Bleeding disorder, platelet-type, 21

Summary

Bleeding disorder, platelet-type, 21 (MONDO:0054577) is a disease caused by FLI1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: FLI1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	bleeding disorder, platelet-type, 21
Mondo ID	MONDO:0054577
OMIM	617443
UMLS	C4479515
MedGen	1386863
GARD	0016230
Is cancer (heuristic)	no

Also known as: BDPLT21 · bleeding disorder, platelet-type, 21

Data availability: 16 ClinVar variants · 6 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 › bleeding disorder, platelet-type, 21

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, 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, 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

16 retrieved; paginated sample, class counts are floors:

4 pathogenic, 4 uncertain significance, 4 conflicting classifications of pathogenicity, 3 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333008	Single allele	FLI1	Pathogenic	criteria provided, single submitter
1703851	NM_002017.5(FLI1):c.844C>T (p.Gln282Ter)	FLI1	Pathogenic	criteria provided, single submitter
217031	NM_002017.5(FLI1):c.970C>T (p.Arg324Trp)	FLI1	Pathogenic	criteria provided, single submitter
424634	NM_002017.5(FLI1):c.992_995del (p.Asn331fs)	FLI1	Pathogenic/Likely pathogenic	no assertion criteria provided
424636	NM_002017.5(FLI1):c.1033A>G (p.Lys345Glu)	FLI1	Pathogenic	no assertion criteria provided
1684367	NM_002017.5(FLI1):c.946G>T (p.Glu316Ter)	FLI1	Likely pathogenic	no assertion criteria provided
1684421	NM_002017.5(FLI1):c.1019G>C (p.Arg340Pro)	FLI1	Likely pathogenic	no assertion criteria provided
424632	NM_002017.5(FLI1):c.1009C>T (p.Arg337Trp)	FLI1	Likely pathogenic	criteria provided, single submitter
424633	NM_002017.5(FLI1):c.1028A>G (p.Tyr343Cys)	FLI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424635	NM_002017.5(FLI1):c.1010G>A (p.Arg337Gln)	FLI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713759	NM_002017.5(FLI1):c.74C>T (p.Ala25Val)	FLI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
988011	NM_002017.5(FLI1):c.203G>T (p.Arg68Leu)	FLI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1684353	NM_002017.5(FLI1):c.812G>A (p.Ser271Asn)	FLI1	Uncertain significance	no assertion criteria provided
3391090	NM_002017.5(FLI1):c.40G>A (p.Asp14Asn)	FLI1	Uncertain significance	criteria provided, single submitter
3850717	NM_002017.5(FLI1):c.463G>A (p.Asp155Asn)	FLI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4531832	NM_002017.5(FLI1):c.850T>C (p.Trp284Arg)	FLI1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 6 · 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
FLI1	Strong	Autosomal dominant	bleeding disorder, platelet-type, 21	6
FLII	Strong	Autosomal dominant	bleeding disorder, platelet-type, 21	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLI1	Orphanet:2308	Jacobsen syndrome
FLI1	Orphanet:248340	Isolated delta-storage pool disease
FLI1	Orphanet:319	Skeletal Ewing sarcoma
FLI1	Orphanet:370334	Extraskeletal Ewing sarcoma
FLI1	Orphanet:370348	Peripheral primitive neuroectodermal tumor
FLI1	Orphanet:851	Paris-Trousseau thrombocytopenia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLI1	HGNC:3749	ENSG00000151702	Q01543	Friend leukemia integration 1 transcription factor	gencc,clinvar
FLII	HGNC:3750	ENSG00000177731	Q13045	Protein flightless-1 homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLI1	Friend leukemia integration 1 transcription factor	Sequence-specific transcriptional activator.
FLII	Protein flightless-1 homolog	Is a regulator of actin polymerization, required for proper myofibril organization and regulation of the length of sarcomeric thin filaments.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLI1	Other/Unknown	no		Ets_dom, Pointed_dom, SAM/pointed_sf
FLII	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, Villin/Gelsolin

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
apex of heart	1
hindlimb stylopod muscle	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLI1	247	ubiquitous	marker	monocyte, leukocyte, mononuclear cell
FLII	134	ubiquitous	marker	lower esophagus mucosa, apex of heart, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLII	2,364
FLI1	1,155

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLI1	Q01543	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FLII	Q13045	81.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Transcriptional regulation of granulopoiesis	1	125.5×	0.008	FLI1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hemostasis	1	842.6×	0.006	FLI1
actin filament severing	1	601.9×	0.006	FLII
myofibril assembly	1	561.7×	0.006	FLII
barbed-end actin filament capping	1	401.2×	0.006	FLII
actin polymerization or depolymerization	1	383.0×	0.006	FLII
megakaryocyte development	1	351.1×	0.006	FLI1
blood circulation	1	255.3×	0.007	FLI1
sarcomere organization	1	191.5×	0.008	FLII
animal organ morphogenesis	1	95.8×	0.014	FLI1
cell differentiation	1	14.6×	0.077	FLI1
positive regulation of DNA-templated transcription	1	14.0×	0.077	FLI1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	FLI1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLI1	0	0
FLII	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FLI1	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	FLI1, FLII

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FLI1	5	—
FLII	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.