ZRS-Related Limb Malformation

Mendelian Pathograph 24 Show in embeddings browser Congenital Disorder Limb Malformation

ZRS-related limb malformation is the continuum of autosomal dominant congenital limb malformations produced by gain-of-function alterations of the zone of polarizing activity regulatory sequence (ZRS), a long-range limb-specific enhancer of SHH lying in intron 5 of LMBR1 roughly 1 Mb from its target gene. Every branch of the spectrum shares one pathograph: ectopic anterior SHH regulatory activity in the developing limb bud, disrupting anterior-posterior digit number and identity specification. What differs between branches is the molecular alteration and its dosage, not the mechanism. Point variants across the ZRS typically produce preaxial polydactyly with or without triphalangeal thumb; the specific position-404 variants produce the more severe Werner mesomelic phenotype that additionally involves the zeugopod; complete duplications produce Haas-type polysyndactyly and triphalangeal thumb-polysyndactyly syndrome, with smaller (<80 kb) duplications producing Laurin-Sandrow syndrome; and rarer point variants in the adjacent pre-ZRS (pZRS) produce triphalangeal thumb-polysyndactyly syndrome. Wieczorek et al. proposed "ZRS-associated syndromes" as the cover term for this continuum (PMID:19847792), and a single ZRS allele can produce several of the named entities within one kindred (PMID:24777739). This entry is curated at the locus level for that reason; the historically named entities are retained as grounded subtypes. Acheiropodia (OMIM:200500) is curated separately: it arises from deletion at the same locus and is a loss-of-function, limb-reduction pathograph running in the opposite direction.

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6
Mappings
2
Inheritance
6
Pathophys.
12
Phenotypes
5
Gaps
24
Pathograph
1
Genes
2
Variants
1
Medical Actions
6
Subtypes
2
Models
🏷

Classifications

ISDS Skeletal Nosology
polydactyly syndactyly triphalangism
🔗

Mappings

MONDO
MONDO:0008605 triphalangeal thumb, Nonopposable Not Yet Curated
skos:narrowMatch MONDO
Isolated triphalangeal thumb is one specific, mild-end presentation of the locus-level spectrum curated by this entry, so the MONDO class is narrower than the entry. MONDO:0008605 is the only MONDO class for isolated triphalangeal thumb as an entity; see the caveat on the Isolated Triphalangeal Thumb subtype about OMIM splitting this presentation across two entries.
MONDO:0008270 polydactyly of a triphalangeal thumb Not Yet Curated
skos:narrowMatch MONDO
Preaxial polydactyly type 2 is the classical ZRS point-variant presentation, one named clinical entity within the broader locus-level spectrum this entry curates.
MONDO:0017454 triphalangeal thumb-polysyndactyly syndrome Not Yet Curated
skos:narrowMatch MONDO
TPT-PS is the duplication-driven presentation combining triphalangeal thumbs with pre- and postaxial polydactyly and syndactyly; a single named entity narrower than the full ZRS spectrum.
MONDO:0008515 syndactyly type 4 Not Yet Curated
skos:narrowMatch MONDO
Haas-type polysyndactyly (syndactyly type IV) is the larger-duplication end of the ZRS dosage series, one named entity within the spectrum.
MONDO:0007615 laurin-Sandrow syndrome Not Yet Curated
skos:narrowMatch MONDO
Laurin-Sandrow syndrome is the smaller-duplication, mirror-image-foot presentation distinguished from Haas-type polysyndactyly, one named entity within the spectrum.
MONDO:0008572 tibia, hypoplasia or aplasia of, with polydactyly Not Yet Curated
skos:narrowMatch MONDO
Werner mesomelic syndrome is the point-variant, zeugopod-involving presentation at the severe end of the spectrum, one named entity narrower than the full locus-level entry.
👪

Inheritance

2
Autosomal Dominant HP:0000006
Pedigrees show autosomal dominant transmission with marked variable expression. Complete penetrance has been documented in individual large families, but a syndrome-wide penetrance percentage is not established.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (2 references)
PMID:23793141 SUPPORT Human Clinical
"Triphalangeal thumb-polysyndactyly syndrome (TPTPS) consists of a triphalangeal thumb, polydactyly, and syndactyly and is transmitted in an autosomal dominant manner with variable expression."
Directly supports autosomal dominant inheritance and variable expressivity in TPT-PS.
PMID:8958333 SUPPORT Human Clinical
"The abnormalities were present only in the upper limbs, and the phenotype was fully penetrant."
Documents full penetrance in one large pedigree; marked PARTIAL because that family-specific estimate is not generalized to all TPT-PS families.
Autosomal Recessive (dosage effect at a dominant locus) HP:0000007
The locus is dominant, but allele dosage modifies severity, so a homozygous genotype can present as a distinct and more severe clinical branch. In two Mexican families a homozygous ZRS 402C>T individual had Werner mesomelic syndrome while heterozygous relatives carrying the same allele had only preaxial polydactyly type 2. OMIM therefore records both AD and AR for OMIM:188740. This is a gene-dosage effect at a dominant locus rather than a conventional recessive disease, and it is one reason the branches of this spectrum are not separable by inheritance pattern.
Autosomal recessive inheritance Expressivity: VARIABLE
Show evidence (1 reference)
PMID:24777739 SUPPORT Human Clinical
"Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes."
Sets up the dosage question this paper then answers, documenting that homozygosity for the novel 402C>T allele produces the more severe Werner phenotype.
◆

Subtypes

6
clinical phenotype
Isolated Triphalangeal Thumb MONDO:0008605
The mildest branch: a three-phalanx thumb without polydactyly. OMIM splits this presentation across two entries, carrying opposable triphalangeal thumb as an included title of PPD2 (OMIM:174500) while OMIM:190600 covers the nonopposable form; MONDO:0008605 is the only MONDO class for isolated triphalangeal thumb as an entity, so it is used here with that caveat. Isolated triphalangeal thumb and PPD2 co-occur in single ZRS kindreds.
Show evidence (1 reference)
PMID:24777739 SUPPORT Human Clinical
"Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet."
Establishes isolated triphalangeal thumb as one of the routine outcomes of ZRS point variants, alongside preaxial polydactyly.
molecular
Preaxial Polydactyly Type 2 MONDO:0008270
Preaxial polydactyly type 2 (PPD2; OMIM:174500; ORPHA:93336), duplication on the radial side of the hand with a usually opposable triphalangeal thumb. The classical ZRS point-variant phenotype. OMIM assigns PPD2 to the ZRS locus entry (OMIM:620738) rather than to LMBR1.
Show evidence (1 reference)
PMID:12837695 SUPPORT Human Clinical
"Here, we show that the chromosome 7q36 associated preaxial polydactyly, a frequently observed congenital limb malformation, results from point mutations in a Shh regulatory element."
The founding demonstration that preaxial polydactyly is a ZRS enhancer point-variant disease.
Triphalangeal Thumb-Polysyndactyly Syndrome MONDO:0017454
Triphalangeal thumb-polysyndactyly syndrome (TPT-PS; OMIM:190605), combining triphalangeal thumbs with pre- and postaxial polydactyly and variable syndactyly of hands and feet. Caused by complete ZRS duplications and, more rarely, by pre-ZRS point variants. OMIM assigns this entry to LMBR1 (OMIM:605522) because the causal duplications span the gene body as well as the enhancer. Orphanet no longer carries a standalone TPT-PS concept: ORPHA:2950 is deprecated and moved to ORPHA:988, the Werner mesomelic spectrum.
Show evidence (3 references)
ORPHA:2950 SUPPORT Other
"**ORPHA:2950** — Triphalangeal thumb-polysyndactyly syndrome (Malformation syndrome, Disorder) **Status:** Deprecated entity; Inactive"
Orphanet's own record for ORPHA:2950 (TPT-PS) carries the "Deprecated entity" and "Inactive" status flags, the literal source for the claim that Orphanet no longer carries a standalone TPT-PS concept.
ORPHA:988 SUPPORT Other
"ORPHA:2950 | Triphalangeal thumb-polysyndactyly syndrome | Moved to | ORPHA:988 | Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome"
Orphanet's disorder-disorder association record confirms ORPHA:2950 (TPT-PS) was moved into ORPHA:988, so Orphanet no longer carries a standalone TPT-PS concept.
PMID:18417549 SUPPORT Human Clinical
"Both TPTPS and SD4 are due to duplications involving ZRS, the limb specific SHH enhancer."
Establishes the ZRS duplication mechanism shared by TPT-PS and syndactyly type IV.
Haas-Type Polysyndactyly (Syndactyly Type IV) MONDO:0008515
Haas-type polysyndactyly (syndactyly type IV; OMIM:186200; ORPHA:93405), complete syndactyly of all fingers giving a cup-shaped or rosebud hand, with polydactyly. Caused by larger (>80 kb) ZRS duplications, and reported within the same families as TPT-PS.
Show evidence (1 reference)
PMID:24456159 SUPPORT Human Clinical
"We show that larger duplications of the ZRS region (>80 kb) are associated with HTS, whereas smaller duplications (<80 kb) result in the LSS phenotype."
Assigns Haas-type polysyndactyly to the larger-duplication end of the ZRS dosage series.
Laurin-Sandrow Syndrome MONDO:0007615
Laurin-Sandrow syndrome (LSS; OMIM:135750; ORPHA:2378), polysyndactyly with mirror-image duplication of the feet, fibular duplication and nasal defects. Caused by smaller (<80 kb) ZRS duplications, and distinguished from Haas-type polysyndactyly by the mirror-image foot phenotype.
Show evidence (1 reference)
PMID:24456159 SUPPORT Human Clinical
"In addition, we show that these small microduplications within the ZRS region are the underlying genetic cause of Laurin-Sandrow syndrome."
Establishes small ZRS microduplication as the cause of Laurin-Sandrow syndrome, placing it inside this locus spectrum.
Werner Mesomelic Syndrome MONDO:0008572
Werner mesomelic syndrome, also curated by OMIM as tibial hypoplasia or aplasia with polydactyly (OMIM:188740, which absorbed the former OMIM:188770; ORPHA:988). The most severe branch: tibial hypo- or aplasia in addition to the hand and foot phenotype, i.e. zeugopod involvement rather than autopod only. Caused by point variants at ZRS position 404, and OMIM assigns it to the ZRS locus entry (OMIM:620738). Inheritance is dominant, but a homozygous ZRS 402C>T individual showed the Werner phenotype while heterozygotes in the same kindred had only PPD2, establishing a dosage effect at this locus. ORPHA:988 absorbed the deprecated TPT-PS concept ORPHA:2950.
Show evidence (3 references)
ORPHA:988 SUPPORT Other
"ORPHA:2950 | Triphalangeal thumb-polysyndactyly syndrome | Moved to | ORPHA:988 | Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome"
Orphanet's own disorder-disorder association record for ORPHA:988 lists the deprecated TPT-PS concept (ORPHA:2950) as "Moved to" this entry, directly confirming that Orphanet no longer maintains TPT-PS as a standalone concept and folded it into the Werner mesomelic spectrum.
PMID:19847792 SUPPORT Human Clinical
"Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs."
Defines the Werner branch by zeugopod involvement added to the shared hand and foot phenotype.
PMID:24777739 SUPPORT Human Clinical
"Here, we describe a novel point mutation in the ZRS, 402C>T (AC007097.4:g.105548C>T), that is transmitted through two Mexican families with one homozygous individual."
Documents the allele whose homozygous form gives Werner mesomelic syndrome and whose heterozygous form gives PPD2 in the same families.
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Discussions and Knowledge Gaps

