Alobar holoprosencephaly

Summary

Alobar holoprosencephaly (MONDO:0019757) is a disease with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Cohort genes: 1
• ClinVar variants: 1
• 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:0008936	Axial hypotonia	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	alobar holoprosencephaly
Mondo ID	MONDO:0019757
Orphanet	93925
ICD-11	381193163
SNOMED CT	253137003
UMLS	C0431363
MedGen	140909
GARD	0016831
Is cancer (heuristic)	no

Data availability: 1 ClinVar variant.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › alobar 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, holoprosencephaly 13, X-linked, holoprosencephaly 14, holoprosencephaly 12 with or without pancreatic agenesis, semilobar holoprosencephaly, holoprosencephaly 10

Subtypes (2): holoprosencephaly 5, holoprosencephaly 9

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
235090	NM_005618.4(DLL1):c.2117C>T (p.Ser706Leu)	DLL1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DLL1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DLL1	Orphanet:220386	Semilobar holoprosencephaly
DLL1	Orphanet:280195	Septopreoptic holoprosencephaly
DLL1	Orphanet:280200	Microform holoprosencephaly
DLL1	Orphanet:93924	Lobar holoprosencephaly
DLL1	Orphanet:93925	Alobar holoprosencephaly
DLL1	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DLL1	HGNC:2908	ENSG00000198719	O00548	Delta-like protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLL1	Delta-like protein 1	Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DLL1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, DSL

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	1
spleen	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DLL1	132	broad	marker	spleen, ventricular zone, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLL1	3,147

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DLL1	O00548	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 1 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
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	1631.4×	0.004	DLL1
MECP2 regulates transcription of neuronal ligands	1	1427.5×	0.004	DLL1
Nephron development	1	878.5×	0.004	DLL1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	761.3×	0.004	DLL1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.004	DLL1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	439.2×	0.004	DLL1
Formation of paraxial mesoderm	1	407.9×	0.004	DLL1
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.004	DLL1
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	278.5×	0.005	DLL1
Somitogenesis	1	233.1×	0.005	DLL1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.005	DLL1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.005	DLL1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cerebellar molecular layer formation	1	16852.0×	0.001	DLL1
regulation of skeletal muscle tissue growth	1	16852.0×	0.001	DLL1
Notch signaling pathway involved in arterial endothelial cell fate commitment	1	16852.0×	0.001	DLL1
cerebellar Purkinje cell layer structural organization	1	8426.0×	0.001	DLL1
negative regulation of epidermal cell differentiation	1	8426.0×	0.001	DLL1
loop of Henle development	1	8426.0×	0.001	DLL1
endothelial tip cell fate specification	1	8426.0×	0.001	DLL1
lateral inhibition	1	5617.3×	0.001	DLL1
inhibition of neuroepithelial cell differentiation	1	4213.0×	0.001	DLL1
compartment pattern specification	1	4213.0×	0.001	DLL1
negative regulation of inner ear auditory receptor cell differentiation	1	4213.0×	0.001	DLL1
skin epidermis development	1	4213.0×	0.001	DLL1
regulation of vascular endothelial growth factor signaling pathway	1	4213.0×	0.001	DLL1
somite specification	1	3370.4×	0.001	DLL1
positive regulation of skeletal muscle tissue growth	1	3370.4×	0.001	DLL1
proximal tubule development	1	3370.4×	0.001	DLL1
regulation of somitogenesis	1	2808.7×	0.001	DLL1
regulation of vascular endothelial growth factor receptor signaling pathway	1	2808.7×	0.001	DLL1
skeletal muscle tissue growth	1	2808.7×	0.001	DLL1
negative regulation of cardiac muscle cell differentiation	1	2407.4×	0.001	DLL1
marginal zone B cell differentiation	1	1872.4×	0.001	DLL1
negative regulation of glial cell apoptotic process	1	1872.4×	0.001	DLL1
retina morphogenesis in camera-type eye	1	1872.4×	0.001	DLL1
nephron development	1	1872.4×	0.001	DLL1
neuroepithelial cell differentiation	1	1532.0×	0.002	DLL1
type B pancreatic cell development	1	1296.3×	0.002	DLL1
negative regulation of epithelial cell differentiation	1	1203.7×	0.002	DLL1
inner ear auditory receptor cell differentiation	1	1203.7×	0.002	DLL1
left/right axis specification	1	1203.7×	0.002	DLL1
astrocyte development	1	1123.5×	0.002	DLL1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DLL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	DLL1

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)
DLL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.