Polydactyly of a triphalangeal thumb

Summary

Polydactyly of a triphalangeal thumb (MONDO:0008270) is a disease caused by variants in SHH and LMBR1, with 3 cohort genes.

At a glance

• Causal genes: SHH (GenCC Definitive), LMBR1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 125

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polydactyly of a triphalangeal thumb
Mondo ID	MONDO:0008270
OMIM	174500
Orphanet	93336
DOID	DOID:0060986
ICD-11	728781925
SNOMED CT	715710001
UMLS	C1868114
MedGen	357423
GARD	0005289
Is cancer (heuristic)	no

Also known as: polydactyly, preaxial II · polydactyly, preaxial type 2 · polydactyly, preaxial type II · PPD2 · preaxial polydactyly type 2 · triphalangeal thumb, type i

Data availability: 125 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › polydactyly › non-syndromic polydactyly › preaxial polydactyly of fingers › polydactyly of a triphalangeal thumb

Related subtypes (2): polydactyly of a biphalangeal thumb, polydactyly of an index finger

Subtypes (2): polydactyly of a triphalangeal thumb, unilateral, polydactyly of a triphalangeal thumb, 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

ClinVar germline variants

125 retrieved; paginated sample, class counts are floors:

52 uncertain significance, 47 benign, 10 pathogenic, 7 conflicting classifications of pathogenicity, 5 likely benign, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30496	NC_000007.14:g.156791579C>T	LMBR1	Pathogenic	no assertion criteria provided
30497	NC_000007.14:g.156791542A>C	LMBR1	Pathogenic	no assertion criteria provided
3061990	NC_000007.14:g.156791548G>C	LMBR1	Pathogenic	no assertion criteria provided
4897	NM_022458.4(LMBR1):c.423+4618C>G	LMBR1	Pathogenic	no assertion criteria provided
4899	NM_022458.4(LMBR1):c.423+4818A>T	LMBR1	Pathogenic	no assertion criteria provided
4900	NM_022458.4(LMBR1):c.423+4842T>C	LMBR1	Pathogenic	no assertion criteria provided
4902	NM_022458.4(LMBR1):c.423+5252A>G	LMBR1	Pathogenic	criteria provided, single submitter
126371	NM_022458.4(LMBR1):c.423+4915C>T	ZRS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3340528	NC_000007.14:g.156791257G>A	ZRS	Pathogenic	criteria provided, single submitter
4903	NM_022458.4(LMBR1):c.423+5134C>G	ZRS	Pathogenic	no assertion criteria provided
4906	NM_022458.4(LMBR1):c.423+4808T>C	ZRS	Pathogenic	criteria provided, single submitter
155923	NM_022458.4(LMBR1):c.423+4919A>G	LMBR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
283575	NM_022458.4(LMBR1):c.843G>A (p.Arg281=)	LMBR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359421	NM_022458.4(LMBR1):c.1399C>G (p.Leu467Val)	LMBR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359426	NM_022458.4(LMBR1):c.770C>T (p.Ser257Leu)	LMBR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359428	NM_022458.4(LMBR1):c.665A>C (p.Gln222Pro)	LMBR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359438	NM_022458.4(LMBR1):c.61T>A (p.Ser21Thr)	LMBR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359440	NM_022458.4(LMBR1):c.16G>A (p.Glu6Lys)	LMBR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135101	NM_000264.5(PTCH1):c.3617G>A (p.Arg1206His)	PTCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359368	NM_022458.4(LMBR1):c.*3180A>C	LMBR1	Uncertain significance	criteria provided, single submitter
359372	NM_022458.4(LMBR1):c.*2899A>T	LMBR1	Uncertain significance	criteria provided, single submitter
359374	NM_022458.4(LMBR1):c.*2798C>T	LMBR1	Uncertain significance	criteria provided, single submitter
359375	NM_022458.4(LMBR1):c.*2773G>T	LMBR1	Uncertain significance	criteria provided, single submitter
359377	NM_022458.4(LMBR1):c.*2744G>T	LMBR1	Uncertain significance	criteria provided, single submitter
359381	NM_022458.4(LMBR1):c.*2500A>G	LMBR1	Uncertain significance	criteria provided, single submitter
359383	NM_022458.4(LMBR1):c.*2477G>A	LMBR1	Uncertain significance	criteria provided, single submitter
359390	NM_022458.4(LMBR1):c.*2016C>T	LMBR1	Uncertain significance	criteria provided, single submitter
359394	NM_022458.4(LMBR1):c.*1862T>A	LMBR1	Uncertain significance	criteria provided, single submitter
359397	NM_022458.4(LMBR1):c.*1534A>G	LMBR1	Uncertain significance	criteria provided, single submitter
359405	NM_022458.4(LMBR1):c.*728G>A	LMBR1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 28 · Orphanet: 28 · 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
SHH	Definitive	Autosomal dominant	polydactyly of a triphalangeal thumb	16
LMBR1	Strong	Autosomal dominant	polydactyly of a triphalangeal thumb	12

