Congenital fibrinogen deficiency

Summary

Congenital fibrinogen deficiency (MONDO:0018060) is a disease caused by variants in FGA, FGB, and FGG, with 3 cohort genes and 5 clinical trials. The dominant Reactome pathway is Aggregated β-amyloid interacts with fibrinogen (3 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe)
• Causal genes: FGA (GenCC Strong), FGB (GenCC Strong), FGG (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 2
• Phenotypes (HPO): 26
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.15	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000054	Micropenis	Very frequent (80-99%)
HP:0000225	Gingival bleeding	Very frequent (80-99%)
HP:0000519	Developmental cataract	Very frequent (80-99%)
HP:0000568	Microphthalmia	Very frequent (80-99%)
HP:0000961	Cyanosis	Very frequent (80-99%)
HP:0000978	Bruising susceptibility	Very frequent (80-99%)
HP:0001649	Tachycardia	Very frequent (80-99%)
HP:0001667	Right ventricular hypertrophy	Very frequent (80-99%)
HP:0001712	Left ventricular hypertrophy	Very frequent (80-99%)
HP:0001892	Abnormal bleeding	Very frequent (80-99%)
HP:0001933	Subcutaneous hemorrhage	Very frequent (80-99%)
HP:0001945	Fever	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0002179	Opisthotonus	Very frequent (80-99%)
HP:0002580	Volvulus	Very frequent (80-99%)
HP:0007185	Loss of consciousness	Very frequent (80-99%)
HP:0008151	Prolonged prothrombin time	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0009723	Abnormality of the subungual region	Very frequent (80-99%)
HP:0011029	Internal hemorrhage	Very frequent (80-99%)
HP:0011884	Abnormal umbilical stump bleeding	Very frequent (80-99%)
HP:0012223	Splenic rupture	Very frequent (80-99%)
HP:0012886	Hemorrhagic ovarian cyst	Very frequent (80-99%)
HP:0030680	Abnormal cardiovascular system morphology	Very frequent (80-99%)
HP:0100759	Clubbing of fingers	Very frequent (80-99%)
HP:0100845	Anaphylactic shock	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital fibrinogen deficiency
Mondo ID	MONDO:0018060
Orphanet	335
ICD-11	1452989457
UMLS	C0019250
MedGen	9230
GARD	0002320
Is cancer (heuristic)	no

Also known as: congenital fibrinogen deficiency · fibrinogen deficiency, congenital

Data availability: 2 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › coagulation protein disease › congenital fibrinogen deficiency

Related subtypes (27): factor XIII deficiency, factor VII deficiency, factor X deficiency, thrombophilia due to activated protein C resistance, hypoplasminogenemia, congenital high-molecular-weight kininogen deficiency, congenital factor XII deficiency, alpha-2-plasmin inhibitor deficiency, Tatsumi factor deficiency, East Texas bleeding disorder, inherited prekallikrein deficiency, congenital plasminogen activator inhibitor type 1 deficiency, thrombomodulin-related bleeding disorder, congenital vitamin K-dependent coagulation factors deficiency, hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation, multiple sclerosis-ichthyosis-factor VIII deficiency syndrome, combined deficiency of factor V and factor VIII, hemophilia, factor V deficiency, acquired coagulation factor deficiency, von Willebrand disease (hereditary or acquired), factor V short isoforms-related bleeding disorder, factor V amsterdam bleeding disorder, factor V atlanta bleeding disorder, combined deficiency of factor VII and factor X, plasminogen deficiency, type II, dysplasminogenemia

