Holoprosencephaly 3

Summary

Holoprosencephaly 3 (MONDO:0007733) is a disease caused by SHH (GenCC Definitive), with 6 cohort genes.

At a glance

• Causal gene: SHH (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 424

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	holoprosencephaly 3
Mondo ID	MONDO:0007733
MeSH	C564181
OMIM	142945
DOID	DOID:0110875
UMLS	C1840529
MedGen	327125
GARD	0024572
Is cancer (heuristic)	no

Also known as: HLP3 · holoprosencephaly 3 · holoprosencephaly caused by mutation in SHH · holoprosencephaly caused by mutation in Shh · holoprosencephaly type 3 · HPE3 · SHH holoprosencephaly · Shh holoprosencephaly

Data availability: 424 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › holoprosencephaly 3

Related subtypes (16): holoprosencephaly 4, holoprosencephaly 2, holoprosencephaly 1, 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

Subtypes (1): solitary median maxillary central incisor syndrome

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

424 retrieved; paginated sample, class counts are floors:

195 uncertain significance, 90 likely benign, 48 pathogenic, 38 benign, 32 likely pathogenic, 12 conflicting classifications of pathogenicity, 6 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
65846	c.1308C>T		Pathogenic	no assertion criteria provided
2579275	GRCh38/hg38 7q36.2-36.3(chr7:154446117-159206757)x1	BLACE	Pathogenic	criteria provided, single submitter
2422565	NC_000007.13:g.(?152617597)(158500659_?)del	CNPY1	Pathogenic	criteria provided, single submitter
1703527	GRCh37/hg19 7q36.2-36.3(chr7:154831466-156356088)	INSIG1	Pathogenic	no assertion criteria provided
1458762	NC_000007.13:g.(?155596114)(155657138_?)del	SHH	Pathogenic	criteria provided, single submitter
2577434	NM_000193.4(SHH):c.705del (p.Leu234_Tyr235insTer)	SHH	Pathogenic	no assertion criteria provided
3254599	NM_000193.4(SHH):c.136C>T (p.Gln46Ter)	SHH	Pathogenic	criteria provided, single submitter
3345617	NM_000193.4(SHH):c.1040C>A (p.Pro347Gln)	SHH	Pathogenic	criteria provided, single submitter
3377926	NM_000193.4(SHH):c.855dup (p.Glu286fs)	SHH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384113	NM_000193.4(SHH):c.1308del (p.Gln437fs)	SHH	Pathogenic	criteria provided, single submitter
374270	NM_000193.4(SHH):c.1284del (p.Thr429fs)	SHH	Pathogenic	criteria provided, single submitter
3775118	NM_000193.4(SHH):c.72C>A (p.Cys24Ter)	SHH	Pathogenic	criteria provided, single submitter
3775119	NM_000193.4(SHH):c.57C>A (p.Cys19Ter)	SHH	Pathogenic	criteria provided, single submitter
3775129	NM_000193.4(SHH):c.388G>T (p.Glu130Ter)	SHH	Pathogenic	criteria provided, single submitter
3775130	NM_000193.4(SHH):c.469A>T (p.Lys157Ter)	SHH	Pathogenic	criteria provided, single submitter
3775138	NM_000193.4(SHH):c.404C>G (p.Ser135Ter)	SHH	Pathogenic	criteria provided, single submitter
3775143	NM_000193.4(SHH):c.730del (p.Arg244fs)	SHH	Pathogenic	criteria provided, single submitter
3775146	NM_000193.4(SHH):c.1015G>T (p.Glu339Ter)	SHH	Pathogenic	criteria provided, single submitter
3775147	NM_000193.4(SHH):c.281_282dup (p.Asp95fs)	SHH	Pathogenic	criteria provided, single submitter
3775148	NM_000193.4(SHH):c.1085C>A (p.Ser362Ter)	SHH	Pathogenic	criteria provided, single submitter
3775149	NM_000193.4(SHH):c.587del (p.Gly196fs)	SHH	Pathogenic	criteria provided, single submitter
3775159	NM_000193.4(SHH):c.121_122del (p.Pro41fs)	SHH	Pathogenic	criteria provided, single submitter
379347	NM_000193.4(SHH):c.423C>A (p.Tyr141Ter)	SHH	Pathogenic	criteria provided, multiple submitters, no conflicts
464839	NM_000193.4(SHH):c.851_873del (p.Glu284fs)	SHH	Pathogenic	criteria provided, single submitter
545575	NM_000193.4(SHH):c.1040C>T (p.Pro347Leu)	SHH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545579	NM_000193.4(SHH):c.1307C>A (p.Ser436Ter)	SHH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545582	NM_000193.4(SHH):c.214C>T (p.Arg72Ter)	SHH	Pathogenic	criteria provided, multiple submitters, no conflicts
646865	NM_000193.4(SHH):c.419_423dup (p.Glu142fs)	SHH	Pathogenic	criteria provided, single submitter
65849	NM_000193.4(SHH):c.1212_1226del (p.Asp405_Gly409del)	SHH	Pathogenic	no assertion criteria provided
65853	NM_000193.4(SHH):c.6_9dup (p.Leu4fs)	SHH	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 21 · 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
SHH	Definitive	Autosomal dominant	holoprosencephaly 3	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SHH	Orphanet:220386	Semilobar holoprosencephaly
SHH	Orphanet:280195	Septopreoptic holoprosencephaly
SHH	Orphanet:280200	Microform holoprosencephaly
SHH	Orphanet:476119	Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome
SHH	Orphanet:485275	Acquired schizencephaly
SHH	Orphanet:93321	Isolated radial hemimelia
SHH	Orphanet:93336	Polydactyly of a triphalangeal thumb
SHH	Orphanet:93405	Syndactyly type 4
SHH	Orphanet:93924	Lobar holoprosencephaly
SHH	Orphanet:93925	Alobar holoprosencephaly
SHH	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
SHH	Orphanet:988	Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome
SHH	Orphanet:98938	Colobomatous microphthalmia
LMBR1	Orphanet:2378	Laurin-Sandrow syndrome
LMBR1	Orphanet:931	Isolated acheiropodia
LMBR1	Orphanet:93321	Isolated radial hemimelia
LMBR1	Orphanet:93336	Polydactyly of a triphalangeal thumb
LMBR1	Orphanet:93405	Syndactyly type 4
LMBR1	Orphanet:988	Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome
DNAJB6	Orphanet:34516	DNAJB6-related limb-girdle muscular dystrophy D1
DNAJB6	Orphanet:708126	DNAJB6-related distal myopathy

