Semilobar holoprosencephaly

Summary

Semilobar holoprosencephaly (MONDO:0700419) is a disease with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Cohort genes: 2
• ClinVar variants: 3
• Phenotypes (HPO): 72

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

72 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000478	Abnormality of the eye	Very frequent (80-99%)
HP:0000601	Hypotelorism	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002033	Poor suck	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0000161	Median cleft lip	Frequent (30-79%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000193	Bifid uvula	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000457	Depressed nasal ridge	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000741	Apathy	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002270	Abnormality of the autonomic nervous system	Frequent (30-79%)
HP:0002363	Abnormal brainstem morphology	Frequent (30-79%)
HP:0002451	Limb dystonia	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0002793	Abnormal pattern of respiration	Frequent (30-79%)
HP:0002871	Central apnea	Frequent (30-79%)
HP:0005968	Temperature instability	Frequent (30-79%)
HP:0006528	Chronic lung disease	Frequent (30-79%)
HP:0006979	Sleep-wake cycle disturbance	Frequent (30-79%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0007301	Oromotor apraxia	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010654	Aplasia of the falx cerebri	Frequent (30-79%)
HP:0011442	Abnormality of central motor function	Frequent (30-79%)
HP:0011951	Aspiration pneumonia	Frequent (30-79%)
HP:0012285	Abnormal hypothalamus physiology	Frequent (30-79%)
HP:0040327	Abnormal morphology of the olfactory bulb	Frequent (30-79%)
HP:0045005	Neural tube defect	Frequent (30-79%)
HP:0100704	Cerebral visual impairment	Frequent (30-79%)
HP:0000119	Abnormality of the genitourinary system	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	semilobar holoprosencephaly
Mondo ID	MONDO:0700419
Orphanet	220386
UMLS	C0751617
MedGen	199694
GARD	0028043
Is cancer (heuristic)	no

Data availability: 3 ClinVar variants.

Disease family

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

Related subtypes (16): holoprosencephaly 3, 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, 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

3 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
235087	NM_023110.3(FGFR1):c.1977+1G>A	FGFR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235080	NM_033163.5(FGF8):c.317C>A (p.Ala106Glu)	FGF8	Likely pathogenic	no assertion criteria provided
235081	NM_033163.5(FGF8):c.356C>T (p.Thr119Met)	FGF8	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 25 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
FGFR1	Orphanet:168953	Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement
FGFR1	Orphanet:2117	Hartsfield syndrome
FGFR1	Orphanet:220386	Semilobar holoprosencephaly
FGFR1	Orphanet:2396	Encephalocraniocutaneous lipomatosis
FGFR1	Orphanet:251576	Gliosarcoma
FGFR1	Orphanet:251579	Giant cell glioblastoma
FGFR1	Orphanet:251615	Pilomyxoid astrocytoma
FGFR1	Orphanet:2645	Osteoglosphonic dysplasia
FGFR1	Orphanet:280200	Microform holoprosencephaly
FGFR1	Orphanet:314950	Primary hypereosinophilic syndrome
FGFR1	Orphanet:3157	Septo-optic dysplasia spectrum
FGFR1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FGFR1	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
FGFR1	Orphanet:478	Kallmann syndrome
FGFR1	Orphanet:93258	Pfeiffer syndrome type 1
FGFR1	Orphanet:93924	Lobar holoprosencephaly
FGFR1	Orphanet:99798	Oligodontia

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
FGF8	HGNC:3686	ENSG00000107831	P55075	Fibroblast growth factor 8	clinvar
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGF8	Fibroblast growth factor 8	Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration.
FGFR1	Fibroblast growth factor receptor 1	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGF8	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2

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
endometrium epithelium	1
metanephric glomerulus	1
primordial germ cell in gonad	1
buccal mucosa cell	1
calcaneal tendon	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGF8	109	tissue_specific	yes	primordial germ cell in gonad, metanephric glomerulus, endometrium epithelium
FGFR1	292	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGFR1	5,693
FGF8	4,536

