Holoprosencephaly 7

Summary

Holoprosencephaly 7 (MONDO:0012562) is a disease caused by PTCH1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PTCH1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 307

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	holoprosencephaly 7
Mondo ID	MONDO:0012562
MeSH	C563660
OMIM	610828
DOID	DOID:0110876
UMLS	C1835820
MedGen	372134
GARD	0024874
Is cancer (heuristic)	no

Also known as: holoprosencephaly 7 · holoprosencephaly caused by mutation in PTCH1 · holoprosencephaly type 7 · HPE7 · PTCH1 holoprosencephaly

Data availability: 307 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › holoprosencephaly 7

Related subtypes (16): holoprosencephaly 3, holoprosencephaly 4, holoprosencephaly 2, holoprosencephaly 1, holoprosencephaly 6, holoprosencephaly 8, 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

307 retrieved; paginated sample, class counts are floors:

113 conflicting classifications of pathogenicity, 87 uncertain significance, 54 benign/likely benign, 31 benign, 9 pathogenic, 5 likely benign, 5 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
409162	NM_000264.5(PTCH1):c.2308C>T (p.Arg770Ter)	LOC100507346	Pathogenic	criteria provided, multiple submitters, no conflicts
219697	NM_000264.5(PTCH1):c.258_259del (p.Leu87fs)	PTCH1	Pathogenic	criteria provided, multiple submitters, no conflicts
3382899	NM_000264.5(PTCH1):c.563dup (p.His189fs)	PTCH1	Pathogenic	criteria provided, single submitter
3775458	NM_000264.5(PTCH1):c.394+1G>C	PTCH1	Pathogenic	criteria provided, multiple submitters, no conflicts
4056454	NM_000264.5(PTCH1):c.637del (p.Thr213fs)	PTCH1	Pathogenic	criteria provided, single submitter
409158	NM_000264.5(PTCH1):c.1602+1G>T	PTCH1	Pathogenic	criteria provided, multiple submitters, no conflicts
409183	NM_000264.5(PTCH1):c.1208_1209del (p.Tyr403fs)	PTCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
428816	NM_000264.5(PTCH1):c.294C>A (p.Cys98Ter)	PTCH1	Pathogenic	criteria provided, multiple submitters, no conflicts
4687921	NM_000264.5(PTCH1):c.1439C>G (p.Ser480Ter)	PTCH1	Pathogenic	criteria provided, single submitter
561094	NM_000264.5(PTCH1):c.1216-1G>A	PTCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8225	NM_000264.5(PTCH1):c.2723T>G (p.Val908Gly)	PTCH1	Pathogenic	no assertion criteria provided
837425	NM_000264.5(PTCH1):c.724C>T (p.Gln242Ter)	PTCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3747861	NM_000264.5(PTCH1):c.1948_1949insAT (p.Phe650fs)	LOC100507346	Likely pathogenic	criteria provided, single submitter
3256739	NM_000264.5(PTCH1):c.202-3C>G	LOC130002132	Likely pathogenic	no assertion criteria provided
3068417	NM_000264.5(PTCH1):c.3272_3273del (p.Gly1091fs)	PTCH1	Likely pathogenic	criteria provided, single submitter
3597832	NM_000264.5(PTCH1):c.2704-1G>T	PTCH1	Likely pathogenic	criteria provided, single submitter
430657	NM_000264.5(PTCH1):c.2834delinsAGATGTTGTGGACCC (p.Arg945fs)	PTCH1	Likely pathogenic	criteria provided, single submitter
1709308	NM_001377229.1(DISP1):c.895C>T (p.Arg299Ter)	DISP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1059612	NM_000264.5(PTCH1):c.2540A>G (p.Tyr847Cys)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1346062	NM_000264.5(PTCH1):c.1981A>G (p.Thr661Ala)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135877	NM_000264.5(PTCH1):c.2177C>G (p.Pro726Arg)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188150	NM_000264.5(PTCH1):c.2440A>C (p.Asn814His)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215456	NM_000264.5(PTCH1):c.1809C>T (p.Arg603=)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
237462	NM_000264.5(PTCH1):c.1989G>C (p.Gln663His)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
237469	NM_000264.5(PTCH1):c.2303C>T (p.Thr768Ile)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255674	NM_000264.5(PTCH1):c.2184G>A (p.Thr728=)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
367669	NM_000264.5(PTCH1):c.1808G>A (p.Arg603His)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
409133	NM_000264.5(PTCH1):c.1855G>A (p.Val619Ile)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
409136	NM_000264.5(PTCH1):c.2333C>T (p.Thr778Met)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
409194	NM_000264.5(PTCH1):c.2176C>T (p.Pro726Ser)	LOC100507346	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 15 · 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
PTCH1	Definitive	Autosomal dominant	holoprosencephaly 7	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
DISP1	Orphanet:220386	Semilobar holoprosencephaly
DISP1	Orphanet:280195	Septopreoptic holoprosencephaly
DISP1	Orphanet:280200	Microform holoprosencephaly
DISP1	Orphanet:93924	Lobar holoprosencephaly
DISP1	Orphanet:93925	Alobar holoprosencephaly
DISP1	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

