Holoprosencephaly 1

Summary

Holoprosencephaly 1 (MONDO:0009349) is a disease with 5 cohort genes.

At a glance

• Cohort genes: 5
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	holoprosencephaly 1
Mondo ID	MONDO:0009349
OMIM	236100
DOID	DOID:0110881
NCIT	C75476
UMLS	C0266667
MedGen	78617
GARD	0024660
Is cancer (heuristic)	no

Also known as: cyclopia · holoprosencephaly 1 · holoprosencephaly 1, isolated cases · holoprosencephaly type 1 · Hpe, familial · HPE1

Data availability: 8 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › holoprosencephaly 1

Related subtypes (16): holoprosencephaly 3, holoprosencephaly 4, holoprosencephaly 2, holoprosencephaly 6, holoprosencephaly 8, holoprosencephaly 7, chromosome 1q41-q42 deletion syndrome, holoprosencephaly 11, microform holoprosencephaly, lobar holoprosencephaly, alobar holoprosencephaly, holoprosencephaly 13, X-linked, holoprosencephaly 14, holoprosencephaly 12 with or without pancreatic agenesis, semilobar holoprosencephaly, holoprosencephaly 10

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 uncertain significance, 2 conflicting classifications of pathogenicity, 2 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
9126	NM_033163.5(FGF8):c.686C>T (p.Thr229Met)	FGF8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259723	NM_001374353.1(GLI2):c.2108G>A (p.Arg703His)	GLI2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31574	NM_002048.3(GAS1):c.599C>G (p.Thr200Arg)	GAS1	Uncertain significance	no assertion criteria provided
31575	NM_002048.3(GAS1):c.776G>A (p.Gly259Glu)	GAS1	Uncertain significance	no assertion criteria provided
689364	NM_007129.5(ZIC2):c.*954T>A	ZIC2	Uncertain significance	criteria provided, single submitter
260799	NM_001378964.1(CDON):c.3662T>A (p.Ile1221Asn)	CDON	Benign	criteria provided, multiple submitters, no conflicts
802628	NM_033163.5(FGF8):c.506C>T (p.Ala169Val)	FGF8	Likely benign	criteria provided, single submitter
801743	NM_001374353.1(GLI2):c.149-274C>G	GLI2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 35 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZIC2	Orphanet:220386	Semilobar holoprosencephaly
ZIC2	Orphanet:280195	Septopreoptic holoprosencephaly
ZIC2	Orphanet:280200	Microform holoprosencephaly
ZIC2	Orphanet:93924	Lobar holoprosencephaly
ZIC2	Orphanet:93925	Alobar holoprosencephaly
ZIC2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
CDON	Orphanet:220386	Semilobar holoprosencephaly
CDON	Orphanet:280195	Septopreoptic holoprosencephaly
CDON	Orphanet:280200	Microform holoprosencephaly
CDON	Orphanet:93924	Lobar holoprosencephaly
CDON	Orphanet:93925	Alobar holoprosencephaly
CDON	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
CDON	Orphanet:95496	Pituitary stalk interruption syndrome
FGF8	Orphanet:220386	Semilobar holoprosencephaly
FGF8	Orphanet:280195	Septopreoptic holoprosencephaly
FGF8	Orphanet:280200	Microform holoprosencephaly
FGF8	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
FGF8	Orphanet:478	Kallmann syndrome
FGF8	Orphanet:93924	Lobar holoprosencephaly
FGF8	Orphanet:93925	Alobar holoprosencephaly
FGF8	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
GAS1	Orphanet:220386	Semilobar holoprosencephaly
GAS1	Orphanet:280195	Septopreoptic holoprosencephaly
GAS1	Orphanet:280200	Microform holoprosencephaly
GAS1	Orphanet:93924	Lobar holoprosencephaly
GAS1	Orphanet:93925	Alobar holoprosencephaly
GAS1	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
GLI2	Orphanet:220386	Semilobar holoprosencephaly
GLI2	Orphanet:280195	Septopreoptic holoprosencephaly
GLI2	Orphanet:280200	Microform holoprosencephaly
GLI2	Orphanet:420584	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
GLI2	Orphanet:93924	Lobar holoprosencephaly
GLI2	Orphanet:93925	Alobar holoprosencephaly
GLI2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
GLI2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZIC2	HGNC:12873	ENSG00000043355	O95409	Zinc finger protein ZIC 2	clinvar
CDON	HGNC:17104	ENSG00000064309	Q4KMG0	Cell adhesion molecule-related/down-regulated by oncogenes	clinvar
FGF8	HGNC:3686	ENSG00000107831	P55075	Fibroblast growth factor 8	clinvar
GAS1	HGNC:4165	ENSG00000180447	P54826	Growth arrest-specific protein 1	clinvar
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZIC2	Zinc finger protein ZIC 2	Acts as a transcriptional activator or repressor.
CDON	Cell adhesion molecule-related/down-regulated by oncogenes	Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells.
FGF8	Fibroblast growth factor 8	Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration.
GAS1	Growth arrest-specific protein 1	Specific growth arrest protein involved in growth suppression.
GLI2	Zinc finger protein GLI2	Functions as a transcription regulator in the hedgehog (Hh) pathway.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

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
Antibody/Immunoglobulin	1	5.8×	0.240
Transcription factor	2	3.3×	0.240
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZIC2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Znf_ZIC
CDON	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
FGF8	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
GAS1	Other/Unknown	no		GDNF/GAS1, GAS1
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
germinal epithelium of ovary	2
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
calcaneal tendon	1
ganglionic eminence	1
endometrium epithelium	1
metanephric glomerulus	1
primordial germ cell in gonad	1
decidua	1
parietal pleura	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZIC2	139	broad	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
CDON	222	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
FGF8	109	tissue_specific	yes	primordial germ cell in gonad, metanephric glomerulus, endometrium epithelium
GAS1	276	broad	marker	germinal epithelium of ovary, decidua, parietal pleura
GLI2	211	ubiquitous	marker	tibia, germinal epithelium of ovary, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF8	4,536
GLI2	3,112
ZIC2	1,738
GAS1	1,121
CDON	1,065