5
Which disease term should ground a locus-level entry when the ontology has classes for every member of a spectrum but none for the spectrum itself?
CURATION TODO OPEN mondo_no_zrs_spectrum_class
Attached to
has_subtypes#Preaxial Polydactyly Type 2 has_subtypes#Triphalangeal Thumb-Polysyndactyly Syndrome has_subtypes#Werner Mesomelic Syndrome
MONDO has classes for all six members curated here, and they are grounded individually via subtype_term, but no class covers the ZRS gain-of-function spectrum as a whole. The members are scattered across unrelated branches: PPD2 sits under preaxial polydactyly of fingers, TPT-PS under congenital limb malformation, syndactyly type IV under non-syndromic syndactyly, and Werner under dysostosis and non-syndromic limb reduction defect, so there is no existing common ancestor below the level of developmental disorders. MONDO's natural construct for this would be a gene-anchored disease series, which is unavailable because ZRS has no HGNC identifier. Rather than ground the entry on the narrowest available member class, which is how this file previously came to be scoped as TPT-PS alone, disease_term is omitted so the gap is recorded. Resolving it needs either a new MONDO grouping class for the spectrum or an agreed convention for locus-level entries with no ontology counterpart. Note also that Orphanet has already partially lumped: ORPHA:2950 (TPT-PS) and ORPHA:3332 are both moved into ORPHA:988, the Werner mesomelic spectrum; ORPHA:2950 is additionally flagged "Deprecated entity" in Orphanet's own record.
Show evidence (4 references)
ORPHA:988 SUPPORT Other
"ORPHA:2950 | Triphalangeal thumb-polysyndactyly syndrome | Moved to | ORPHA:988 | Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome"
Orphanet's own disorder-disorder association list for ORPHA:988 records ORPHA:2950 (TPT-PS) as "Moved to" this entry, directly documenting half of the lumping this discussion notes.
ORPHA:988 SUPPORT Other
"ORPHA:3332 | Hypoplastic tibiae-postaxial polydactyly syndrome | Moved to | ORPHA:988 | Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome"
The same association list also records ORPHA:3332 as "Moved to" ORPHA:988, documenting the other half of the lumping this discussion notes.
PMID:19847792 SUPPORT Human Clinical
"We suggest the term "ZRS-associated syndromes" and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS."
The literature proposes a cover term for exactly the grouping that no ontology class currently provides.
+ 1 more reference
How should a disease entry ground its causal entity when that entity is a cis-regulatory element rather than a gene?
CURATION TODO OPEN zrs_regulatory_element_not_groundable
Attached to
genetic#ZRS/pZRS cis-regulatory locus controlling limb-specific SHH expression pathophysiology#ZRS or pZRS Regulatory Gain of Ectopic Expression
The causal entity for this spectrum is the ZRS enhancer. The LMBR1 protein is a bystander - no LMBR1 coding variant causes any branch - and OMIM records this by maintaining a separate locus entry for the enhancer (OMIM:620738, NCBI Gene 105804841, Homo sapiens chromosome 7). The schema cannot express that. The gene slot binds to the GeneTerm enum, which is HGNC-only, and HGNC has no entry for ZRS because HGNC names genes; a lookup by NCBI Gene ID returns nothing, and a search for the symbol returns LMBR1 as an alias. There is no regulatory-element or genomic-feature descriptor in the schema: regulatory_element_type records that an ENHANCER was disrupted but has no companion slot for which enhancer. The entry is therefore grounded on hgnc:13243 LMBR1, which reproduces the gene-centric conflation OMIM moved away from. A regulatory_element_term slot alongside gene_term, rangeable over NCBI Gene or OMIM locus entries, would fix this; ZRS is the canonical test case because here the element is the disease locus and the gene is incidental. Note also that the schema is internally inconsistent on this point: GeneDescriptor is documented as "bindable to HGNC or other gene databases", while the gene_term slot is documented as "The HGNC term for this gene" and the enum admits HGNC alone.
How does a limb-specific enhancer produce the nasal defects reported in Laurin-Sandrow syndrome?
KNOWLEDGE GAP OPEN lss_nasal_defects_outside_limb_enhancer_scope
Attached to
has_subtypes#Laurin-Sandrow Syndrome pathophysiology#Ectopic Limb-Bud SHH Regulatory Activity
Nasal defects are part of the clinical definition of Laurin-Sandrow syndrome, but every mechanism curated in this entry is limb-restricted. ZRS drives SHH expression specifically in the limb bud, and the pathograph runs from ectopic limb-bud enhancer activity to autopod and zeugopod patterning; there is no curated route from that lesion to the developing face. The nasal phenotype is therefore recorded in the Laurin-Sandrow subtype description but is deliberately not curated as a phenotype record, because doing so would attach a disconnected node asserting a causal path the evidence does not support. Candidate explanations that would need testing: the smaller (<80 kb) duplications associated with Laurin-Sandrow may disturb regulatory elements or topological boundaries beyond ZRS itself, giving a craniofacial effect that larger duplications and point variants do not; alternatively the nasal finding may be a variable or coincidental association in a small reported series. Distinguishing these matters for the spectrum's boundaries, since it is the one curated feature that a purely limb-specific mechanism cannot explain.
Show evidence (1 reference)
PMID:24456159 SUPPORT Human Clinical
"Laurin-Sandrow syndrome (LSS) is a rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia."
Establishes nasal defects as part of the syndrome definition, which is what makes their absence from the limb-restricted mechanism a gap.
Are the pZRS-associated contact changes measured in patient skin fibroblasts and the ectopic reporter activity measured in transgenic mouse limbs faithful to endogenous regulation in the human embryonic limb bud?
HUMAN MODEL MISMATCH OPEN pzrs_fibroblast_mouse_limb_bud_model_mismatch
Attached to
experimental_models#Patient-skin-fibroblast SHH-LMBR1 4C-seq model animal_models#Human pZRS mutant transgenic mouse enhancer-reporter assay pathophysiology#Altered SHH-LMBR1 Regulatory-Domain Contacts pathophysiology#Ectopic Limb-Bud SHH Regulatory Activity
Existing model evidence is informative but not anatomically equivalent to the human embryonic limb. The 4C-seq result comes from one affected donor's skin fibroblasts, while the mouse assay measures an isolated human regulatory construct and reporter rather than the intact human SHH-LMBR1 locus or endogenous SHH transcription. Their fidelity to the disease-relevant human developmental cell state therefore remains open.
Proposed experiments
Isogenic pZRS human limb-bud context-fidelity study
pzrs_isogenic_limb_bud_context_fidelity
Introduce and correct the recurrent pZRS variant in isogenic human iPSC-derived limb-bud mesenchymal models, then jointly measure enhancer accessibility, SHH-LMBR1 contacts, endogenous SHH expression, and Hedgehog-response gradients across the developmental time course. Compare those readouts directly with the fibroblast 4C-seq and mouse-reporter observations to establish which model findings translate to human limb-bud biology.
Readouts
Difference in SHH-LMBR1 contact frequency
pathophysiology#Altered SHH-LMBR1 Regulatory-Domain Contacts
Spatial and temporal endogenous SHH expression
pathophysiology#Ectopic Limb-Bud SHH Regulatory Activity
Show evidence (2 references)
PMID:35821352 SUPPORT In Vitro
"Finally, we performed a circular chromatin conformation capture-sequencing (4C-seq) assay on skin fibroblasts of one affected family member and control samples to examine potential alterations in the SHH regulatory domain and functionally characterize the identified variant."
Confirms the 4C-seq model is a single-donor skin-fibroblast system, the basis for the fibroblast side of the human-model-fidelity mismatch.
PMID:29543231 SUPPORT Model Organism
"Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5)."
Identifies the mouse readout as a transgenic enhancer assay and reports its ectopic-expression result, the basis for the mouse-model side of the fidelity mismatch. That such an assay scores a reporter construct rather than endogenous SHH transcription is domain knowledge about the assay type, not a claim the quote itself makes.
Do altered SHH-LMBR1 chromatin contacts causally mediate pZRS-dependent ectopic endogenous SHH expression?
KNOWLEDGE GAP OPEN pzrs_chromatin_contact_causality
Attached to
pathophysiology#ZRS or pZRS Regulatory Gain of Ectopic Expression pathophysiology#Altered SHH-LMBR1 Regulatory-Domain Contacts pathophysiology#Ectopic Limb-Bud SHH Regulatory Activity
The patient-fibroblast study associates the pZRS variant with increased TAD contacts, and the mouse reporter assay separately shows ectopic regulatory activity. Neither study perturbs chromatin contacts independently of pZRS genotype, so they do not establish that the contact change causes endogenous SHH misexpression. The source explicitly states that the contact change arose by an unknown mechanism.
Proposed experiments
Orthogonal SHH-LMBR1 contact-causality test
pzrs_contact_causality_perturbation
In pZRS-mutant and corrected human iPSC-derived limb-bud mesenchyme, disrupt or restore the relevant regulatory-domain contacts while holding pZRS genotype constant. Jointly measure contact frequency, endogenous SHH transcription, and Hedgehog-response output to test whether expression follows contact manipulation independently of the sequence variant.
Readouts
SHH-LMBR1 contact frequency under orthogonal perturbation
pathophysiology#Altered SHH-LMBR1 Regulatory-Domain Contacts
Endogenous SHH transcription at fixed pZRS genotype
pathophysiology#Ectopic Limb-Bud SHH Regulatory Activity
Show evidence (1 reference)
PMID:35821352 SUPPORT In Vitro
"The pathogenic mutation causative for TPT-PS in our patient gave rise to increased interactions within the SHH regulatory domain in yet unknown mechanism."
The authors explicitly identify the mechanism connecting the pZRS variant to altered contacts as unresolved.
⚙

