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Lobar holoprosencephaly

disease
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Summary

Lobar holoprosencephaly (MONDO:0019756) is a disease with 3 cohort genes.

At a glance

  • Prevalence: 1-9 / 100 000 (Europe)
  • Cohort genes: 3
  • ClinVar variants: 4
  • Phenotypes (HPO): 72

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

TypeClassValueGeographyValidation
Point prevalence1-9 / 100 000EuropeNot yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO IDTermFrequency
HP:0000601HypotelorismVery frequent (80-99%)
HP:0011968Feeding difficultiesVery frequent (80-99%)
HP:0000161Median cleft lipFrequent (30-79%)
HP:0000175Cleft palateFrequent (30-79%)
HP:0000218High palateFrequent (30-79%)
HP:0000407Sensorineural hearing impairmentFrequent (30-79%)
HP:0000457Depressed nasal ridgeFrequent (30-79%)
HP:0000478Abnormality of the eyeFrequent (30-79%)
HP:0000708Atypical behaviorFrequent (30-79%)
HP:0000716DepressionFrequent (30-79%)
HP:0000737IrritabilityFrequent (30-79%)
HP:0000739AnxietyFrequent (30-79%)
HP:0000818Abnormality of the endocrine systemFrequent (30-79%)
HP:0000873Diabetes insipidusFrequent (30-79%)
HP:0001249Intellectual disabilityFrequent (30-79%)
HP:0001328Specific learning disabilityFrequent (30-79%)
HP:0001508Failure to thriveFrequent (30-79%)
HP:0001510Growth delayFrequent (30-79%)
HP:0002019ConstipationFrequent (30-79%)
HP:0002020Gastroesophageal refluxFrequent (30-79%)
HP:0002033Poor suckFrequent (30-79%)
HP:0002270Abnormality of the autonomic nervous systemFrequent (30-79%)
HP:0002465Poor speechFrequent (30-79%)
HP:0004322Short statureFrequent (30-79%)
HP:0006528Chronic lung diseaseFrequent (30-79%)
HP:0006979Sleep-wake cycle disturbanceFrequent (30-79%)
HP:0007018Attention deficit hyperactivity disorderFrequent (30-79%)
HP:0011442Abnormality of central motor functionFrequent (30-79%)
HP:0011951Aspiration pneumoniaFrequent (30-79%)
HP:0012285Abnormal hypothalamus physiologyFrequent (30-79%)
HP:0008936Axial hypotoniaOccasional (5-29%)
HP:0000119Abnormality of the genitourinary systemOccasional (5-29%)
HP:0000193Bifid uvulaOccasional (5-29%)
HP:0000238HydrocephalusOccasional (5-29%)
HP:0000252MicrocephalyOccasional (5-29%)
HP:0000256MacrocephalyOccasional (5-29%)
HP:0000741ApathyOccasional (5-29%)
HP:0000824Decreased response to growth hormone stimulation testOccasional (5-29%)
HP:0000871PanhypopituitarismOccasional (5-29%)
HP:0000924Abnormality of the skeletal systemOccasional (5-29%)
HP:0001250SeizureOccasional (5-29%)
HP:0001254LethargyOccasional (5-29%)
HP:0001257SpasticityOccasional (5-29%)
HP:0001274Agenesis of corpus callosumOccasional (5-29%)
HP:0001627Abnormal heart morphologyOccasional (5-29%)
HP:0002013VomitingOccasional (5-29%)
HP:0002015DysphagiaOccasional (5-29%)
HP:0002363Abnormal brainstem morphologyOccasional (5-29%)
HP:0002451Limb dystoniaOccasional (5-29%)
HP:0002650ScoliosisOccasional (5-29%)

Identifiers

Disease identifiers

FieldValue
Canonical namelobar holoprosencephaly
Mondo IDMONDO:0019756
Orphanet93924
ICD-11121649206
SNOMED CT253136007
UMLSC0431362
MedGen96559
GARD0016830
Is cancer (heuristic)no

Data availability: 4 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › lobar 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, alobar 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

4 retrieved; paginated sample, class counts are floors:

2 pathogenic, 2 uncertain significance

ClinVarVariant (HGVS)GeneClassificationReview
1275753NC_000013.10:g.99162946_101376965delCLYBLPathogenicno assertion criteria provided
235084NM_023110.3(FGFR1):c.749G>C (p.Arg250Pro)FGFR1Pathogeniccriteria provided, single submitter
235091NM_001377229.1(DISP1):c.1087A>G (p.Asn363Asp)DISP1Uncertain significanceno assertion criteria provided
235092NM_001377229.1(DISP1):c.1657G>A (p.Glu553Lys)DISP1Uncertain significanceno assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 23 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
DISP1Orphanet:220386Semilobar holoprosencephaly
DISP1Orphanet:280195Septopreoptic holoprosencephaly
DISP1Orphanet:280200Microform holoprosencephaly
DISP1Orphanet:93924Lobar holoprosencephaly
DISP1Orphanet:93925Alobar holoprosencephaly
DISP1Orphanet:93926Midline interhemispheric variant of holoprosencephaly
FGFR1Orphanet:168953Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement
FGFR1Orphanet:2117Hartsfield syndrome
FGFR1Orphanet:220386Semilobar holoprosencephaly
FGFR1Orphanet:2396Encephalocraniocutaneous lipomatosis
FGFR1Orphanet:251576Gliosarcoma
FGFR1Orphanet:251579Giant cell glioblastoma
FGFR1Orphanet:251615Pilomyxoid astrocytoma
FGFR1Orphanet:2645Osteoglosphonic dysplasia
FGFR1Orphanet:280200Microform holoprosencephaly
FGFR1Orphanet:314950Primary hypereosinophilic syndrome
FGFR1Orphanet:3157Septo-optic dysplasia spectrum
FGFR1Orphanet:3366Non-syndromic metopic craniosynostosis
FGFR1Orphanet:432Normosmic congenital hypogonadotropic hypogonadism
FGFR1Orphanet:478Kallmann syndrome
FGFR1Orphanet:93258Pfeiffer syndrome type 1
FGFR1Orphanet:93924Lobar holoprosencephaly
FGFR1Orphanet:99798Oligodontia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence3

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
CLYBLHGNC:18355ENSG00000125246Q8N0X4Citramalyl-CoA lyase, mitochondrialclinvar
DISP1HGNC:19711ENSG00000154309Q96F81Protein dispatched homolog 1clinvar
FGFR1HGNC:3688ENSG00000077782P11362Fibroblast growth factor receptor 1clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
CLYBLCitramalyl-CoA lyase, mitochondrialMitochondrial enzyme required to detoxify vitamin B12-poisoning metabolites.
DISP1Protein dispatched homolog 1Functions in hedgehog (Hh) signaling.
FGFR1Fibroblast growth factor receptor 1Tyrosine-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: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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.

FamilyGenesFoldFDR
Kinase218.5×0.008
Other/Unknown10.6×0.914

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
CLYBLKinaseyes4.1.3.6Aldolase/citrate-lyase_domain, Citrate_lyase_beta/mcl1/mcl2, Pyrv/PenolPyrv_kinase-like_dom
DISP1Other/UnknownnoSSD, MMPL_dom, Dispatched_Hh_regulator
FGFR1Kinaseyes2.7.10.1Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)3
unknown0

Top tissues across cohort

TissueCohort genes
kidney epithelium1
liver1
right lobe of liver1
left testis1
male germ line stem cell (sensu Vertebrata) in testis1
right testis1
buccal mucosa cell1
calcaneal tendon1
stromal cell of endometrium1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
CLYBL234ubiquitousmarkerkidney epithelium, right lobe of liver, liver
DISP1221ubiquitousmarkermale germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
FGFR1292ubiquitousmarkerbuccal mucosa cell, stromal cell of endometrium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
FGFR15,693
CLYBL2,156
DISP1621

Structural data

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

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
FGFR1P1136283
DISP1Q96F814
CLYBLQ8N0X43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 3 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.

PathwayCohort genesFoldFDRSample cohort genes
Signaling by FGFR1 amplification mutants15710.0×0.003FGFR1
FGFR1c and Klotho ligand binding and activation12855.0×0.003FGFR1
Signaling by plasma membrane FGFR1 fusions12855.0×0.003FGFR1
Epithelial-Mesenchymal Transition (EMT) during gastrulation11427.5×0.003FGFR1
FGFR1b ligand binding and activation11268.9×0.003FGFR1
Signaling by activated point mutants of FGFR11951.7×0.004FGFR1
FGFR1c ligand binding and activation1761.3×0.004FGFR1
Phospholipase C-mediated cascade: FGFR11671.8×0.004FGFR1
Downstream signaling of activated FGFR11543.8×0.004FGFR1
Signal transduction by L11519.1×0.004FGFR1
PI-3K cascade:FGFR11519.1×0.004FGFR1
SHC-mediated cascade:FGFR11496.5×0.004FGFR1
FRS-mediated FGFR1 signaling1456.8×0.004FGFR1
Formation of paraxial mesoderm1407.9×0.004FGFR1
Negative regulation of FGFR1 signaling1368.4×0.004FGFR1
Signaling by FGFR1 in disease1292.8×0.004FGFR1
PI3K Cascade1271.9×0.004FGFR1
NCAM signaling for neurite out-growth1271.9×0.004FGFR1
Constitutive Signaling by Aberrant PI3K in Cancer1126.9×0.009FGFR1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling196.8×0.011FGFR1
PIP3 activates AKT signaling166.8×0.016FGFR1
RAF/MAP kinase cascade161.1×0.016FGFR1

GO biological processes 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.