Subtypes (1): familial dysfibrinogenemia

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

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
547969	NM_021870.3(FGG):c.323C>G (p.Ala108Gly)	FGG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779652	NM_005141.5(FGB):c.1346G>A (p.Gly449Asp)	FGB	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 29 · Orphanet: 13 · 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
FGA	Definitive	Autosomal recessive	congenital afibrinogenemia	14
FGB	Strong	Autosomal recessive	congenital afibrinogenemia	7
FGG	Strong	Autosomal recessive	congenital afibrinogenemia	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGB	Orphanet:101041	Familial hypofibrinogenemia
FGB	Orphanet:248408	Familial hypodysfibrinogenemia
FGB	Orphanet:98880	Familial afibrinogenemia
FGB	Orphanet:98881	Familial dysfibrinogenemia
FGG	Orphanet:101041	Familial hypofibrinogenemia
FGG	Orphanet:248408	Familial hypodysfibrinogenemia
FGG	Orphanet:98880	Familial afibrinogenemia
FGG	Orphanet:98881	Familial dysfibrinogenemia
FGA	Orphanet:101041	Familial hypofibrinogenemia
FGA	Orphanet:248408	Familial hypodysfibrinogenemia
FGA	Orphanet:93562	AFib amyloidosis
FGA	Orphanet:98880	Familial afibrinogenemia
FGA	Orphanet:98881	Familial dysfibrinogenemia

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
FGB	HGNC:3662	ENSG00000171564	P02675	Fibrinogen beta chain	gencc,clinvar
FGG	HGNC:3694	ENSG00000171557	P02679	Fibrinogen gamma chain	gencc,clinvar
FGA	HGNC:3661	ENSG00000171560	P02671	Fibrinogen alpha chain	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGB	Fibrinogen beta chain	Cleaved by the protease thrombin to yield monomers which, together with fibrinogen alpha (FGA) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix.
FGG	Fibrinogen gamma chain	Together with fibrinogen alpha (FGA) and fibrinogen beta (FGB), polymerizes to form an insoluble fibrin matrix.
FGA	Fibrinogen alpha chain	Cleaved by the protease thrombin to yield monomers which, together with fibrinogen beta (FGB) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix.

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)
FGB	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_coil_dom, Fibrinogen_a/b/g_C_1
FGG	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_coil_dom, Fibrinogen_a/b/g_C_1
FGA	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_coil_dom, Fibrinogen_a/b/g_C_1

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
liver	3
right lobe of liver	3
type B pancreatic cell	2
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGB	159	broad	marker	right lobe of liver, liver, type B pancreatic cell
FGG	157	broad	marker	right lobe of liver, liver, type B pancreatic cell
FGA	153	tissue_specific	marker	right lobe of liver, liver, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGB	2,503
FGA	2,327
FGG	2,018

Intra-cohort edges

A	B	Sources
FGA	FGB	intact, string_interaction
FGA	FGG	biogrid_interaction, intact, string_interaction
FGB	FGG	biogrid_interaction, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGG	P02679	47
FGB	P02675	41
FGA	P02671	39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
Aggregated β-amyloid interacts with fibrinogen	3	2855.0×	4e-10	FGB, FGG, FGA
Fibrin formation	3	878.5×	1e-08	FGB, FGG, FGA
p130Cas linkage to MAPK signaling for integrins	3	761.3×	1e-08	FGB, FGG, FGA
GRB2:SOS provides linkage to MAPK signaling for Integrins	3	713.8×	1e-08	FGB, FGG, FGA
MyD88 deficiency (TLR2/4)	3	601.0×	2e-08	FGB, FGG, FGA
IRAK4 deficiency (TLR2/4)	3	571.0×	2e-08	FGB, FGG, FGA
Regulation of TLR by endogenous ligand	3	496.5×	2e-08	FGB, FGG, FGA
Integrin signaling	3	423.0×	3e-08	FGB, FGG, FGA
Signaling by high-kinase activity BRAF mutants	3	317.2×	7e-08	FGB, FGG, FGA
MAP2K and MAPK activation	3	285.5×	9e-08	FGB, FGG, FGA
Signaling by RAF1 mutants	3	278.5×	9e-08	FGB, FGG, FGA
Signaling by moderate kinase activity BRAF mutants	3	253.8×	9e-08	FGB, FGG, FGA
Paradoxical activation of RAF signaling by kinase inactive BRAF	3	253.8×	9e-08	FGB, FGG, FGA
Signaling downstream of RAS mutants	3	253.8×	9e-08	FGB, FGG, FGA
Signaling by BRAF and RAF1 fusions	3	170.4×	3e-07	FGB, FGG, FGA
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	3	152.3×	4e-07	FGB, FGG, FGA
Integrin cell surface interactions	3	134.3×	5e-07	FGB, FGG, FGA
ER-Phagosome pathway	3	129.8×	5e-07	FGB, FGG, FGA
Platelet degranulation	3	87.8×	2e-06	FGB, FGG, FGA
Post-translational protein phosphorylation	2	66.8×	3e-04	FGG, FGA
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	2	57.7×	4e-04	FGG, FGA
Amyloid fiber formation	1	34.3×	0.029	FGA