Pathophysiology

6
ZRS or pZRS Regulatory Gain of Ectopic Expression
A heterozygous duplication encompassing ZRS or a pathogenic pZRS point variant changes the activity of the limb-specific SHH enhancer domain. This is a noncoding gain-of-ectopic-expression mechanism, not SHH protein loss of function and not a coding LMBR1 defect.
LMBR1 hgnc:13243 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LMBR1 (hgnc:13243). hgnc:13243 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Ectopic Limb-Bud SHH Regulatory Activity Increased enhancer dosage or altered pZRS sequence directly changes the spatial activity of the limb-specific SHH regulatory domain.
Altered SHH-LMBR1 Regulatory-Domain Contacts Patient fibroblasts carrying the pZRS variant show increased contacts across the SHH-LMBR1 TAD, but the causal path from the variant to this contact pattern is unresolved.
Show evidence (2 references)
PMID:18417549 SUPPORT Human Clinical
"Point mutations in the ZRS and duplications encompassing the ZRS cause distinctive limb phenotypes."
Establishes regulatory alteration of ZRS as a limb-patterning lesion and distinguishes variant-class-specific phenotypes.
PMID:29543231 SUPPORT Human Clinical
"Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb."
Supports the rarer pZRS regulatory route to TPT-PS.
Ectopic Limb-Bud SHH Regulatory Activity
Mutant regulatory sequences activate a reporter outside the normal posterior zone of polarizing activity, extending activity across the limb bud. This establishes spatial gain of enhancer activity; it should not be overread as a measurement of endogenous human SHH protein abundance.
Smoothened signaling pathway GO:0007224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Smoothened signaling pathway (GO:0007224). GO:0007224 is a biological process from the Gene Ontology. ⚠ ABNORMAL
limb bud UBERON:0004347 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in limb bud (UBERON:0004347). UBERON:0004347 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Human pZRS mutant transgenic mouse enhancer-reporter assay Mus musculus recapitulates The reporter assay directly reproduces the spatial gain of enhancer activity caused by the patient allele.
Downstream
Disrupted Digit Number and Identity Specification Spatially deregulated SHH regulatory activity perturbs the anterior-posterior information used to specify digit number and identity.
Disrupted Zeugopod Element Specification Lesion class determines how far proximally the defect reaches. The ZRS position-404 point variants drive strong ectopic SHH expression and add zeugopod involvement, whereas complete ZRS duplications leave lower-limb development unaffected. This is the branch point that separates Werner mesomelic syndrome from the duplication phenotypes.
Show evidence (1 reference)
PMID:29543231 SUPPORT Model Organism
"Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5)."
Direct functional evidence for ectopic limb-bud enhancer activity.
Altered SHH-LMBR1 Regulatory-Domain Contacts
Circular chromatin-conformation capture in patient skin fibroblasts found increased contacts across the SHH-LMBR1 TAD. The observation is real, but its mechanistic relationship to ectopic embryonic limb expression is uncertain because fibroblasts are not limb-bud tissue and the authors did not resolve how the variant changes contacts.
Experimental models
Patient-skin-fibroblast SHH-LMBR1 4C-seq model PRIMARY CELL CULTURE The primary cells reproduce the patient-associated chromatin-contact phenotype measured in the study.
Show evidence (1 reference)
PMID:35821352 SUPPORT In Vitro
"The results of 4C-seq experiments revealed increased interactions within the whole SHH regulatory domain (SHH-LMBR1 TAD) in the patient compared to controls."
Directly supports the measured chromatin-contact phenotype in patient fibroblasts.
Disrupted Digit Number and Identity Specification
The abnormal spatial SHH signal perturbs anterior-posterior digit-number, digit-identity, and phalangeal-segmentation programs in the developing autopod.
Chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
Anterior/posterior pattern specification GO:0009952 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Anterior/posterior pattern specification (GO:0009952). GO:0009952 is a biological process from the Gene Ontology. ⚠ ABNORMAL Embryonic limb morphogenesis GO:0030326 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Embryonic limb morphogenesis (GO:0030326). GO:0030326 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Serially Homologous Autopod Malformation Altered digit specification produces the coordinated triphalangism, polydactyly, and syndactyly phenotype across the hands and feet.
Show evidence (1 reference)
PMID:18417549 SUPPORT Human Clinical
"The Sonic hedgehog (SHH) protein produced in the zone of polarising activity (ZPA) is a major determinant of the identity and numbers of digits in early limb development."
Establishes SHH-dependent digit-number and identity specification as the affected developmental program.
Serially Homologous Autopod Malformation
Because homologous digit-patterning programs operate in the forelimb and hindlimb autopods, the single cis-regulatory lesion can produce a variable bundle of triphalangeal thumbs, preaxial and postaxial polydactyly, and finger or foot syndactyly rather than an isolated single-element defect.
Chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
Limb morphogenesis GO:0035108 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Limb morphogenesis (GO:0035108). GO:0035108 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Triphalangeal Thumb
Preaxial Hand Polydactyly
Postaxial Hand Polydactyly
Finger Syndactyly
Preaxial Foot Polydactyly
Postaxial Foot Polydactyly
Mirror Image Foot Polydactyly
Absent Thumb
Show evidence (1 reference)
PMID:10594878 SUPPORT Human Clinical
"The characteristic findings in this family are triphalangeal thumb, webbing between 3rd, 4th, and 5th fingers associated with bony synostosis in the distal phalanges of the same fingers, and pre- and postaxial polysyndactyly of feet."
Directly supports the coordinated hand-foot malformation bundle.
Disrupted Zeugopod Element Specification
In the strong-ectopic-expression branch the patterning defect is not confined to the autopod: specification of the zeugopod elements is also disturbed, producing tibial hypoplasia or aplasia, abnormal or duplicated fibulae, and mesomelic shortening of the limb. This node is what distinguishes Werner mesomelic syndrome and the fibular phenotype of Laurin-Sandrow syndrome from the autopod-only branches of the spectrum, and it is engaged in a lesion-class-dependent way rather than by every ZRS alteration.
Embryonic limb morphogenesis GO:0030326 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Embryonic limb morphogenesis (GO:0030326). GO:0030326 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Tibial Hypoplasia or Aplasia
Fibular Duplication
Mesomelic Limb Shortening
Patellar Aplasia
Show evidence (2 references)
PMID:19847792 SUPPORT Human Clinical
"Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs."
Establishes zeugopod involvement as an addition to, not a replacement for, the shared autopod phenotype.
PMID:24777739 SUPPORT Human Clinical
"Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet."
States the proximal extension of the defect into the distal long bones as the feature that marks the severe branch.
⬡

