Rieger anomaly

Summary

Rieger anomaly (MONDO:0019628) is a disease with 7 cohort genes.

At a glance

• Cohort genes: 7
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Rieger anomaly
Mondo ID	MONDO:0019628
Orphanet	91483
UMLS	C0265341
MedGen	78558
GARD	0016482
MedDRA	10059198
Is cancer (heuristic)	no

Data availability: 8 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › anterior segment dysgenesis › iridogoniodysgenesis › Rieger anomaly

Related subtypes (6): congenital microcoria, aniridia-cerebellar ataxia-intellectual disability syndrome, chromosome 6pter-p24 deletion syndrome, bilateral acute depigmentation of the iris, congenital ectropion uveae, FOXC1-related anterior segment dysgenesis

Subtypes (1): anterior segment dysgenesis 4

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

8 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 3 likely benign, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
492756	NM_000325.6(PITX2):c.307C>T (p.Gln103Ter)	PITX2	Pathogenic	criteria provided, single submitter
268022	46;XY;t(2;4)(p23;q27)dn		Likely pathogenic	criteria provided, single submitter
221949	NM_025074.7(FRAS1):c.3700G>A (p.Ala1234Thr)	FRAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30767	NM_001379081.2(FREM1):c.1493G>A (p.Arg498Gln)	FREM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
132723	NM_000264.5(PTCH1):c.3947A>G (p.Tyr1316Cys)	PTCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
221947	NM_024533.4(CHST5):c.737T>C (p.Ile246Thr)	CHST5	Likely benign	criteria provided, single submitter
221948	NM_001079520.2(DACT1):c.1899G>C (p.Lys633Asn)	DACT1	Likely benign	criteria provided, single submitter
132738	NM_000264.5(PTCH1):c.3889C>T (p.Arg1297Trp)	PTCH1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 29 · 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
FOXC1	Definitive	Autosomal dominant	Axenfeld-Rieger syndrome type 3	10
PITX2	Definitive	Autosomal dominant	Axenfeld-Rieger syndrome type 1	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PITX2	Orphanet:334	Hereditary atrial fibrillation
PITX2	Orphanet:708	Peters anomaly
PITX2	Orphanet:782	Axenfeld-Rieger syndrome
PITX2	Orphanet:91481	Ring dermoid of cornea
PITX2	Orphanet:91483	Rieger anomaly
PITX2	Orphanet:98978	Axenfeld anomaly
FOXC1	Orphanet:250923	Isolated aniridia
FOXC1	Orphanet:708	Peters anomaly
FOXC1	Orphanet:782	Axenfeld-Rieger syndrome
FOXC1	Orphanet:91483	Rieger anomaly
FOXC1	Orphanet:98978	Axenfeld anomaly
DACT1	Orphanet:268823	Occipital encephalocele
DACT1	Orphanet:63260	Craniorachischisis
DACT1	Orphanet:857	Townes-Brocks syndrome
FRAS1	Orphanet:2052	Fraser syndrome
FRAS1	Orphanet:93100	Renal agenesis, unilateral
FREM1	Orphanet:217266	BNAR syndrome
FREM1	Orphanet:2717	Oculotrichoanal syndrome
FREM1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FREM1	Orphanet:93100	Renal agenesis, unilateral
PTCH1	Orphanet:220386	Semilobar holoprosencephaly
PTCH1	Orphanet:2353	Schilbach-Rott syndrome
PTCH1	Orphanet:280195	Septopreoptic holoprosencephaly
PTCH1	Orphanet:280200	Microform holoprosencephaly
PTCH1	Orphanet:377	Gorlin syndrome
PTCH1	Orphanet:77301	Monosomy 9q22.3 syndrome
PTCH1	Orphanet:93924	Lobar holoprosencephaly
PTCH1	Orphanet:93925	Alobar holoprosencephaly
PTCH1	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PITX2	HGNC:9005	ENSG00000164093	Q99697	Pituitary homeobox 2	gencc,clinvar
FOXC1	HGNC:3800	ENSG00000054598	Q12948	Forkhead box protein C1	gencc
DACT1	HGNC:17748	ENSG00000165617	Q9NYF0	Dapper homolog 1	clinvar
FRAS1	HGNC:19185	ENSG00000138759	Q86XX4	Extracellular matrix organizing protein FRAS1	clinvar
CHST5	HGNC:1973	ENSG00000135702	Q9GZS9	Carbohydrate sulfotransferase 5	clinvar
FREM1	HGNC:23399	ENSG00000164946	Q5H8C1	FRAS1-related extracellular matrix protein 1	clinvar
PTCH1	HGNC:9585	ENSG00000185920	Q13635	Protein patched homolog 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PITX2	Pituitary homeobox 2	May play a role in myoblast differentiation.
FOXC1	Forkhead box protein C1	DNA-binding transcriptional factor that plays a role in a broad range of cellular and developmental processes such as eye, bones, cardiovascular, kidney and skin development.
DACT1	Dapper homolog 1	Involved in regulation of intracellular signaling pathways during development.
FRAS1	Extracellular matrix organizing protein FRAS1	Involved in extracellular matrix organization.
CHST5	Carbohydrate sulfotransferase 5	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues and O-linked sugars of mucin-type acceptors.
FREM1	FRAS1-related extracellular matrix protein 1	Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development.
PTCH1	Protein patched homolog 1	Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH).

