Tibial hemimelia

Summary

Tibial hemimelia (MONDO:0010144) is a disease with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.1	Europe	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0001762	Talipes equinovarus	Very frequent (80-99%)
HP:0009556	Absent tibia	Very frequent (80-99%)
HP:0001171	Split hand	Frequent (30-79%)
HP:0004987	Mesomelic leg shortening	Frequent (30-79%)
HP:0006380	Knee flexion contracture	Frequent (30-79%)
HP:0001159	Syndactyly	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001839	Split foot	Occasional (5-29%)
HP:0001840	Metatarsus adductus	Occasional (5-29%)
HP:0001849	Foot oligodactyly	Occasional (5-29%)
HP:0003974	Absent radius	Occasional (5-29%)
HP:0004059	Radial club hand	Occasional (5-29%)
HP:0005736	Short tibia	Occasional (5-29%)
HP:0005892	Proximal tibial and fibular fusion	Occasional (5-29%)
HP:0006426	Rudimentary to absent tibiae	Occasional (5-29%)
HP:0006460	Increased laxity of ankles	Occasional (5-29%)
HP:0008368	Tarsal synostosis	Occasional (5-29%)
HP:0010037	Aplasia of the 2nd metacarpal	Occasional (5-29%)
HP:0010043	Aplasia of the 4th metacarpal	Occasional (5-29%)
HP:0010442	Polydactyly	Occasional (5-29%)
HP:0010554	Cutaneous finger syndactyly	Occasional (5-29%)
HP:0012165	Oligodactyly	Occasional (5-29%)
HP:0012386	Absent hallux	Occasional (5-29%)
HP:0030032	Partial absence of foot	Occasional (5-29%)
HP:0000028	Cryptorchidism	Very rare (<1-4%)
HP:0000047	Hypospadias	Very rare (<1-4%)
HP:0000062	Ambiguous genitalia	Very rare (<1-4%)
HP:0000175	Cleft palate	Very rare (<1-4%)
HP:0000365	Hearing impairment	Very rare (<1-4%)
HP:0002475	Myelomeningocele	Very rare (<1-4%)
HP:0002673	Coxa valga	Very rare (<1-4%)
HP:0002827	Hip dislocation	Very rare (<1-4%)
HP:0002937	Hemivertebrae	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	tibial hemimelia
Mondo ID	MONDO:0010144
MeSH	C535563
OMIM	275220
Orphanet	93322
ICD-11	1111258427
SNOMED CT	79177001
UMLS	C0265633
MedGen	120551
GARD	0008707
Is cancer (heuristic)	no

Also known as: absence of tibia · bilateral absence of the tibia · congenital absence of tibia · congenital aplasia and dysplasia of the tibia with intact fibula · congenital longitudinal deficiency of the tibia · tibial hemimelia · tibial longitudinal meromelia

Data availability: 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › hemimelia › tibial hemimelia

Related subtypes (4): ulnar hemimelia, radial hemimelia, fibular hemimelia, complete hemimelia

Subtypes (2): tibial hemimelia, unilateral, tibial hemimelia, bilateral

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 7 · 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
GLI3	Supportive	Autosomal dominant	tibial hemimelia	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLI3	Orphanet:36	Acrocallosal syndrome
GLI3	Orphanet:380	Greig cephalopolysyndactyly syndrome
GLI3	Orphanet:672	Pallister-Hall syndrome
GLI3	Orphanet:93322	Isolated tibial hemimelia
GLI3	Orphanet:93334	Postaxial polydactyly type A
GLI3	Orphanet:93335	Postaxial polydactyly type B
GLI3	Orphanet:93338	Polysyndactyly

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
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

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
olfactory bulb	1
tendon of biceps brachii	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI3	2,825

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLI3	P10071	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	1631.4×	0.003	GLI3
RUNX2 regulates osteoblast differentiation	1	456.8×	0.005	GLI3
GLI3 is processed to GLI3R by the proteasome	1	223.9×	0.006	GLI3
Hedgehog ‘off’ state	1	178.4×	0.006	GLI3
Hedgehog ‘on’ state	1	158.6×	0.006	GLI3

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
lateral ganglionic eminence cell proliferation	1	16852.0×	7e-04	GLI3
lambdoid suture morphogenesis	1	16852.0×	7e-04	GLI3
sagittal suture morphogenesis	1	16852.0×	7e-04	GLI3
mammary gland specification	1	16852.0×	7e-04	GLI3
anterior semicircular canal development	1	16852.0×	7e-04	GLI3
lateral semicircular canal development	1	16852.0×	7e-04	GLI3
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	8426.0×	9e-04	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	8426.0×	9e-04	GLI3
larynx morphogenesis	1	8426.0×	9e-04	GLI3
nose morphogenesis	1	5617.3×	1e-03	GLI3
negative regulation of alpha-beta T cell differentiation	1	5617.3×	1e-03	GLI3
frontal suture morphogenesis	1	5617.3×	1e-03	GLI3
cell differentiation involved in kidney development	1	5617.3×	1e-03	GLI3
hindgut morphogenesis	1	4213.0×	0.001	GLI3
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	4213.0×	0.001	GLI3
optic nerve morphogenesis	1	3370.4×	0.001	GLI3
regulation of bone development	1	3370.4×	0.001	GLI3
forebrain radial glial cell differentiation	1	2808.7×	0.001	GLI3
forebrain dorsal/ventral pattern formation	1	2106.5×	0.002	GLI3
tongue development	1	2106.5×	0.002	GLI3
alpha-beta T cell differentiation	1	1872.4×	0.002	GLI3
embryonic neurocranium morphogenesis	1	1872.4×	0.002	GLI3
positive regulation of alpha-beta T cell differentiation	1	1685.2×	0.002	GLI3
negative thymic T cell selection	1	1404.3×	0.002	GLI3
artery development	1	1404.3×	0.002	GLI3
thymocyte apoptotic process	1	1404.3×	0.002	GLI3
layer formation in cerebral cortex	1	1123.5×	0.002	GLI3
limb morphogenesis	1	1053.2×	0.002	GLI3
embryonic digestive tract development	1	991.3×	0.002	GLI3
embryonic digestive tract morphogenesis	1	936.2×	0.003	GLI3

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
GLI3	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	GLI3

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)
GLI3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.