Pathograph

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Pathograph: causal mechanism network for ZRS-Related Limb Malformation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

12
Limbs 5
Triphalangeal Thumb HP:0001199 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Triphalangeal thumb (HP:0001199). HP:0001199 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10594878 SUPPORT Human Clinical
"The characteristic findings in this family are triphalangeal thumb, webbing between 3rd, 4th, and 5th fingers associated with bony synostosis in the distal phalanges of the same fingers, and pre- and postaxial polysyndactyly of feet."
Directly documents triphalangeal thumb in a TPT-PS pedigree.
Preaxial Hand Polydactyly HP:0001177 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Preaxial hand polydactyly (HP:0001177). HP:0001177 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10594878 SUPPORT Human Clinical
"Triphalangeal thumb-polysyndactyly (TPT-PS) is an isolated limb malformation consisting of pre- and postaxial polysyndactyly of hands and feet."
Directly supports preaxial polysyndactyly of the hands in TPT-PS.
Postaxial Hand Polydactyly HP:0001162 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postaxial hand polydactyly (HP:0001162). HP:0001162 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10594878 SUPPORT Human Clinical
"Triphalangeal thumb-polysyndactyly (TPT-PS) is an isolated limb malformation consisting of pre- and postaxial polysyndactyly of hands and feet."
Directly supports postaxial polysyndactyly of the hands in TPT-PS.
Finger Syndactyly HP:0006101 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Finger syndactyly (HP:0006101). HP:0006101 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10594878 SUPPORT Human Clinical
"Some individuals show a more severe phenotype with a complete syndactyly of all fingers giving a "cup-like" appearance to the hands."
Documents severe complete finger syndactyly within a TPT-PS family.
Absent Thumb HP:0009777 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent thumb (HP:0009777). HP:0009777 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19847792 SUPPORT Human Clinical
"Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs."
Documents the five-fingered hand with absent thumbs in the Werner branch.
PMID:10869115 SUPPORT Human Clinical
"His daughter was more severely affected, having complete syndactyly of five-fingered hands in rosebud fashion (Haas-type syndactyly), hypoplastic tibiae, absent patellae, thick and displaced fibulae, preaxial polysyndactyly of triphalangeal toes, and cutaneous syndactyly of some toes, the..."
Documents the five-fingered hand in the Haas-type configuration, in a patient whose father had TPT-PS.
Other 7
Preaxial Foot Polydactyly HP:0001841 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Preaxial foot polydactyly (HP:0001841). HP:0001841 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10594878 SUPPORT Human Clinical
"The characteristic findings in this family are triphalangeal thumb, webbing between 3rd, 4th, and 5th fingers associated with bony synostosis in the distal phalanges of the same fingers, and pre- and postaxial polysyndactyly of feet."
Directly supports preaxial foot polydactyly in TPT-PS.
Postaxial Foot Polydactyly HP:0001830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postaxial foot polydactyly (HP:0001830). HP:0001830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10594878 SUPPORT Human Clinical
"The characteristic findings in this family are triphalangeal thumb, webbing between 3rd, 4th, and 5th fingers associated with bony synostosis in the distal phalanges of the same fingers, and pre- and postaxial polysyndactyly of feet."
Directly supports postaxial foot polydactyly in TPT-PS.
Mirror Image Foot Polydactyly HP:0010691 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mirror image foot polydactyly (HP:0010691). HP:0010691 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24456159 SUPPORT Human Clinical
"Laurin-Sandrow syndrome (LSS) is a rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia."
Defines mirror-image foot duplication as a core Laurin-Sandrow feature.
Tibial Hypoplasia or Aplasia Aplasia/Hypoplasia of the tibia HP:0005772 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia/Hypoplasia of the tibia (HP:0005772). HP:0005772 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19847792 SUPPORT Human Clinical
"Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs."
Directly defines tibial hypo- or aplasia as the characteristic Werner feature.
PMID:10869115 SUPPORT Human Clinical
"His daughter was more severely affected, having complete syndactyly of five-fingered hands in rosebud fashion (Haas-type syndactyly), hypoplastic tibiae, absent patellae, thick and displaced fibulae, preaxial polysyndactyly of triphalangeal toes, and cutaneous syndactyly of some toes, the..."
Documents hypoplastic tibiae in a daughter whose father had autopod-only TPT-PS, showing the zeugopod branch arising within one family.
Fibular Duplication HP:0010503 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fibular duplication (HP:0010503). HP:0010503 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24456159 SUPPORT Human Clinical
"Clinically, the patients show polysyndactyly phenotypes and various types of lower limb malformations ranging from syndactyly to mirror image polydactyly with duplications of the fibulae."
Directly documents fibular duplication in ZRS-microduplication patients.
Mesomelic Limb Shortening Mesomelia HP:0003027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mesomelia (HP:0003027). HP:0003027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24777739 SUPPORT Human Clinical
"Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet."
Identifies involvement of the distal long bones, the mesomelic segment, as the discriminating severe-branch feature.
Patellar Aplasia HP:0006443 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patellar aplasia (HP:0006443). HP:0006443 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10869115 SUPPORT Human Clinical
"His daughter was more severely affected, having complete syndactyly of five-fingered hands in rosebud fashion (Haas-type syndactyly), hypoplastic tibiae, absent patellae, thick and displaced fibulae, preaxial polysyndactyly of triphalangeal toes, and cutaneous syndactyly of some toes, the..."
Directly documents absent patellae in the zeugopod-involving branch.
🧬