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 5 · 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
Transcription factor	2	2.4×	0.332
Other/Unknown	5	1.3×	0.332

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PITX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
FOXC1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
DACT1	Other/Unknown	no		Dapper
FRAS1	Other/Unknown	no		EGF, VWF_dom, Calx_beta
CHST5	Other/Unknown	no		Sulfotransferase_dom, Carbohydrate_sulfotransferase, P-loop_NTPase
FREM1	Other/Unknown	no		C-type_lectin-like, Calx_beta, C-type_lectin-like/link_sf
PTCH1	Other/Unknown	no		SSD, TM_rcpt_patched, HMGCR/SNAP/NPC1-like_SSD

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
trigeminal ganglion	2
biceps brachii	1
gingiva	1
gingival epithelium	1
parotid gland	1
vena cava	1
cortical plate	1
gall bladder	1
right coronary artery	1
germinal epithelium of ovary	1
parietal pleura	1
renal medulla	1
duodenum	1
mucosa of transverse colon	1
rectum	1
kidney epithelium	1
metanephros	1
smooth muscle tissue	1
dorsal root ganglion	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PITX2	166	broad	marker	gingiva, biceps brachii, gingival epithelium
FOXC1	267	ubiquitous	marker	parotid gland, vena cava, trigeminal ganglion
DACT1	200	ubiquitous	marker	cortical plate, right coronary artery, gall bladder
FRAS1	212	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, renal medulla
CHST5	117	tissue_specific	marker	duodenum, rectum, mucosa of transverse colon
FREM1	171	broad	marker	kidney epithelium, smooth muscle tissue, metanephros
PTCH1	275	ubiquitous	marker	tibia, dorsal root ganglion, trigeminal ganglion

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTCH1	3,368
FOXC1	2,896
FRAS1	2,552
PITX2	2,389
FREM1	1,541
DACT1	1,107
CHST5	355

Intra-cohort edges

A	B	Sources
FOXC1	PITX2	intact, string_interaction
FRAS1	FREM1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTCH1	Q13635	16
PITX2	Q99697	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHST5	Q9GZS9	88.60
FREM1	Q5H8C1	75.75
FOXC1	Q12948	56.09
DACT1	Q9NYF0	50.95
FRAS1	Q86XX4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 7 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	571.0×	0.010	PITX2
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	326.3×	0.010	PTCH1
Ligand-receptor interactions	1	285.5×	0.010	PTCH1
Formation of intermediate mesoderm	1	285.5×	0.010	FOXC1
Activation of SMO	1	126.9×	0.017	PTCH1
Formation of the ureteric bud	1	99.3×	0.018	FOXC1
Keratan sulfate biosynthesis	1	76.1×	0.021	CHST5
Degradation of DVL	1	47.6×	0.029	DACT1
Class B/2 (Secretin family receptors)	1	38.1×	0.030	PTCH1
Hedgehog ‘off’ state	1	35.7×	0.030	PTCH1
Hedgehog ‘on’ state	1	31.7×	0.031	PTCH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
anatomical structure morphogenesis	4	79.6×	1e-05	PITX2, FRAS1, FREM1, FOXC1
cell communication	2	240.7×	0.002	FRAS1, FREM1
in utero embryonic development	3	30.9×	0.005	PITX2, FOXC1, PTCH1
embryonic limb morphogenesis	2	114.6×	0.005	FRAS1, PTCH1
camera-type eye development	2	102.4×	0.005	PITX2, FOXC1
subthalamic nucleus development	1	2407.4×	0.007	PITX2
superior vena cava morphogenesis	1	2407.4×	0.007	PITX2
glomerular epithelium development	1	2407.4×	0.007	FOXC1
positive regulation of hematopoietic stem cell differentiation	1	2407.4×	0.007	FOXC1
apoptotic process involved in outflow tract morphogenesis	1	1203.7×	0.007	FOXC1
response to chlorate	1	1203.7×	0.007	PTCH1
hypothalamus cell migration	1	1203.7×	0.007	PITX2
neural plate axis specification	1	1203.7×	0.007	PTCH1
prolactin secreting cell differentiation	1	1203.7×	0.007	PITX2
left lung morphogenesis	1	1203.7×	0.007	PITX2
pulmonary vein morphogenesis	1	1203.7×	0.007	PITX2
cell proliferation involved in outflow tract morphogenesis	1	1203.7×	0.007	PITX2
cell proliferation involved in metanephros development	1	1203.7×	0.007	PTCH1
negative regulation of apoptotic process involved in outflow tract morphogenesis	1	1203.7×	0.007	FOXC1
positive regulation of core promoter binding	1	1203.7×	0.007	FOXC1
negative regulation of transcription by RNA polymerase II	4	10.1×	0.007	PITX2, DACT1, FOXC1, PTCH1
pulmonary myocardium development	1	802.5×	0.007	PITX2
protein sulfation	1	802.5×	0.007	CHST5
vascular associated smooth muscle cell differentiation	1	802.5×	0.007	PITX2
deltoid tuberosity development	1	802.5×	0.007	PITX2
embryonic hindgut morphogenesis	1	802.5×	0.007	DACT1
cell differentiation involved in kidney development	1	802.5×	0.007	PTCH1
endodermal digestive tract morphogenesis	1	802.5×	0.007	PITX2
negative regulation of lymphangiogenesis	1	802.5×	0.007	FOXC1
positive regulation of hematopoietic progenitor cell differentiation	1	802.5×	0.007	FOXC1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 1 of 7 evidence-associated genes (14%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PITX2	0	0
FOXC1	0	0
DACT1	0	0
FRAS1	0	0
CHST5	0	0
FREM1	0	0
PTCH1	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
PTCH1	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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	7	PITX2, FOXC1, DACT1, FRAS1, CHST5, FREM1, PTCH1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PITX2	0	—
FOXC1	0	—
DACT1	0	—
FRAS1	0	—
CHST5	0	—
FREM1	0	—
PTCH1	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.