IRIDA syndrome

Summary

IRIDA syndrome (MONDO:0008788) is a disease caused by TMPRSS6 (GenCC Definitive), with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include ferric pyrophosphate citrate and ferrous sulfate.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TMPRSS6 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 46
• Phenotypes (HPO): 10
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		75	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0001891	Iron deficiency anemia	Very frequent (80-99%)
HP:0004840	Hypochromic microcytic anemia	Very frequent (80-99%)
HP:0025066	Decreased mean corpuscular volume	Very frequent (80-99%)
HP:0012464	Decreased transferrin saturation	Frequent (30-79%)
HP:0031877	Elevated circulating hepcidin concentration	Frequent (30-79%)
HP:0040303	Decreased serum iron	Frequent (30-79%)
HP:0001017	Anemic pallor	Occasional (5-29%)
HP:0030318	Angular cheilitis	Occasional (5-29%)
HP:0001596	Alopecia	Very rare (<1-4%)
HP:0001598	Concave nail	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	IRIDA syndrome
Mondo ID	MONDO:0008788
MeSH	C562385
OMIM	206200
Orphanet	209981
SNOMED CT	722005000
UMLS	C0085576
MedGen	39081
GARD	0010957
Is cancer (heuristic)	no

Also known as: anemia, hypochromic microcytic, with defect in iron metabolism · IRIDA · IRIDA syndrome · iron-refractory iron deficiency anaemia · iron-refractory iron deficiency anemia · pseudo-iron-deficiency Anaemia

Data availability: 46 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › microcytic anemia › IRIDA syndrome

Related subtypes (2): hypochromic microcytic anemia, fetal erythroblastosis

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

46 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 11 pathogenic, 8 benign, 5 likely pathogenic, 3 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579193	GRCh38/hg38 22q12.3(chr22:37098319-37127846)x1	LOC130067341	Pathogenic	criteria provided, single submitter
1399	NM_001374504.1(TMPRSS6):c.1877_1878dup (p.Lys627fs)	TMPRSS6	Pathogenic	no assertion criteria provided
1400	NM_001374504.1(TMPRSS6):c.1786del (p.Ala596fs)	TMPRSS6	Pathogenic	no assertion criteria provided
1401	NM_001374504.1(TMPRSS6):c.1555+1G>A	TMPRSS6	Pathogenic	no assertion criteria provided
1402	NM_001374504.1(TMPRSS6):c.2113+1G>C	TMPRSS6	Pathogenic	no assertion criteria provided
1403	NM_001374504.1(TMPRSS6):c.1297G>A (p.Gly433Arg)	TMPRSS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1407	NM_001374504.1(TMPRSS6):c.1152T>G (p.Tyr384Ter)	TMPRSS6	Pathogenic	no assertion criteria provided
1408	NM_001374504.1(TMPRSS6):c.1768C>T (p.Arg590Ter)	TMPRSS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1409	NM_001374504.1(TMPRSS6):c.2028_2031dup (p.Val678fs)	TMPRSS6	Pathogenic	no assertion criteria provided
1410	NM_001374504.1(TMPRSS6):c.326C>A (p.Ala109Asp)	TMPRSS6	Pathogenic	no assertion criteria provided
2412690	NM_001374504.1(TMPRSS6):c.1055C>A (p.Ser352Ter)	TMPRSS6	Pathogenic	criteria provided, single submitter
2906057	NM_001374504.1(TMPRSS6):c.1342+1G>A	TMPRSS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30802	NM_001374504.1(TMPRSS6):c.1537G>A (p.Glu513Lys)	TMPRSS6	Pathogenic	no assertion criteria provided
3380919	NM_001374504.1(TMPRSS6):c.1655C>A (p.Ser552Ter)	TMPRSS6	Pathogenic	criteria provided, multiple submitters, no conflicts
1299579	NM_001374504.1(TMPRSS6):c.1547G>A (p.Cys516Tyr)	TMPRSS6	Likely pathogenic	criteria provided, single submitter
1404	NM_001374504.1(TMPRSS6):c.1534G>A (p.Asp512Asn)	TMPRSS6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405	NM_001374504.1(TMPRSS6):c.1038C>A (p.Tyr346Ter)	TMPRSS6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1406	NM_001374504.1(TMPRSS6):c.1355del (p.Glu452fs)	TMPRSS6	Likely pathogenic	criteria provided, single submitter
4077699	NM_001374504.1(TMPRSS6):c.2062G>T (p.Glu688Ter)	TMPRSS6	Likely pathogenic	criteria provided, single submitter
1049820	NM_001374504.1(TMPRSS6):c.457C>T (p.Arg153Cys)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341581	NM_001374504.1(TMPRSS6):c.2058C>G (p.Phe686Leu)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
734033	NM_001374504.1(TMPRSS6):c.844G>A (p.Gly282Ser)	TMPRSS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1301819	NM_001374504.1(TMPRSS6):c.1842-31CCCCA[2]	TMPRSS6	Uncertain significance	criteria provided, single submitter
1366522	NM_001374504.1(TMPRSS6):c.631G>T (p.Gly211Cys)	TMPRSS6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1969149	NM_001374504.1(TMPRSS6):c.808G>A (p.Gly270Arg)	TMPRSS6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2062877	NM_001374504.1(TMPRSS6):c.1021G>A (p.Val341Ile)	TMPRSS6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2437122	NM_001374504.1(TMPRSS6):c.2128G>A (p.Ala710Thr)	TMPRSS6	Uncertain significance	criteria provided, single submitter
2437123	NM_001374504.1(TMPRSS6):c.65C>T (p.Ala22Val)	TMPRSS6	Uncertain significance	criteria provided, single submitter
2500843	NM_001374504.1(TMPRSS6):c.836+1G>A	TMPRSS6	Uncertain significance	criteria provided, single submitter
2500890	NM_001374504.1(TMPRSS6):c.1842_1843insCCACC (p.Met615fs)	TMPRSS6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
TMPRSS6	Definitive	Autosomal recessive	IRIDA syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMPRSS6	Orphanet:209981	IRIDA syndrome