Genetic Associations

1
ZRS/pZRS cis-regulatory locus controlling limb-specific SHH expression (Causative noncoding regulatory variants in the ZRS enhancer and its flanking pre-ZRS, which lie within the LMBR1 locus, alter limb-specific SHH expression)
Gene: ZRS enhancer, within the LMBR1 locus (hgnc:13243) hgnc:13243 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ZRS enhancer, within the LMBR1 locus (hgnc:13243), annotated with LMBR1 (hgnc:13243). hgnc:13243 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:18417549 SUPPORT Human Clinical
"Both TPTPS and SD4 are due to duplications involving ZRS, the limb specific SHH enhancer."
Supports the causal LMBR1/ZRS regulatory locus while distinguishing the distant functional target, SHH.
Variants (2)
Heterozygous genomic duplications encompassing ZRS Pathogenic
Gene: LMBR1 hgnc:13243 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in LMBR1 (hgnc:13243). hgnc:13243 is a gene from the HUGO Gene Nomenclature Committee. copy-number gain GOE
Copy-number gains spanning the limb-specific ZRS enhancer segregate with TPT-PS and/or syndactyly type IV; in six families, minimum duplications ranged from 131 kb to 398 kb.
Functional effects
limb-specific SHH expression gain of ectopic expression GOE ENHANCER
Increased ZRS dosage produces gain of ectopic SHH regulatory activity during embryonic limb development.
Mechanism: Duplication of the long-range limb-specific enhancer increases or spatially deregulates its activity in the limb bud.
Developmental stage: embryonic limb development
Show evidence (1 reference)
PMID:18417549 SUPPORT Human Clinical
"Using real-time quantitative polymerase chain reaction (qPCR), we identified duplication of ZRS and found that this duplication segregated with the limb phenotypes in all families but was not detected in unaffected family members or in unrelated control individuals."
Segregation across six families establishes ZRS-encompassing duplications as a principal pathogenic variant class.
Heterozygous pre-ZRS point variant Pathogenic
Gene: LMBR1 hgnc:13243 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in LMBR1 (hgnc:13243). hgnc:13243 is a gene from the HUGO Gene Nomenclature Committee. single-nucleotide regulatory variant GOE
The recurrent pZRS variant chr7:156585476G>C (GRCh37/hg19; NC_000007.14:g.156792782C>G on GRCh38) segregates with TPT-PS and drives ectopic enhancer-reporter activity throughout the developing mouse limb bud.
Functional effects
limb-specific SHH expression gain of ectopic expression GOE ENHANCER
The pZRS variant produces spatial gain of ectopic regulatory activity during limb development.
Mechanism: Alteration of an evolutionarily conserved sequence adjacent to ZRS changes enhancer activity; the exact transcription-factor and chromatin-contact mechanism remains unresolved.
Developmental stage: embryonic limb development
Show evidence (1 reference)
PMID:29543231 SUPPORT Human Clinical
"A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members."
Identifies the pZRS variant in every affected member of the studied TPT-PS family.
💊

Medical Actions

1
Individualized triphalangeal-thumb and polydactyly reconstruction
Action: orthopedic hand surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthopedic hand surgery, annotated with Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Hand surgery may remove an accessory/delta phalanx, reconstruct ligaments, perform osteotomy, or rebalance soft tissues according to the individual's anatomy and functional goals. It corrects established anatomy and does not reverse the embryonic SHH-patterning lesion.
Target Phenotypes: Triphalangeal thumb HP:0001199 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Triphalangeal thumb (HP:0001199). HP:0001199 is a phenotype from the Human Phenotype Ontology. Preaxial hand polydactyly HP:0001177 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Preaxial hand polydactyly (HP:0001177). HP:0001177 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30223699 SUPPORT Human Clinical
"The aim of surgical treatment is to reconstruct or correct the anatomic anomalies to obtain greater function and a more acceptable appearance."
Supports individualized reconstructive surgery for the triphalangeal thumb phenotype.
PMID:30223699 SUPPORT Human Clinical
"In our series, operations varied from removal of the delta phalanx with ligament reconstruction to multiple osteotomies and rebalancing of soft tissues."
Documents the range of anatomy-directed reconstructive procedures.
🔬

Diagnosis

1
ZRS copy-number analysis with pZRS sequencing
Molecular evaluation should be able to detect copy-number gains spanning ZRS and point variants in the adjacent pZRS. A coding-only gene panel or exome may miss both regulatory variant classes.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:35821352 SUPPORT Human Clinical
"Our study expands the number of TPT-PS families carrying a pathogenic alteration of the pZRS and underlines the importance of routine pZRS sequencing in the genetic diagnostics of patients with TPT-PS or similar phenotypes."
Directly supports pZRS sequencing after routine approaches do not find a ZRS alteration.
PMID:18417549 SUPPORT Human Clinical
"We designed 17 additional qPCR assays and defined the minimum duplications in all six families, ranging from 131kb to 398kb."
Supports copy-number-sensitive analysis for the common ZRS-encompassing duplication class.
📊

Prevalence

1
Global
Unknown Rare
Every branch of the ZRS spectrum is consistently described as rare, but no population-based numeric prevalence estimate was identified either for the locus-level spectrum or for its individual subtypes.
🧫

Experimental Models

1
Patient-skin-fibroblast SHH-LMBR1 4C-seq model PRIMARY_CELL_CULTURE
Circular chromatin-conformation capture compared skin fibroblasts from one affected pZRS-variant carrier with controls and measured increased contacts across the SHH-LMBR1 TAD.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Skin fibroblasts from one affected family member and controls
Culture
Primary fibroblast monolayer analyzed by 4C-seq
Publication
PMID:35821352
Pathograph links
Altered SHH-LMBR1 Regulatory-Domain Contacts recapitulates fidelity: low The primary cells reproduce the patient-associated chromatin-contact phenotype measured in the study.
Limitations: One affected donor was studied, the cells were skin fibroblasts rather than embryonic limb-bud mesenchyme, and the contact change was not linked experimentally to endogenous SHH expression.
Readouts
SHH-LMBR1 TAD contact frequency by 4C-seq
Direction: INCREASED
Interpretation: Increased local interaction frequency is the molecular phenotype measured in patient fibroblasts.
Show evidence (1 reference)
PMID:35821352 SUPPORT In Vitro
"The results of 4C-seq experiments revealed increased interactions within the whole SHH regulatory domain (SHH-LMBR1 TAD) in the patient compared to controls."
Directly reports the readout and direction.
Show evidence (1 reference)
PMID:35821352 SUPPORT In Vitro
"Finally, we performed a circular chromatin conformation capture-sequencing (4C-seq) assay on skin fibroblasts of one affected family member and control samples to examine potential alterations in the SHH regulatory domain and functionally characterize the identified variant."
Establishes the patient-derived primary-cell model and its purpose.
Show evidence (1 reference)
PMID:35821352 SUPPORT In Vitro
"Finally, we performed a circular chromatin conformation capture-sequencing (4C-seq) assay on skin fibroblasts of one affected family member and control samples to examine potential alterations in the SHH regulatory domain and functionally characterize the identified variant."
Directly describes the primary-fibroblast 4C-seq system.
🐁

Animal Models

1
Human pZRS mutant transgenic mouse enhancer-reporter assay
A mouse transgenic enhancer assay tested the human patient pZRS allele at embryonic day 11.5 and showed extended ectopic reporter expression across the developing limb bud.
Species
Mus musculus
Genotype
Transgenic reporter carrying the human TPT-PS-associated pZRS chr7:156585476G>C allele
Publication
PMID:29543231
Pathograph links
Ectopic Limb-Bud SHH Regulatory Activity recapitulates fidelity: moderate The reporter assay directly reproduces the spatial gain of enhancer activity caused by the patient allele.
Limitations: The assay uses an isolated human regulatory construct and reporter in a mouse embryo; it does not reproduce the full human SHH-LMBR1 locus, endogenous SHH transcription, or the mature hand-foot phenotype.
Readouts
Limb-bud enhancer-reporter expression at E11.5
Direction: INCREASED
Interpretation: Spatially extended reporter expression is the direct readout of ectopic pZRS enhancer activity.
Show evidence (1 reference)
PMID:29543231 SUPPORT Model Organism
"Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5)."
Directly reports the model readout and developmental time point.
Show evidence (1 reference)
PMID:29543231 SUPPORT Model Organism
"Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5)."
Supports using the assay as a model of the ectopic regulatory-activity node.
Show evidence (1 reference)
PMID:29543231 SUPPORT Model Organism
"METHODS: We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay."
Directly identifies the transgenic mouse enhancer model used in the study.
{ }