Intra-cohort edges

A	B	Sources
FGF8	FGFR1	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR1	P11362	83
FGF8	P55075	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 48. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by activated point mutants of FGFR1	2	951.7×	3e-05	FGF8, FGFR1
FGFR1c ligand binding and activation	2	761.3×	3e-05	FGF8, FGFR1
Phospholipase C-mediated cascade: FGFR1	2	671.8×	3e-05	FGF8, FGFR1
Downstream signaling of activated FGFR1	2	543.8×	3e-05	FGF8, FGFR1
PI-3K cascade:FGFR1	2	519.1×	3e-05	FGF8, FGFR1
SHC-mediated cascade:FGFR1	2	496.5×	3e-05	FGF8, FGFR1
FRS-mediated FGFR1 signaling	2	456.8×	3e-05	FGF8, FGFR1
Negative regulation of FGFR1 signaling	2	368.4×	4e-05	FGF8, FGFR1
Signaling by FGFR1 in disease	2	292.8×	6e-05	FGF8, FGFR1
PI3K Cascade	2	271.9×	6e-05	FGF8, FGFR1
Constitutive Signaling by Aberrant PI3K in Cancer	2	126.9×	3e-04	FGF8, FGFR1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	96.8×	4e-04	FGF8, FGFR1
PIP3 activates AKT signaling	2	66.8×	8e-04	FGF8, FGFR1
RAF/MAP kinase cascade	2	61.1×	9e-04	FGF8, FGFR1
Signaling by FGFR1 amplification mutants	1	2855.0×	0.001	FGFR1
FGFR1c and Klotho ligand binding and activation	1	1427.5×	0.002	FGFR1
Signaling by plasma membrane FGFR1 fusions	1	1427.5×	0.002	FGFR1
FGFR3b ligand binding and activation	1	815.7×	0.003	FGF8
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	713.8×	0.004	FGFR1
FGFR1b ligand binding and activation	1	634.4×	0.004	FGFR1
Formation of the posterior neural plate	1	571.0×	0.004	FGF8
Signaling by activated point mutants of FGFR3	1	475.8×	0.004	FGF8
FGFR3c ligand binding and activation	1	439.2×	0.004	FGF8
FGFR2c ligand binding and activation	1	439.2×	0.004	FGF8
Phospholipase C-mediated cascade; FGFR3	1	439.2×	0.004	FGF8
FGFRL1 modulation of FGFR1 signaling	1	439.2×	0.004	FGF8
FGFR4 ligand binding and activation	1	407.9×	0.004	FGF8
Phospholipase C-mediated cascade; FGFR4	1	380.7×	0.005	FGF8
Activated point mutants of FGFR2	1	335.9×	0.005	FGF8
Phospholipase C-mediated cascade; FGFR2	1	317.2×	0.005	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
branching involved in salivary gland morphogenesis	2	1404.3×	4e-05	FGF8, FGFR1
organ induction	2	1203.7×	4e-05	FGF8, FGFR1
positive regulation of stem cell proliferation	2	526.6×	1e-04	FGF8, FGFR1
stem cell proliferation	2	312.1×	3e-04	FGF8, FGFR1
fibroblast growth factor receptor signaling pathway	2	285.6×	3e-04	FGF8, FGFR1
positive regulation of cell differentiation	2	267.5×	3e-04	FGF8, FGFR1
MAPK cascade	2	153.2×	8e-04	FGF8, FGFR1
pallium development	1	8426.0×	0.002	FGF8
midbrain-hindbrain boundary development	1	4213.0×	0.002	FGF8
negative regulation of cardiac muscle tissue development	1	4213.0×	0.002	FGF8
vitamin D3 metabolic process	1	4213.0×	0.002	FGFR1
cell migration involved in mesendoderm migration	1	4213.0×	0.002	FGF8
larynx morphogenesis	1	4213.0×	0.002	FGF8
positive regulation of mitotic cell cycle DNA replication	1	4213.0×	0.002	FGFR1
positive regulation of parathyroid hormone secretion	1	4213.0×	0.002	FGFR1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	4213.0×	0.002	FGFR1
positive regulation of MAPK cascade	2	80.6×	0.002	FGF8, FGFR1
neural plate morphogenesis	1	2808.7×	0.002	FGF8
regulation of phosphate transport	1	2808.7×	0.002	FGFR1
subpallium development	1	2808.7×	0.002	FGF8
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development	1	2808.7×	0.002	FGFR1
regulation of lateral mesodermal cell fate specification	1	2808.7×	0.002	FGFR1
corticotropin hormone secreting cell differentiation	1	2808.7×	0.002	FGF8
ventricular zone neuroblast division	1	2106.5×	0.002	FGFR1
dorsal/ventral axon guidance	1	2106.5×	0.002	FGF8
negative regulation of fibroblast growth factor production	1	2106.5×	0.002	FGFR1
mesodermal cell migration	1	1685.2×	0.002	FGF8
positive regulation of phospholipase activity	1	1685.2×	0.002	FGFR1
regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling	1	1685.2×	0.002	FGFR1
diphosphate metabolic process	1	1685.2×	0.002	FGFR1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
FGFR1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR1	93	4
FGF8	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
FEDRATINIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	FGFR1
CABOZANTINIB	4	FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	FGFR1
NINTEDANIB ESYLATE	4	FGFR1
BRIGATINIB	4	FGFR1
ERDAFITINIB	4	FGFR1
UPADACITINIB	4	FGFR1
FUTIBATINIB	4	FGFR1
PAZOPANIB	4	FGFR1
SUNITINIB	4	FGFR1
DASATINIB	4	FGFR1
MIDOSTAURIN	4	FGFR1
LINIFANIB	3	FGFR1
SEMAXANIB	3	FGFR1
OLVEREMBATINIB	3	FGFR1
BRIVANIB ALANINATE	3	FGFR1
ORANTINIB	3	FGFR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FGFR1	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
FGFR1	1,465

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

30 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)
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
FEDRATINIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	FGFR1
CABOZANTINIB	4	FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	FGFR1
NINTEDANIB ESYLATE	4	FGFR1
BRIGATINIB	4	FGFR1
ERDAFITINIB	4	FGFR1
UPADACITINIB	4	FGFR1
FUTIBATINIB	4	FGFR1
PAZOPANIB	4	FGFR1
SUNITINIB	4	FGFR1
DASATINIB	4	FGFR1
MIDOSTAURIN	4	FGFR1
LINIFANIB	3	FGFR1
SEMAXANIB	3	FGFR1
OLVEREMBATINIB	3	FGFR1
BRIVANIB ALANINATE	3	FGFR1
ORANTINIB	3	FGFR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FGFR1
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	1	FGF8

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FGF8	0	FGFR1

Clinical trials & evidence

Clinical trials

Clinical trials: 0.