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
TMPRSS6	HGNC:16517	ENSG00000187045	Q8IU80	Transmembrane protease serine 6	gencc,clinvar
TOX	HGNC:18988	ENSG00000198846	O94900	Thymocyte selection-associated high mobility group box protein TOX	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMPRSS6	Transmembrane protease serine 6	Membrane-bound serine protease.
TOX	Thymocyte selection-associated high mobility group box protein TOX	Transcriptional regulator with a major role in neural stem cell commitment and corticogenesis as well as in lymphoid cell development and lymphoid tissue organogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMPRSS6	Protease	yes	3.4.21.109	SEA_dom, CUB_dom, Trypsin_dom
TOX	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf, TOX_HMG-box_domain

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
mammary duct	1
right lobe of liver	1
cortical plate	1
endothelial cell	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMPRSS6	142	tissue_specific	yes	right lobe of liver, liver, mammary duct
TOX	231	ubiquitous	marker	cortical plate, endothelial cell, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TOX	1,112
TMPRSS6	897

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TMPRSS6	Q8IU80	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TOX	O94900	54.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Collagen degradation	1	175.7×	0.008	TMPRSS6
Degradation of the extracellular matrix	1	117.7×	0.008	TMPRSS6

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
NK T cell lineage commitment	1	8426.0×	0.001	TOX
CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment	1	4213.0×	0.001	TOX
CD4-positive, alpha-beta T cell lineage commitment	1	4213.0×	0.001	TOX
CD8-positive, alpha-beta T cell lineage commitment	1	4213.0×	0.001	TOX
regulation of positive thymic T cell selection	1	4213.0×	0.001	TOX
leukocyte differentiation	1	1685.2×	0.003	TOX
Peyer’s patch development	1	1053.2×	0.004	TOX
positive regulation of natural killer cell differentiation	1	842.6×	0.004	TOX
self proteolysis	1	766.0×	0.004	TMPRSS6
cerebral cortex neuron differentiation	1	601.9×	0.004	TOX
membrane protein proteolysis	1	526.6×	0.004	TMPRSS6
natural killer cell differentiation	1	443.5×	0.005	TOX
lymph node development	1	401.2×	0.005	TOX
positive regulation of neural precursor cell proliferation	1	383.0×	0.005	TOX
multicellular organismal-level iron ion homeostasis	1	290.6×	0.006	TMPRSS6
positive regulation of transcription by RNA polymerase II	2	14.9×	0.007	TMPRSS6, TOX
collagen catabolic process	1	195.9×	0.008	TMPRSS6
extracellular matrix disassembly	1	183.2×	0.008	TMPRSS6
negative regulation of BMP signaling pathway	1	145.3×	0.009	TMPRSS6
intracellular iron ion homeostasis	1	122.1×	0.011	TMPRSS6
BMP signaling pathway	1	100.3×	0.012	TMPRSS6
positive regulation of neuron projection development	1	68.5×	0.017	TOX
chromatin organization	1	49.6×	0.023	TOX
negative regulation of DNA-templated transcription	1	15.8×	0.068	TMPRSS6
negative regulation of transcription by RNA polymerase II	1	8.9×	0.114	TMPRSS6
regulation of transcription by RNA polymerase II	1	5.8×	0.164	TOX

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
TMPRSS6	0	0
TOX	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
TMPRSS6	21	Binding:21

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TMPRSS6	3.4.21.109	matriptase

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	1	TMPRSS6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TOX

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)
TMPRSS6	21	—
TOX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02905981	PHASE2	TERMINATED	Triferic IRIDA (Iron-Refractory Iron-Deficiency Anemia) Protocol

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FERRIC PYROPHOSPHATE CITRATE	4	1
FERROUS SULFATE	4	1