Source YAML

click to show 
name: ZRS-Related Limb Malformation
creation_date: '2026-04-04T00:00:00Z'
description: >-
  ZRS-related limb malformation is the continuum of autosomal dominant congenital
  limb malformations produced by gain-of-function alterations of the zone of
  polarizing activity regulatory sequence (ZRS), a long-range limb-specific
  enhancer of SHH lying in intron 5 of LMBR1 roughly 1 Mb from its target gene.
  Every branch of the spectrum shares one pathograph: ectopic anterior SHH
  regulatory activity in the developing limb bud, disrupting anterior-posterior
  digit number and identity specification. What differs between branches is the
  molecular alteration and its dosage, not the mechanism. Point variants across
  the ZRS typically produce preaxial polydactyly with or without triphalangeal
  thumb; the specific position-404 variants produce the more severe Werner
  mesomelic phenotype that additionally involves the zeugopod; complete
  duplications produce Haas-type polysyndactyly and triphalangeal
  thumb-polysyndactyly syndrome, with smaller (<80 kb) duplications producing
  Laurin-Sandrow syndrome; and rarer point variants in the adjacent pre-ZRS
  (pZRS) produce triphalangeal thumb-polysyndactyly syndrome. Wieczorek et al.
  proposed "ZRS-associated syndromes" as the cover term for this continuum
  (PMID:19847792), and a single ZRS allele can produce several of the named
  entities within one kindred (PMID:24777739). This entry is curated at the locus
  level for that reason; the historically named entities are retained as grounded
  subtypes. Acheiropodia (OMIM:200500) is curated separately: it arises from
  deletion at the same locus and is a loss-of-function, limb-reduction pathograph
  running in the opposite direction.
category: Mendelian
parents:
- Congenital Disorder
- Limb Malformation
synonyms:
- ZRS-associated syndromes
- ZRS-associated limb malformation
- SHH ZRS enhancer gain-of-function limb malformation spectrum
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008605
      label: triphalangeal thumb, Nonopposable
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      Isolated triphalangeal thumb is one specific, mild-end presentation of
      the locus-level spectrum curated by this entry, so the MONDO class is
      narrower than the entry. MONDO:0008605 is the only MONDO class for
      isolated triphalangeal thumb as an entity; see the caveat on the
      Isolated Triphalangeal Thumb subtype about OMIM splitting this
      presentation across two entries.
  - term:
      id: MONDO:0008270
      label: polydactyly of a triphalangeal thumb
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      Preaxial polydactyly type 2 is the classical ZRS point-variant
      presentation, one named clinical entity within the broader locus-level
      spectrum this entry curates.
  - term:
      id: MONDO:0017454
      label: triphalangeal thumb-polysyndactyly syndrome
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      TPT-PS is the duplication-driven presentation combining triphalangeal
      thumbs with pre- and postaxial polydactyly and syndactyly; a single
      named entity narrower than the full ZRS spectrum.
  - term:
      id: MONDO:0008515
      label: syndactyly type 4
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      Haas-type polysyndactyly (syndactyly type IV) is the larger-duplication
      end of the ZRS dosage series, one named entity within the spectrum.
  - term:
      id: MONDO:0007615
      label: laurin-Sandrow syndrome
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      Laurin-Sandrow syndrome is the smaller-duplication, mirror-image-foot
      presentation distinguished from Haas-type polysyndactyly, one named
      entity within the spectrum.
  - term:
      id: MONDO:0008572
      label: tibia, hypoplasia or aplasia of, with polydactyly
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      Werner mesomelic syndrome is the point-variant, zeugopod-involving
      presentation at the severe end of the spectrum, one named entity
      narrower than the full locus-level entry.
has_subtypes:
- name: Isolated Triphalangeal Thumb
  classification: clinical_phenotype
  subtype_term:
    preferred_term: triphalangeal thumb, nonopposable
    term:
      id: MONDO:0008605
      label: triphalangeal thumb, Nonopposable
  description: >-
    The mildest branch: a three-phalanx thumb without polydactyly. OMIM splits
    this presentation across two entries, carrying opposable triphalangeal thumb
    as an included title of PPD2 (OMIM:174500) while OMIM:190600 covers the
    nonopposable form; MONDO:0008605 is the only MONDO class for isolated
    triphalangeal thumb as an entity, so it is used here with that caveat.
    Isolated triphalangeal thumb and PPD2 co-occur in single ZRS kindreds.
  evidence:
  - reference: PMID:24777739
    reference_title: >-
      A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous
      form and Werner mesomelic syndrome in a homozygous form.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although most mutations cause preaxial polydactyly (PPD), triphalangeal
      thumb (TPT) or both, a mutation in position 404 of the ZRS causes more
      severe Werner mesomelic syndrome (WMS) for which malformations include the
      distal arm or leg bones in addition to the hands and/or feet.
    explanation: >-
      Establishes isolated triphalangeal thumb as one of the routine outcomes of
      ZRS point variants, alongside preaxial polydactyly.
- name: Preaxial Polydactyly Type 2
  classification: molecular
  subtype_term:
    preferred_term: polydactyly of a triphalangeal thumb
    term:
      id: MONDO:0008270
      label: polydactyly of a triphalangeal thumb
  description: >-
    Preaxial polydactyly type 2 (PPD2; OMIM:174500; ORPHA:93336), duplication on
    the radial side of the hand with a usually opposable triphalangeal thumb.
    The classical ZRS point-variant phenotype. OMIM assigns PPD2 to the ZRS locus
    entry (OMIM:620738) rather than to LMBR1.
  evidence:
  - reference: PMID:12837695
    reference_title: >-
      A long-range Shh enhancer regulates expression in the developing limb and
      fin and is associated with preaxial polydactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we show that the chromosome 7q36 associated preaxial polydactyly, a
      frequently observed congenital limb malformation, results from point
      mutations in a Shh regulatory element.
    explanation: >-
      The founding demonstration that preaxial polydactyly is a ZRS enhancer
      point-variant disease.
- name: Triphalangeal Thumb-Polysyndactyly Syndrome
  classification: molecular
  subtype_term:
    preferred_term: triphalangeal thumb-polysyndactyly syndrome
    term:
      id: MONDO:0017454
      label: triphalangeal thumb-polysyndactyly syndrome
  description: >-
    Triphalangeal thumb-polysyndactyly syndrome (TPT-PS; OMIM:190605), combining
    triphalangeal thumbs with pre- and postaxial polydactyly and variable
    syndactyly of hands and feet. Caused by complete ZRS duplications and, more
    rarely, by pre-ZRS point variants. OMIM assigns this entry to LMBR1
    (OMIM:605522) because the causal duplications span the gene body as well as
    the enhancer. Orphanet no longer carries a standalone TPT-PS concept:
    ORPHA:2950 is deprecated and moved to ORPHA:988, the Werner mesomelic
    spectrum.
  evidence:
  - reference: ORPHA:2950
    reference_title: "Triphalangeal thumb-polysyndactyly syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      **ORPHA:2950** — Triphalangeal thumb-polysyndactyly syndrome (Malformation syndrome, Disorder)

