Tibia, hypoplasia or aplasia of, with polydactyly

Summary

Tibia, hypoplasia or aplasia of, with polydactyly (MONDO:0008572) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 4
• Phenotypes (HPO): 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		94	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0002991	Abnormal fibula morphology	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005772	Aplasia/Hypoplasia of the tibia	Very frequent (80-99%)
HP:0006443	Patellar aplasia	Very frequent (80-99%)
HP:0005048	Synostosis of carpal bones	Frequent (30-79%)
HP:0009601	Aplasia/Hypoplasia of the thumb	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	tibia, hypoplasia or aplasia of, with polydactyly
Mondo ID	MONDO:0008572
MeSH	C535564, C566046
OMIM	188740
Orphanet	988, 3332
DOID	DOID:0111564
SNOMED CT	716741008
UMLS	C1861098
MedGen	348786
GARD	0008309
Is cancer (heuristic)	no

Also known as: absence of tibia with polydactyly · absent tibia-polydactyly syndrome · hypoplastic tibiae-postaxial polydactyly syndrome · polydactyly with absent tibia · THYP · tibia, hypoplasia or aplasia of, with polydactyly

Data availability: 4 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › tibia, hypoplasia or aplasia of, with polydactyly

Related subtypes (107): trigonocephaly, spondylocostal dysostosis, synostosis, Adams-Oliver syndrome, adactylia, unilateral, ADULT syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Cooks syndrome, brachydactyly-arterial hypertension syndrome, fibular aplasia-ectrodactyly syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, congenital pseudoarthrosis of clavicle, external auditory canal atresia-vertical talus-hypertelorism syndrome, femoral-facial syndrome, hand-foot-genital syndrome, oculoauriculovertebral spectrum with radial defects, IVIC syndrome, nail-patella syndrome, patella aplasia/hypoplasia, pelvis-shoulder dysplasia, phocomelia-ectrodactyly-deafness-sinus arrhythmia syndrome, postaxial tetramelic oligodactyly, Currarino triad, radio-renal syndrome, splenogonadal fusion-limb defects-micrognathia syndrome, Karsch-Neugebauer syndrome, tetramelic monodactyly, humerus trochlea aplasia, Aphalangy-hemivertebrae-urogenital-intestinal dysgenesis syndrome, camptodactyly syndrome, Guadalajara type 2, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, split hand-foot malformation 1 with sensorineural hearing loss, EEM syndrome, lethal faciocardiomelic dysplasia, femur-fibula-ulna complex, Gollop-Wolfgang complex, acromesomelic dysplasia 2B, Fuhrmann syndrome, absence deformity of leg-cataract syndrome, intellectual disability-spasticity-ectrodactyly syndrome, fibular aplasia, tibial campomelia, and oligosyndactyly syndrome, otoonychoperoneal syndrome, pelviscapular dysplasia, rapadilino syndrome, EEC syndrome, spondylocostal dysostosis-anal and genitourinary malformations syndrome, tetraamelia-multiple malformations syndrome, thrombocytopenia-absent radius syndrome, phocomelia, Schinzel type, ulna hypoplasia-intellectual disability syndrome, absent radius-anogenital anomalies syndrome, ulnar hypoplasia-split foot syndrome, aphalangy-syndactyly-microcephaly syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, autosomal recessive amelia, pelvic dysplasia-arthrogryposis of lower limbs syndrome, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, genitopatellar syndrome, Duane-radial ray syndrome, intellectual disability-brachydactyly-Pierre Robin syndrome, camptodactyly syndrome, Guadalajara type 3, mammary-digital-nail syndrome, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, split-foot malformation-mesoaxial polydactyly syndrome, amniotic band syndrome, radial deficiency-tibial hypoplasia syndrome, mandibulofacial dysostosis, oromandibular-limb anomalies syndrome, congenital pseudoarthrosis of the limbs, oculomaxillofacial dysostosis, shoulder and thorax deformity-congenital heart disease syndrome, femoral agenesis/hypoplasia, progressive non-infectious anterior vertebral fusion, hemimelia, heart-hand syndrome, split hand-foot malformation, Melhem-Fahl syndrome, limb transversal defect-cardiac anomaly syndrome, frontonasal dysplasia, imperforate oropharynx-costo vetebral anomalies syndrome, non-syndromic amelia, congenital absence of upper arm and forearm with hand present, congenital absence of thigh and lower leg with foot present, congenital absence of both forearm and hand, congenital absence of both lower leg and foot, acheiria, apodia, split hand, split foot, hyperphalangy, Prata-Liberal-Goncalves syndrome, syngnathia multiple anomalies, hereditary thrombocytosis with transverse limb defect, thalidomide embryopathy, tibial aplasia-ectrodactyly syndrome, bipartite talus, acrofacial dysostosis, adactyly of foot, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, Rubinstein-Taybi syndrome, ischio-vertebral syndrome, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, preaxial digit brachydactyly-webbed fingers, proximal femoral focal deficiency, dysostosis multiplex, Ain-Naz type

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, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
155921	NC_000007.14:g.156791472C>G	LMBR1	Pathogenic	no assertion criteria provided
126371	NM_022458.4(LMBR1):c.423+4915C>T	ZRS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4898	NM_022458.4(LMBR1):c.423+4917G>A	ZRS	Pathogenic	no assertion criteria provided
155923	NM_022458.4(LMBR1):c.423+4919A>G	LMBR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

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
LMBR1	HGNC:13243	ENSG00000105983	Q8WVP7	Limb region 1 protein homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LMBR1	Limb region 1 protein homolog	Putative membrane receptor.

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)
LMBR1	Other/Unknown	no		LMBR1-like_membr_prot, LIMR

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
adrenal tissue	1
calcaneal tendon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LMBR1	249	ubiquitous	marker	adrenal tissue, sural nerve, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMBR1	977

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LMBR1	Q8WVP7	79.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
embryonic digit morphogenesis	1	300.9×	0.007	LMBR1
signal transduction	1	16.1×	0.062	LMBR1

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
LMBR1	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	LMBR1

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)
LMBR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.