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SHH	HGNC:10848	ENSG00000164690	Q15465	Sonic hedgehog protein	gencc,clinvar
LMBR1	HGNC:13243	ENSG00000105983	Q8WVP7	Limb region 1 protein homolog	clinvar
DNAJB6	HGNC:14888	ENSG00000105993	O75190	DnaJ homolog subfamily B member 6	clinvar
BLACE	HGNC:20484	ENSG00000204960	A4D250	B-cell acute lymphoblastic leukemia-expressed protein	clinvar
CNPY1	HGNC:27786	ENSG00000146910	Q3B7I2	Protein canopy homolog 1	clinvar
INSIG1	HGNC:6083	ENSG00000186480	O15503	Insulin-induced gene 1 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SHH	Sonic hedgehog protein	The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity.
LMBR1	Limb region 1 protein homolog	Putative membrane receptor.
DNAJB6	DnaJ homolog subfamily B member 6	Has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70.
INSIG1	Insulin-induced gene 1 protein	Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 6 · 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	6	1.8×	0.030

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint
LMBR1	Other/Unknown	no		LMBR1-like_membr_prot, LIMR
DNAJB6	Other/Unknown	no		DnaJ_domain, DnaJ_domain_CS, J_dom_sf
BLACE	Other/Unknown	no
CNPY1	Other/Unknown	no		DUF3456, CNPY
INSIG1	Other/Unknown	no		INSIG_fam

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)	1
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
buccal mucosa cell	1
epithelial cell of pancreas	1
adrenal tissue	1
calcaneal tendon	1
sural nerve	1
cortical plate	1
ganglionic eminence	1
primordial germ cell in gonad	1
muscle tissue	1
pancreas	1
testis	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
cartilage tissue	1
liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SHH	131	broad	marker	buccal mucosa cell, right lobe of liver, epithelial cell of pancreas
LMBR1	249	ubiquitous	marker	adrenal tissue, sural nerve, calcaneal tendon
DNAJB6	283	ubiquitous	marker	cortical plate, primordial germ cell in gonad, ganglionic eminence
BLACE	10		yes	pancreas, muscle tissue, testis
CNPY1	49	tissue_specific	yes	cerebellar hemisphere, cerebellar cortex, cerebellum
INSIG1	291	ubiquitous	marker	cartilage tissue, right lobe of liver, liver

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SHH	4,953
DNAJB6	3,518
INSIG1	1,818
LMBR1	977
CNPY1	408
BLACE	0

Intra-cohort edges

A	B	Sources
LMBR1	SHH	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SHH	Q15465	20
DNAJB6	O75190	4
INSIG1	O15503	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CNPY1	Q3B7I2	79.89
LMBR1	Q8WVP7	79.49
BLACE	A4D250	29.53