      **Status:** Deprecated entity; Inactive
    explanation: >-
      Orphanet's own record for ORPHA:2950 (TPT-PS) carries the "Deprecated
      entity" and "Inactive" status flags, the literal source for the claim
      that Orphanet no longer carries a standalone TPT-PS concept.
  - reference: ORPHA:988
    reference_title: "Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ORPHA:2950 | Triphalangeal thumb-polysyndactyly syndrome | Moved to |
      ORPHA:988 | Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome
    explanation: >-
      Orphanet's disorder-disorder association record confirms ORPHA:2950
      (TPT-PS) was moved into ORPHA:988, so Orphanet no longer carries a
      standalone TPT-PS concept.
  - reference: PMID:18417549
    reference_title: >-
      Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are
      caused by genomic duplications involving the long range, limb-specific
      SHH enhancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both TPTPS and SD4 are due to duplications involving ZRS, the limb
      specific SHH enhancer.
    explanation: >-
      Establishes the ZRS duplication mechanism shared by TPT-PS and syndactyly
      type IV.
- name: Haas-Type Polysyndactyly
  display_name: Haas-Type Polysyndactyly (Syndactyly Type IV)
  classification: molecular
  subtype_term:
    preferred_term: syndactyly type 4
    term:
      id: MONDO:0008515
      label: syndactyly type 4
  description: >-
    Haas-type polysyndactyly (syndactyly type IV; OMIM:186200; ORPHA:93405),
    complete syndactyly of all fingers giving a cup-shaped or rosebud hand, with
    polydactyly. Caused by larger (>80 kb) ZRS duplications, and reported within
    the same families as TPT-PS.
  evidence:
  - reference: PMID:24456159
    reference_title: >-
      Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are
      associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that larger duplications of the ZRS region (>80 kb) are associated
      with HTS, whereas smaller duplications (<80 kb) result in the LSS
      phenotype.
    explanation: >-
      Assigns Haas-type polysyndactyly to the larger-duplication end of the ZRS
      dosage series.
- name: Laurin-Sandrow Syndrome
  classification: molecular
  subtype_term:
    preferred_term: Laurin-Sandrow syndrome
    term:
      id: MONDO:0007615
      label: laurin-Sandrow syndrome
  description: >-
    Laurin-Sandrow syndrome (LSS; OMIM:135750; ORPHA:2378), polysyndactyly with
    mirror-image duplication of the feet, fibular duplication and nasal defects.
    Caused by smaller (<80 kb) ZRS duplications, and distinguished from Haas-type
    polysyndactyly by the mirror-image foot phenotype.
  evidence:
  - reference: PMID:24456159
    reference_title: >-
      Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are
      associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we show that these small microduplications within the ZRS
      region are the underlying genetic cause of Laurin-Sandrow syndrome.
    explanation: >-
      Establishes small ZRS microduplication as the cause of Laurin-Sandrow
      syndrome, placing it inside this locus spectrum.
- name: Werner Mesomelic Syndrome
  classification: molecular
  subtype_term:
    preferred_term: tibia, hypoplasia or aplasia of, with polydactyly
    term:
      id: MONDO:0008572
      label: tibia, hypoplasia or aplasia of, with polydactyly
  description: >-
    Werner mesomelic syndrome, also curated by OMIM as tibial hypoplasia or
    aplasia with polydactyly (OMIM:188740, which absorbed the former OMIM:188770;
    ORPHA:988). The most severe branch: tibial hypo- or aplasia in addition to
    the hand and foot phenotype, i.e. zeugopod involvement rather than autopod
    only. Caused by point variants at ZRS position 404, and OMIM assigns it to
    the ZRS locus entry (OMIM:620738). Inheritance is dominant, but a homozygous
    ZRS 402C>T individual showed the Werner phenotype while heterozygotes in the
    same kindred had only PPD2, establishing a dosage effect at this locus.
    ORPHA:988 absorbed the deprecated TPT-PS concept ORPHA:2950.
  evidence:
  - reference: ORPHA:988
    reference_title: "Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ORPHA:2950 | Triphalangeal thumb-polysyndactyly syndrome | Moved to |
      ORPHA:988 | Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome
    explanation: >-
      Orphanet's own disorder-disorder association record for ORPHA:988 lists
      the deprecated TPT-PS concept (ORPHA:2950) as "Moved to" this entry,
      directly confirming that Orphanet no longer maintains TPT-PS as a
      standalone concept and folded it into the Werner mesomelic spectrum.
  - reference: PMID:19847792
    reference_title: >-
      A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS)
      causes Werner mesomelic syndrome (WMS) while complete ZRS duplications
      underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or
      without triphalangeal thumb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with
      unknown molecular etiology characterized by hypo- or aplasia of the tibiae
      in addition to the preaxial polydactyly (PPD) of the hands and feet and/or
      five-fingered hand with absence of thumbs.
    explanation: >-
      Defines the Werner branch by zeugopod involvement added to the shared hand
      and foot phenotype.
  - reference: PMID:24777739
    reference_title: >-
      A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous
      form and Werner mesomelic syndrome in a homozygous form.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a novel point mutation in the ZRS, 402C>T
      (AC007097.4:g.105548C>T), that is transmitted through two Mexican families
      with one homozygous individual.
    explanation: >-
      Documents the allele whose homozygous form gives Werner mesomelic syndrome
      and whose heterozygous form gives PPD2 in the same families.
classifications:
  isds_skeletal_category:
  - classification_value: polydactyly_syndactyly_triphalangism
    notes: >-
      Members of this spectrum sit in the ISDS Polydactyly-Syndactyly-Triphalangism
      group. The ISDS row cited in PMID:31633310 names PPD2/triphalangeal thumb.
      That grouping is a nosology bucket admitting members on any of polydactyly,
      syndactyly or triphalangism; it is not an identity claim about its members,
      and it is much broader than this locus (it also holds GLI3-, HOXD13- and
      ciliopathy-related entities).
prevalence:
- population: Global
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    Every branch of the ZRS spectrum is consistently described as rare, but no
    population-based numeric prevalence estimate was identified either for the
    locus-level spectrum or for its individual subtypes.
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >-
    Pedigrees show autosomal dominant transmission with marked variable
    expression. Complete penetrance has been documented in individual large
    families, but a syndrome-wide penetrance percentage is not established.
  evidence:
  - reference: PMID:23793141
    reference_title: >-
      Confirmation of genetic homogeneity of syndactyly type IV and
      triphalangeal thumb-polysyndactyly syndrome in a Chinese family and
      review of the literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Triphalangeal thumb-polysyndactyly syndrome (TPTPS) consists of a
      triphalangeal thumb, polydactyly, and syndactyly and is transmitted in an
      autosomal dominant manner with variable expression.
    explanation: >-
      Directly supports autosomal dominant inheritance and variable
      expressivity in TPT-PS.
  - reference: PMID:8958333
    reference_title: >-
      An autosomal dominant triphalangeal thumb: polysyndactyly syndrome with
      variable expression in a large Indian family maps to 7q36.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The abnormalities were present only in the upper limbs, and the
      phenotype was fully penetrant.
    explanation: >-
      Documents full penetrance in one large pedigree; marked PARTIAL because
      that family-specific estimate is not generalized to all TPT-PS families.
- name: Autosomal Recessive (dosage effect at a dominant locus)
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  description: >-
    The locus is dominant, but allele dosage modifies severity, so a homozygous
    genotype can present as a distinct and more severe clinical branch. In two
    Mexican families a homozygous ZRS 402C>T individual had Werner mesomelic
    syndrome while heterozygous relatives carrying the same allele had only
    preaxial polydactyly type 2. OMIM therefore records both AD and AR for
    OMIM:188740. This is a gene-dosage effect at a dominant locus rather than a
    conventional recessive disease, and it is one reason the branches of this
    spectrum are not separable by inheritance pattern.
  evidence:
  - reference: PMID:24777739
    reference_title: >-
      A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous
      form and Werner mesomelic syndrome in a homozygous form.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of more than 15 reported families with ZRS mutations, only one homozygous
      individual has been reported, with no change in phenotype compared with
      heterozygotes.
    explanation: >-
      Sets up the dosage question this paper then answers, documenting that
      homozygosity for the novel 402C>T allele produces the more severe Werner
      phenotype.
genetic:
- name: ZRS/pZRS cis-regulatory locus controlling limb-specific SHH expression
  gene_term:
    preferred_term: ZRS enhancer, within the LMBR1 locus (hgnc:13243)
    term:
      id: hgnc:13243
      label: LMBR1
  association: >-
    Causative noncoding regulatory variants in the ZRS enhancer and its flanking
    pre-ZRS, which lie within the LMBR1 locus, alter limb-specific SHH expression
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    ZRS is a long-range limb-specific SHH enhancer embedded in intron 5 of LMBR1,
    about 1 Mb from its target gene. The causal entity for this entry is the
    enhancer, not the LMBR1 protein: no LMBR1 coding variant causes any branch of
    this spectrum, and SHH is the distant regulatory target whose spatial
    expression is altered. OMIM recognises this by maintaining a separate locus
    entry for the enhancer, ZRS (OMIM:620738, NCBI Gene 105804841), and it splits
    the spectrum's phenotypes between the two identifiers by lesion class rather
    than by clinical entity. Sequence variants of the enhancer itself are assigned
    to ZRS - PPD2 (OMIM:174500) and Werner mesomelic syndrome (OMIM:188740) -
    while structural lesions of the surrounding interval are assigned to LMBR1
    (OMIM:605522), because the causal duplications and deletions span the gene
    body as well as the enhancer: TPT-PS (OMIM:190605), syndactyly type IV
    (OMIM:186200), Laurin-Sandrow syndrome (OMIM:135750) and acheiropodia
    (OMIM:200500). This entry is grounded on hgnc:13243 LMBR1 only because ZRS has
    no HGNC identifier and the schema's gene slot accepts HGNC terms alone; see
    the zrs_regulatory_element_not_groundable discussion.
    Lesion class does not map cleanly onto clinical entity in either direction:
    complete ZRS duplications underlie Haas-type polysyndactyly and preaxial
    polydactyly with or without triphalangeal thumb as well as TPT-PS