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
SHH	Orphanet:220386	Semilobar holoprosencephaly
SHH	Orphanet:280195	Septopreoptic holoprosencephaly
SHH	Orphanet:280200	Microform holoprosencephaly
SHH	Orphanet:476119	Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome
SHH	Orphanet:485275	Acquired schizencephaly
SHH	Orphanet:93321	Isolated radial hemimelia
SHH	Orphanet:93336	Polydactyly of a triphalangeal thumb
SHH	Orphanet:93405	Syndactyly type 4
SHH	Orphanet:93924	Lobar holoprosencephaly
SHH	Orphanet:93925	Alobar holoprosencephaly
SHH	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
SHH	Orphanet:988	Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome
SHH	Orphanet:98938	Colobomatous microphthalmia
PTCH1	Orphanet:220386	Semilobar holoprosencephaly
PTCH1	Orphanet:2353	Schilbach-Rott syndrome
PTCH1	Orphanet:280195	Septopreoptic holoprosencephaly
PTCH1	Orphanet:280200	Microform holoprosencephaly
PTCH1	Orphanet:377	Gorlin syndrome
PTCH1	Orphanet:77301	Monosomy 9q22.3 syndrome
PTCH1	Orphanet:93924	Lobar holoprosencephaly
PTCH1	Orphanet:93925	Alobar holoprosencephaly
PTCH1	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LMBR1	HGNC:13243	ENSG00000105983	Q8WVP7	Limb region 1 protein homolog	gencc,clinvar
SHH	HGNC:10848	ENSG00000164690	Q15465	Sonic hedgehog protein	gencc
PTCH1	HGNC:9585	ENSG00000185920	Q13635	Protein patched homolog 1	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.
SHH	Sonic hedgehog protein	The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity.
PTCH1	Protein patched homolog 1	Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LMBR1	Other/Unknown	no		LMBR1-like_membr_prot, LIMR
SHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint
PTCH1	Other/Unknown	no		SSD, TM_rcpt_patched, HMGCR/SNAP/NPC1-like_SSD

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)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
calcaneal tendon	1
sural nerve	1
buccal mucosa cell	1
epithelial cell of pancreas	1
right lobe of liver	1
dorsal root ganglion	1
tibia	1
trigeminal ganglion	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
SHH	131	broad	marker	buccal mucosa cell, right lobe of liver, epithelial cell of pancreas
PTCH1	275	ubiquitous	marker	tibia, dorsal root ganglion, trigeminal ganglion

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SHH	4,953
PTCH1	3,368
LMBR1	977

Intra-cohort edges

A	B	Sources
LMBR1	SHH	string_interaction
PTCH1	SHH	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SHH	Q15465	20
PTCH1	Q13635	16