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 6 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
HHAT G278V doesn’t palmitoylate Hh-Np	1	761.3×	0.013	SHH
Formation of lateral plate mesoderm	1	761.3×	0.013	SHH
Release of Hh-Np from the secreting cell	1	475.8×	0.013	SHH
Hh mutants abrogate ligand secretion	1	475.8×	0.013	SHH
Ligand-receptor interactions	1	475.8×	0.013	SHH
Formation of axial mesoderm	1	271.9×	0.018	SHH
Activation of SMO	1	211.5×	0.019	SHH
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	200.3×	0.019	SHH
Attenuation phase	1	135.9×	0.023	DNAJB6
HSF1 activation	1	126.9×	0.023	DNAJB6
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	105.7×	0.023	INSIG1
HSF1-dependent transactivation	1	105.7×	0.023	DNAJB6
Developmental Lineage of Pancreatic Acinar Cells	1	100.2×	0.023	SHH
Gastrulation	1	86.5×	0.025	SHH
Hh mutants are degraded by ERAD	1	81.0×	0.025	SHH
Developmental Cell Lineages	1	74.6×	0.025	SHH
Hedgehog ligand biogenesis	1	70.5×	0.025	SHH
Class B/2 (Secretin family receptors)	1	63.4×	0.026	SHH
Signaling by Hedgehog	1	61.4×	0.026	SHH
Hedgehog ‘on’ state	1	52.9×	0.028	SHH
Regulation of HSF1-mediated heat shock response	1	46.4×	0.030	DNAJB6
Metabolism of steroids	1	45.9×	0.030	INSIG1
GPCR ligand binding	1	21.4×	0.060	SHH
Diseases of signal transduction by growth factor receptors and second messengers	1	18.9×	0.065	SHH
Signaling by GPCR	1	13.4×	0.088	SHH
Metabolism of lipids	1	10.5×	0.106	INSIG1
Developmental Biology	1	4.8×	0.215	SHH
Disease	1	4.4×	0.227	SHH
Metabolism	1	3.9×	0.245	INSIG1
Signal Transduction	1	3.4×	0.267	SHH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
polarity specification of anterior/posterior axis	1	4213.0×	0.002	SHH
trachea morphogenesis	1	4213.0×	0.002	SHH
right lung development	1	4213.0×	0.002	SHH
left lung development	1	4213.0×	0.002	SHH
primary prostatic bud elongation	1	4213.0×	0.002	SHH
regulation of prostatic bud formation	1	4213.0×	0.002	SHH
obsolete regulation of mesenchymal cell proliferation involved in prostate gland development	1	4213.0×	0.002	SHH
mesenchymal smoothened signaling pathway involved in prostate gland development	1	4213.0×	0.002	SHH
positive regulation of sclerotome development	1	4213.0×	0.002	SHH
negative regulation of protein exit from endoplasmic reticulum	1	4213.0×	0.002	INSIG1
negative regulation of cargo loading into COPII-coated vesicle	1	4213.0×	0.002	INSIG1
tracheoesophageal septum formation	1	4213.0×	0.002	SHH
negative regulation of ureter smooth muscle cell differentiation	1	4213.0×	0.002	SHH
positive regulation of ureter smooth muscle cell differentiation	1	4213.0×	0.002	SHH
negative regulation of kidney smooth muscle cell differentiation	1	4213.0×	0.002	SHH
positive regulation of kidney smooth muscle cell differentiation	1	4213.0×	0.002	SHH
embryonic digit morphogenesis	2	150.5×	0.002	SHH, LMBR1
roof of mouth development	2	123.9×	0.002	SHH, INSIG1
intermediate filament organization	2	120.4×	0.002	SHH, DNAJB6
positive regulation of skeletal muscle cell proliferation	1	2106.5×	0.003	SHH
intein-mediated protein splicing	1	2106.5×	0.003	SHH
SREBP-SCAP complex retention in endoplasmic reticulum	1	2106.5×	0.003	INSIG1
trunk neural crest cell migration	1	2106.5×	0.003	SHH
regulation of nodal signaling pathway	1	2106.5×	0.003	SHH
positive regulation of mesenchymal cell proliferation involved in ureter development	1	2106.5×	0.003	SHH
ventral midline development	1	1404.3×	0.004	SHH
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	1404.3×	0.004	SHH
negative regulation of alpha-beta T cell differentiation	1	1404.3×	0.004	SHH
regulation of glial cell proliferation	1	1404.3×	0.004	SHH
bud outgrowth involved in lung branching	1	1404.3×	0.004	SHH

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SHH	VISMODEGIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SHH	1	4
LMBR1	0	0
DNAJB6	0	0
BLACE	0	0
CNPY1	0	0
INSIG1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VISMODEGIB	4	SHH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SHH	27	Binding:23, Functional:4
DNAJB6	2	Binding:2
INSIG1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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)
VISMODEGIB	4	SHH

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SHH
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	5	LMBR1, DNAJB6, BLACE, CNPY1, INSIG1

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)
LMBR1	0	SHH
DNAJB6	2	—
BLACE	0	—
CNPY1	0	—
INSIG1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.