GO termCohort genesFoldFDRSample cohort genes
patched ligand maturation15617.3×0.004DISP1
regulation of cobalamin metabolic process15617.3×0.004CLYBL
positive regulation of cobalamin metabolic process15617.3×0.004CLYBL
vitamin D3 metabolic process12808.7×0.004FGFR1
positive regulation of mitotic cell cycle DNA replication12808.7×0.004FGFR1
positive regulation of parathyroid hormone secretion12808.7×0.004FGFR1
regulation of extrinsic apoptotic signaling pathway in absence of ligand12808.7×0.004FGFR1
regulation of phosphate transport11872.4×0.004FGFR1
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development11872.4×0.004FGFR1
regulation of lateral mesodermal cell fate specification11872.4×0.004FGFR1
peptide transport11404.3×0.004DISP1
ventricular zone neuroblast division11404.3×0.004FGFR1
negative regulation of fibroblast growth factor production11404.3×0.004FGFR1
positive regulation of phospholipase activity11123.5×0.004FGFR1
regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling11123.5×0.004FGFR1
diphosphate metabolic process11123.5×0.004FGFR1
chordate embryonic development1936.2×0.005FGFR1
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway1936.2×0.005FGFR1
cementum mineralization1802.5×0.005FGFR1
auditory receptor cell development1624.1×0.006FGFR1
diaphragm development1624.1×0.006DISP1
paraxial mesoderm development1561.7×0.006FGFR1
lung-associated mesenchyme development1561.7×0.006FGFR1
response to sodium phosphate1561.7×0.006FGFR1
outer ear morphogenesis1510.7×0.006FGFR1
regulation of protein secretion1510.7×0.006DISP1
branching involved in salivary gland morphogenesis1468.1×0.006FGFR1
organ induction1401.2×0.007FGFR1
mesenchymal cell proliferation1374.5×0.007FGFR1
protein homotrimerization1330.4×0.008CLYBL

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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.

SymbolExample approved molecule
FGFR1PONATINIB

Top cohort targets by molecule count

SymbolMoleculesMax phase
FGFR1934
CLYBL00
DISP100

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
PONATINIB4FGFR1
PEMIGATINIB4FGFR1
NINTEDANIB4FGFR1
FEDRATINIB4FGFR1
TIVOZANIB4FGFR1
LENVATINIB4FGFR1
AXITINIB4FGFR1
SORAFENIB4FGFR1
NICLOSAMIDE4FGFR1
INFIGRATINIB PHOSPHATE4FGFR1
INFIGRATINIB4FGFR1
REGORAFENIB4FGFR1
ENTRECTINIB4FGFR1
CABOZANTINIB4FGFR1
CAPIVASERTIB4FGFR1
VANDETANIB4FGFR1
NINTEDANIB ESYLATE4FGFR1
BRIGATINIB4FGFR1
ERDAFITINIB4FGFR1
UPADACITINIB4FGFR1
FUTIBATINIB4FGFR1
PAZOPANIB4FGFR1
SUNITINIB4FGFR1
DASATINIB4FGFR1
MIDOSTAURIN4FGFR1
LINIFANIB3FGFR1
SEMAXANIB3FGFR1
OLVEREMBATINIB3FGFR1
BRIVANIB ALANINATE3FGFR1
ORANTINIB3FGFR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

SymbolAssaysType breakdown
FGFR11,465Binding:1428, Functional:24, ADMET:13

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
CLYBL4.1.3.6citrate (pro-3S)-lyase
FGFR12.7.10.1receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

SymbolChEMBL assays
FGFR11,465

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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.

CompoundMax phaseCohort target (bioactivity)
PONATINIB4FGFR1
PEMIGATINIB4FGFR1
NINTEDANIB4FGFR1
FEDRATINIB4FGFR1
TIVOZANIB4FGFR1
LENVATINIB4FGFR1
AXITINIB4FGFR1
SORAFENIB4FGFR1
NICLOSAMIDE4FGFR1
INFIGRATINIB PHOSPHATE4FGFR1
INFIGRATINIB4FGFR1
REGORAFENIB4FGFR1
ENTRECTINIB4FGFR1
CABOZANTINIB4FGFR1
CAPIVASERTIB4FGFR1
VANDETANIB4FGFR1
NINTEDANIB ESYLATE4FGFR1
BRIGATINIB4FGFR1
ERDAFITINIB4FGFR1
UPADACITINIB4FGFR1
FUTIBATINIB4FGFR1
PAZOPANIB4FGFR1
SUNITINIB4FGFR1
DASATINIB4FGFR1
MIDOSTAURIN4FGFR1
LINIFANIB3FGFR1
SEMAXANIB3FGFR1
OLVEREMBATINIB3FGFR1
BRIVANIB ALANINATE3FGFR1
ORANTINIB3FGFR1

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)1FGFR1
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug1CLYBL
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug1DISP1

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
CLYBL0—
DISP10—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
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Sources 70

This page pulls from 70 datasets indexed by BioBTree:

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