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LMBR1	Q8WVP7	79.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 3 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
Ligand-receptor interactions	2	1427.5×	1e-05	SHH, PTCH1
Activation of SMO	2	634.4×	3e-05	SHH, PTCH1
Class B/2 (Secretin family receptors)	2	190.3×	2e-04	SHH, PTCH1
Hedgehog ‘on’ state	2	158.6×	2e-04	SHH, PTCH1
HHAT G278V doesn’t palmitoylate Hh-Np	1	1142.0×	0.004	SHH
Formation of lateral plate mesoderm	1	1142.0×	0.004	SHH
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	815.7×	0.004	PTCH1
Release of Hh-Np from the secreting cell	1	713.8×	0.004	SHH
Hh mutants abrogate ligand secretion	1	713.8×	0.004	SHH
Formation of axial mesoderm	1	407.9×	0.006	SHH
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	300.5×	0.007	SHH
Developmental Lineage of Pancreatic Acinar Cells	1	150.3×	0.013	SHH
Gastrulation	1	129.8×	0.014	SHH
Hh mutants are degraded by ERAD	1	121.5×	0.014	SHH
Developmental Cell Lineages	1	112.0×	0.014	SHH
Hedgehog ligand biogenesis	1	105.7×	0.014	SHH
Signaling by Hedgehog	1	92.1×	0.015	SHH
Hedgehog ‘off’ state	1	89.2×	0.015	PTCH1
GPCR ligand binding	1	32.1×	0.039	SHH
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.042	SHH
Signaling by GPCR	1	20.0×	0.056	SHH
Developmental Biology	1	7.2×	0.146	SHH
Disease	1	6.5×	0.153	SHH
Signal Transduction	1	5.1×	0.187	SHH

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 term	Cohort genes	Fold	FDR	Sample cohort genes
metanephric collecting duct development	2	1123.5×	1e-04	SHH, PTCH1
prostate gland development	2	936.2×	1e-04	SHH, PTCH1
somite development	2	749.0×	1e-04	SHH, PTCH1
smooth muscle tissue development	2	702.2×	1e-04	SHH, PTCH1
spinal cord motor neuron differentiation	2	624.1×	1e-04	SHH, PTCH1
dorsal/ventral neural tube patterning	2	535.0×	1e-04	SHH, PTCH1
dorsal/ventral pattern formation	2	280.9×	5e-04	SHH, PTCH1
embryonic limb morphogenesis	2	267.5×	5e-04	SHH, PTCH1
branching involved in ureteric bud morphogenesis	2	244.2×	5e-04	SHH, PTCH1
stem cell proliferation	2	208.1×	6e-04	SHH, PTCH1
embryonic digit morphogenesis	2	200.6×	6e-04	LMBR1, SHH
polarity specification of anterior/posterior axis	1	5617.3×	0.001	SHH
trachea morphogenesis	1	5617.3×	0.001	SHH
right lung development	1	5617.3×	0.001	SHH
left lung development	1	5617.3×	0.001	SHH
primary prostatic bud elongation	1	5617.3×	0.001	SHH
regulation of prostatic bud formation	1	5617.3×	0.001	SHH
obsolete regulation of mesenchymal cell proliferation involved in prostate gland development	1	5617.3×	0.001	SHH
mesenchymal smoothened signaling pathway involved in prostate gland development	1	5617.3×	0.001	SHH
positive regulation of sclerotome development	1	5617.3×	0.001	SHH
tracheoesophageal septum formation	1	5617.3×	0.001	SHH
negative regulation of ureter smooth muscle cell differentiation	1	5617.3×	0.001	SHH
positive regulation of ureter smooth muscle cell differentiation	1	5617.3×	0.001	SHH
negative regulation of kidney smooth muscle cell differentiation	1	5617.3×	0.001	SHH
positive regulation of kidney smooth muscle cell differentiation	1	5617.3×	0.001	SHH
response to chlorate	1	2808.7×	0.002	PTCH1
positive regulation of skeletal muscle cell proliferation	1	2808.7×	0.002	SHH
intein-mediated protein splicing	1	2808.7×	0.002	SHH
neural plate axis specification	1	2808.7×	0.002	PTCH1
trunk neural crest cell migration	1	2808.7×	0.002	SHH

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
SHH	VISMODEGIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SHH	1	4
LMBR1	0	0
PTCH1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VISMODEGIB	4	SHH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SHH	27	Binding:23, Functional:4
PTCH1	4	Binding:4

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

1 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)
VISMODEGIB	4	SHH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SHH
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	2	LMBR1, PTCH1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LMBR1	0	SHH
PTCH1	4	SHH

Clinical trials & evidence

Clinical trials

Clinical trials: 0.