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, fibrin clot formation	3	1685.2×	2e-09	FGB, FGG, FGA
positive regulation of peptide hormone secretion	3	1532.0×	2e-09	FGB, FGG, FGA
plasminogen activation	3	1296.3×	2e-09	FGB, FGG, FGA
positive regulation of heterotypic cell-cell adhesion	3	1296.3×	2e-09	FGB, FGG, FGA
protein polymerization	3	991.3×	4e-09	FGB, FGG, FGA
fibrinolysis	3	842.6×	6e-09	FGB, FGG, FGA
positive regulation of vasoconstriction	3	601.9×	1e-08	FGB, FGG, FGA
positive regulation of exocytosis	3	601.9×	1e-08	FGB, FGG, FGA
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	3	581.1×	1e-08	FGB, FGG, FGA
negative regulation of endothelial cell apoptotic process	3	495.6×	2e-08	FGB, FGG, FGA
positive regulation of substrate adhesion-dependent cell spreading	3	374.5×	4e-08	FGB, FGG, FGA
positive regulation of protein secretion	3	343.9×	5e-08	FGB, FGG, FGA
platelet aggregation	3	337.0×	5e-08	FGB, FGG, FGA
response to calcium ion	3	318.0×	5e-08	FGB, FGG, FGA
cell-matrix adhesion	3	163.6×	4e-07	FGB, FGG, FGA
induction of bacterial agglutination	2	1872.4×	5e-07	FGB, FGA
protein-containing complex assembly	3	113.9×	9e-07	FGB, FGG, FGA
positive regulation of ERK1 and ERK2 cascade	3	85.1×	2e-06	FGB, FGG, FGA
blood coagulation, common pathway	1	2808.7×	4e-04	FGA
adaptive immune response	2	56.2×	5e-04	FGB, FGA
cellular response to leptin stimulus	1	510.7×	0.002	FGB
innate immune response	2	22.4×	0.003	FGB, FGA
cellular response to interleukin-1	1	93.6×	0.011	FGB
protein secretion	1	87.8×	0.011	FGG

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
FGB	1	2
FGG	0	0
FGA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SANGUINARIUM	2	FGB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FGB	2	Binding:2

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

1 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)
SANGUINARIUM	2	FGB

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	1	FGB
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FGG, FGA

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)
FGG	0	FGB
FGA	0	FGB

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02267226	PHASE3	COMPLETED	Efficacy and Safety Study of Octafibrin for On-demand Treatment of Acute Bleeding and to Prevent Bleeding During and After Surgery
NCT02408484	PHASE3	COMPLETED	Study to Assess the Efficacy, Safety and Pharmacokinetic of Octafibrin in Paediatric Subjects With Fibrinogen Deficiency
NCT01575756	PHASE2	COMPLETED	Pharmacokinetic, Efficacy, and Safety Study of Octafibrin Compared to Haemocomplettan/Riastap
NCT02427217	Not specified	COMPLETED	An Observational Cohort Study of the Safety and Efficacy of Fibrinogen Concentrate, Human (FCH) in Subjects With Congenital Fibrinogen Deficiency
NCT03793426	Not specified	TERMINATED	Safety and Efficacy of Fibryga in Congenital Fibrinogen Deficiency