-IX-V activation signalling	3	951.7×	2e-09	GP1BA, GP1BB, GP9
Platelet Adhesion to exposed collagen	3	671.8×	5e-09	GP1BA, GP1BB, GP9
Amplification and propagation of coagulation cascade	3	634.4×	5e-09	GP1BA, GP1BB, GP9
Platelet Aggregation (Plug Formation)	3	439.2×	1e-08	GP1BA, GP1BB, GP9
Regulation of clotting cascade	3	233.1×	8e-08	GP1BA, GP1BB, GP9
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	40.1×	0.025	GP1BA

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
blood coagulation, intrinsic pathway	3	2106.5×	8e-10	GP1BA, GP1BB, GP9
positive regulation of platelet activation	3	1296.3×	2e-09	GP1BA, GP1BB, GP9
megakaryocyte development	3	702.2×	9e-09	GP1BA, GP1BB, GP9
release of sequestered calcium ion into cytosol	3	343.9×	6e-08	GP1BA, GP1BB, GP9
cell adhesion	3	37.5×	4e-05	GP1BA, GP1BB, GP9
platelet activation	2	178.3×	8e-05	GP1BA, GP1BB
blood coagulation	2	115.8×	2e-04	GP1BA, GP9
cell surface receptor signaling pathway	2	42.7×	1e-03	GP1BA, GP1BB
regulation of blood coagulation	1	624.1×	0.002	GP1BA
fibrinolysis	1	280.9×	0.004	GP1BA
cell morphogenesis	1	52.5×	0.019	GP1BA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GP1BA	0	0
GP1BB	0	0
GP9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	GP1BA, GP1BB, GP9

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GP1BA	0	—
GP1BB	0	—
GP9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.