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
PTCH1	HGNC:9585	ENSG00000185920	Q13635	Protein patched homolog 1	gencc,clinvar
DISP1	HGNC:19711	ENSG00000154309	Q96F81	Protein dispatched homolog 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTCH1	Protein patched homolog 1	Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH).
DISP1	Protein dispatched homolog 1	Functions in hedgehog (Hh) signaling.

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)
PTCH1	Other/Unknown	no		SSD, TM_rcpt_patched, HMGCR/SNAP/NPC1-like_SSD
DISP1	Other/Unknown	no		SSD, MMPL_dom, Dispatched_Hh_regulator

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
dorsal root ganglion	1
tibia	1
trigeminal ganglion	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTCH1	275	ubiquitous	marker	tibia, dorsal root ganglion, trigeminal ganglion
DISP1	221	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTCH1	3,368
DISP1	621

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTCH1	Q13635	16
DISP1	Q96F81	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	1631.4×	0.002	PTCH1
Ligand-receptor interactions	1	1427.5×	0.002	PTCH1
Activation of SMO	1	634.4×	0.003	PTCH1
Class B/2 (Secretin family receptors)	1	190.3×	0.006	PTCH1
Hedgehog ‘off’ state	1	178.4×	0.006	PTCH1
Hedgehog ‘on’ state	1	158.6×	0.006	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dorsal/ventral pattern formation	2	421.3×	3e-04	PTCH1, DISP1
patched ligand maturation	1	8426.0×	0.003	DISP1
response to chlorate	1	4213.0×	0.003	PTCH1
neural plate axis specification	1	4213.0×	0.003	PTCH1
cell proliferation involved in metanephros development	1	4213.0×	0.003	PTCH1
cell differentiation involved in kidney development	1	2808.7×	0.004	PTCH1
peptide transport	1	2106.5×	0.004	DISP1
epidermal cell fate specification	1	1685.2×	0.004	PTCH1
neural tube patterning	1	1404.3×	0.004	PTCH1
hindlimb morphogenesis	1	1404.3×	0.004	PTCH1
negative regulation of cell division	1	1203.7×	0.004	PTCH1
mammary gland duct morphogenesis	1	1203.7×	0.004	PTCH1
positive regulation of epidermal cell differentiation	1	1053.2×	0.005	PTCH1
diaphragm development	1	936.2×	0.005	DISP1
metanephric collecting duct development	1	842.6×	0.005	PTCH1
response to alkaloid	1	766.0×	0.005	PTCH1
regulation of protein secretion	1	766.0×	0.005	DISP1
prostate gland development	1	702.2×	0.005	PTCH1
mammary gland epithelial cell differentiation	1	601.9×	0.005	PTCH1
negative regulation of multicellular organism growth	1	561.7×	0.005	PTCH1
somite development	1	561.7×	0.005	PTCH1
limb morphogenesis	1	526.6×	0.005	PTCH1
smooth muscle tissue development	1	526.6×	0.005	PTCH1
commissural neuron axon guidance	1	495.6×	0.005	PTCH1
cell fate determination	1	468.1×	0.005	PTCH1
spinal cord motor neuron differentiation	1	468.1×	0.005	PTCH1
cellular response to cholesterol	1	421.3×	0.005	PTCH1
negative regulation of stem cell proliferation	1	421.3×	0.005	PTCH1
dorsal/ventral neural tube patterning	1	401.2×	0.005	PTCH1
pharyngeal system development	1	401.2×	0.005	PTCH1

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
PTCH1	0	0
DISP1	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: 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	PTCH1, DISP1

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)
PTCH1	4	—
DISP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.