Intra-cohort edges

A	B	Sources
CDON	GAS1	string_interaction
CDON	GLI2	string_interaction
GAS1	GLI2	string_interaction
GAS1	ZIC2	string_interaction
GLI2	ZIC2	biogrid_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDON	Q4KMG0	3
FGF8	P55075	1
GAS1	P54826	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZIC2	O95409	51.36
GLI2	P10070	42.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 5 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
Ligand-receptor interactions	2	571.0×	2e-04	CDON, GAS1
Activation of SMO	2	253.8×	6e-04	CDON, GAS1
Hedgehog ‘on’ state	2	63.4×	0.007	CDON, GLI2
RUNX2 regulates chondrocyte maturation	1	456.8×	0.017	GLI2
FGFR3b ligand binding and activation	1	326.3×	0.017	FGF8
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	326.3×	0.017	GLI2
Formation of the posterior neural plate	1	228.4×	0.017	FGF8
Formation of the anterior neural plate	1	207.6×	0.017	ZIC2
Signaling by activated point mutants of FGFR1	1	190.3×	0.017	FGF8
Signaling by activated point mutants of FGFR3	1	190.3×	0.017	FGF8
FGFR3c ligand binding and activation	1	175.7×	0.017	FGF8
FGFR2c ligand binding and activation	1	175.7×	0.017	FGF8
Phospholipase C-mediated cascade; FGFR3	1	175.7×	0.017	FGF8
FGFRL1 modulation of FGFR1 signaling	1	175.7×	0.017	FGF8
FGFR4 ligand binding and activation	1	163.1×	0.017	FGF8
FGFR1c ligand binding and activation	1	152.3×	0.017	FGF8
Phospholipase C-mediated cascade; FGFR4	1	152.3×	0.017	FGF8
Activated point mutants of FGFR2	1	134.3×	0.017	FGF8
Phospholipase C-mediated cascade: FGFR1	1	134.3×	0.017	FGF8
Phospholipase C-mediated cascade; FGFR2	1	126.9×	0.017	FGF8
PI-3K cascade:FGFR3	1	126.9×	0.017	FGF8
SHC-mediated cascade:FGFR3	1	120.2×	0.017	FGF8
PI-3K cascade:FGFR4	1	114.2×	0.017	FGF8
Downstream signaling of activated FGFR1	1	108.8×	0.017	FGF8
FRS-mediated FGFR3 signaling	1	108.8×	0.017	FGF8
SHC-mediated cascade:FGFR4	1	108.8×	0.017	FGF8
PI-3K cascade:FGFR1	1	103.8×	0.017	FGF8
SHC-mediated cascade:FGFR1	1	99.3×	0.017	FGF8
PI-3K cascade:FGFR2	1	99.3×	0.017	FGF8
FRS-mediated FGFR4 signaling	1	99.3×	0.017	FGF8

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
developmental growth	2	293.1×	0.002	GAS1, GLI2
cell fate commitment	2	118.3×	0.007	FGF8, GAS1
pallium development	1	3370.4×	0.009	FGF8
midbrain-hindbrain boundary development	1	1685.2×	0.009	FGF8
negative regulation of cardiac muscle tissue development	1	1685.2×	0.009	FGF8
cell migration involved in mesendoderm migration	1	1685.2×	0.009	FGF8
larynx morphogenesis	1	1685.2×	0.009	FGF8
neural plate morphogenesis	1	1123.5×	0.009	FGF8
ventral midline development	1	1123.5×	0.009	GLI2
floor plate formation	1	1123.5×	0.009	GLI2
subpallium development	1	1123.5×	0.009	FGF8
spinal cord ventral commissure morphogenesis	1	1123.5×	0.009	GLI2
corticotropin hormone secreting cell differentiation	1	1123.5×	0.009	FGF8
smoothened signaling pathway	2	72.5×	0.009	CDON, GLI2
hindgut morphogenesis	1	842.6×	0.009	GLI2
dorsal/ventral axon guidance	1	842.6×	0.009	FGF8
tube development	1	842.6×	0.009	GLI2
mesodermal cell migration	1	674.1×	0.010	FGF8
cerebellar cortex morphogenesis	1	561.7×	0.010	GLI2
positive regulation of skeletal muscle tissue development	1	561.7×	0.010	CDON
thyroid-stimulating hormone-secreting cell differentiation	1	561.7×	0.010	FGF8
mitotic nuclear division	1	561.7×	0.010	FGF8
forebrain neuron development	1	481.5×	0.010	FGF8
regulation of odontogenesis of dentin-containing tooth	1	481.5×	0.010	FGF8
embryonic retina morphogenesis in camera-type eye	1	481.5×	0.010	CDON
embryonic body morphogenesis	1	421.3×	0.010	CDON
skeletal muscle satellite cell differentiation	1	421.3×	0.010	CDON
spinal cord dorsal/ventral patterning	1	421.3×	0.010	GLI2
forebrain dorsal/ventral pattern formation	1	421.3×	0.010	FGF8
otic vesicle formation	1	421.3×	0.010	FGF8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ZIC2	0	0
CDON	0	0
FGF8	0	0
GAS1	0	0
GLI2	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
GLI2	6	Binding:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	CDON
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	ZIC2, FGF8, GAS1, GLI2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZIC2	0	—
CDON	0	—
FGF8	0	—
GAS1	0	—
GLI2	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.