    (PMID:19847792), and the 404G>A allele reported as the "Cuban mutation" of
    PPD2 was reclassified once the index patient was found to also have tibial
    hypoplasia. Kantaputra and Chalidapong additionally reported PPD3 within this
    spectrum (PMID:10869115), though OMIM assigns no gene or locus to
    OMIM:174600, so that branch is noted rather than curated as a subtype.
  variants:
  - name: Heterozygous genomic duplications encompassing ZRS
    description: >-
      Copy-number gains spanning the limb-specific ZRS enhancer segregate
      with TPT-PS and/or syndactyly type IV; in six families, minimum
      duplications ranged from 131 kb to 398 kb.
    gene:
      preferred_term: LMBR1
      term:
        id: hgnc:13243
        label: LMBR1
    type: copy-number gain
    clinical_significance: PATHOGENIC
    regulatory_category: GOE
    functional_effects:
    - function: limb-specific SHH expression
      description: >-
        Increased ZRS dosage produces gain of ectopic SHH regulatory activity
        during embryonic limb development.
      type: gain of ectopic expression
      regulatory_category: GOE
      regulatory_element_type: ENHANCER
      affected_developmental_stage: embryonic limb development
      regulatory_mechanism: >-
        Duplication of the long-range limb-specific enhancer increases or
        spatially deregulates its activity in the limb bud.
    evidence:
    - reference: PMID:18417549
      reference_title: >-
        Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are
        caused by genomic duplications involving the long range, limb-specific
        SHH enhancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Using real-time quantitative polymerase chain reaction (qPCR), we
        identified duplication of ZRS and found that this duplication
        segregated with the limb phenotypes in all families but was not
        detected in unaffected family members or in unrelated control
        individuals.
      explanation: >-
        Segregation across six families establishes ZRS-encompassing
        duplications as a principal pathogenic variant class.
  - name: Heterozygous pre-ZRS point variant
    description: >-
      The recurrent pZRS variant chr7:156585476G>C (GRCh37/hg19;
      NC_000007.14:g.156792782C>G on GRCh38) segregates with TPT-PS and drives
      ectopic enhancer-reporter activity throughout the developing mouse limb
      bud.
    gene:
      preferred_term: LMBR1
      term:
        id: hgnc:13243
        label: LMBR1
    type: single-nucleotide regulatory variant
    clinical_significance: PATHOGENIC
    regulatory_category: GOE
    functional_effects:
    - function: limb-specific SHH expression
      description: >-
        The pZRS variant produces spatial gain of ectopic regulatory activity
        during limb development.
      type: gain of ectopic expression
      regulatory_category: GOE
      regulatory_element_type: ENHANCER
      affected_developmental_stage: embryonic limb development
      regulatory_mechanism: >-
        Alteration of an evolutionarily conserved sequence adjacent to ZRS
        changes enhancer activity; the exact transcription-factor and
        chromatin-contact mechanism remains unresolved.
    evidence:
    - reference: PMID:29543231
      reference_title: >-
        A point mutation in the pre-ZRS disrupts sonic hedgehog expression in
        the limb bud and results in triphalangeal thumb-polysyndactyly
        syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was
        detected in all affected family members.
      explanation: >-
        Identifies the pZRS variant in every affected member of the studied
        TPT-PS family.
  evidence:
  - reference: PMID:18417549
    reference_title: >-
      Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are
      caused by genomic duplications involving the long range, limb-specific
      SHH enhancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both TPTPS and SD4 are due to duplications involving ZRS, the limb
      specific SHH enhancer.
    explanation: >-
      Supports the causal LMBR1/ZRS regulatory locus while distinguishing the
      distant functional target, SHH.
phenotypes:
- category: Musculoskeletal
  name: Triphalangeal Thumb
  subtypes:
  - Isolated Triphalangeal Thumb
  - Preaxial Polydactyly Type 2
  - Triphalangeal Thumb-Polysyndactyly Syndrome
  - Werner Mesomelic Syndrome
  description: >-
    The thumb contains three phalanges rather than two. Shape, opposability,
    stiffness, and laterality vary among affected individuals.
  phenotype_term:
    preferred_term: Triphalangeal thumb
    term:
      id: HP:0001199
      label: Triphalangeal thumb
  evidence:
  - reference: PMID:10594878
    reference_title: >-
      Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome
      linked to chromosome 7q36.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The characteristic findings in this family are triphalangeal thumb,
      webbing between 3rd, 4th, and 5th fingers associated with bony synostosis
      in the distal phalanges of the same fingers, and pre- and postaxial
      polysyndactyly of feet.
    explanation: >-
      Directly documents triphalangeal thumb in a TPT-PS pedigree.
- category: Musculoskeletal
  name: Preaxial Hand Polydactyly
  subtypes:
  - Preaxial Polydactyly Type 2
  - Triphalangeal Thumb-Polysyndactyly Syndrome
  - Werner Mesomelic Syndrome
  description: >-
    Extra digit elements occur on the radial/thumb side of the hand as part of
    the polysyndactyly phenotype.
  phenotype_term:
    preferred_term: Preaxial hand polydactyly
    term:
      id: HP:0001177
      label: Preaxial hand polydactyly
  evidence:
  - reference: PMID:10594878
    reference_title: >-
      Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome
      linked to chromosome 7q36.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Triphalangeal thumb-polysyndactyly (TPT-PS) is an isolated limb
      malformation consisting of pre- and postaxial polysyndactyly of hands and
      feet.
    explanation: >-
      Directly supports preaxial polysyndactyly of the hands in TPT-PS.
- category: Musculoskeletal
  name: Postaxial Hand Polydactyly
  subtypes:
  - Triphalangeal Thumb-Polysyndactyly Syndrome
  description: >-
    Extra digit elements can also occur on the ulnar side of the hand,
    contributing to the variable complex polysyndactyly phenotype.
  phenotype_term:
    preferred_term: Postaxial hand polydactyly
    term:
      id: HP:0001162
      label: Postaxial hand polydactyly
  evidence:
  - reference: PMID:10594878
    reference_title: >-
      Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome
      linked to chromosome 7q36.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Triphalangeal thumb-polysyndactyly (TPT-PS) is an isolated limb
      malformation consisting of pre- and postaxial polysyndactyly of hands and
      feet.
    explanation: >-
      Directly supports postaxial polysyndactyly of the hands in TPT-PS.
- category: Musculoskeletal
  name: Finger Syndactyly
  subtypes:
  - Triphalangeal Thumb-Polysyndactyly Syndrome
  - Haas-Type Polysyndactyly
  - Laurin-Sandrow Syndrome
  description: >-
    Cutaneous webbing can progress to complete syndactyly and may be
    accompanied by distal phalangeal synostosis.
  phenotype_term:
    preferred_term: Finger syndactyly
    term:
      id: HP:0006101
      label: Finger syndactyly
  evidence:
  - reference: PMID:10594878
    reference_title: >-
      Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome
      linked to chromosome 7q36.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some individuals show a more severe phenotype with a complete syndactyly
      of all fingers giving a "cup-like" appearance to the hands.
    explanation: >-
      Documents severe complete finger syndactyly within a TPT-PS family.
- category: Musculoskeletal
  name: Preaxial Foot Polydactyly
  subtypes:
  - Triphalangeal Thumb-Polysyndactyly Syndrome
  - Werner Mesomelic Syndrome
  - Laurin-Sandrow Syndrome
  description: >-
    Extra digits may occur on the medial/hallux side of the foot.
  phenotype_term:
    preferred_term: Preaxial foot polydactyly
    term:
      id: HP:0001841
      label: Preaxial foot polydactyly
  evidence:
  - reference: PMID:10594878
    reference_title: >-
      Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome
      linked to chromosome 7q36.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The characteristic findings in this family are triphalangeal thumb,
      webbing between 3rd, 4th, and 5th fingers associated with bony synostosis
      in the distal phalanges of the same fingers, and pre- and postaxial
      polysyndactyly of feet.
    explanation: >-
      Directly supports preaxial foot polydactyly in TPT-PS.
- category: Musculoskeletal
  name: Postaxial Foot Polydactyly
  subtypes:
  - Triphalangeal Thumb-Polysyndactyly Syndrome
  description: >-
    Extra digits may occur on the lateral side of the foot.
  phenotype_term:
    preferred_term: Postaxial foot polydactyly
    term:
      id: HP:0001830
      label: Postaxial foot polydactyly
  evidence:
  - reference: PMID:10594878
    reference_title: >-
      Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome
      linked to chromosome 7q36.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The characteristic findings in this family are triphalangeal thumb,
      webbing between 3rd, 4th, and 5th fingers associated with bony synostosis
      in the distal phalanges of the same fingers, and pre- and postaxial
      polysyndactyly of feet.
    explanation: >-
      Directly supports postaxial foot polydactyly in TPT-PS.
- category: Musculoskeletal
  name: Mirror Image Foot Polydactyly
  subtypes:
  - Laurin-Sandrow Syndrome
  description: >-
    Duplication of the foot about its anteroposterior axis, giving a symmetrical
    double-posterior appearance rather than a simple supernumerary digit. This is
    the feature that separates Laurin-Sandrow syndrome from Haas-type
    polysyndactyly, whose digital phenotype otherwise overlaps it.
  phenotype_term:
    preferred_term: Mirror image foot polydactyly
    term:
      id: HP:0010691
      label: Mirror image foot polydactyly
  evidence:
  - reference: PMID:24456159
    reference_title: >-
      Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are
      associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laurin-Sandrow syndrome (LSS) is a rare autosomal dominant disorder
      characterized by polysyndactyly of hands and/or feet, mirror image
      duplication of the feet, nasal defects, and loss of identity between fibula
      and tibia.
    explanation: >-
      Defines mirror-image foot duplication as a core Laurin-Sandrow feature.
- category: Musculoskeletal
  name: Absent Thumb
  subtypes:
  - Werner Mesomelic Syndrome
  - Haas-Type Polysyndactyly
  description: >-
    Loss of a recognisable thumb, giving a five-fingered hand in which digit 1
    carries finger rather than thumb identity. In Haas-type polysyndactyly the
    five-fingered hand is additionally fused into a cup-shaped or rosebud
    configuration.
  phenotype_term:
    preferred_term: Absent thumb
    term:
      id: HP:0009777
      label: Absent thumb
  evidence:
  - reference: PMID:19847792
    reference_title: >-
      A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS)
      causes Werner mesomelic syndrome (WMS) while complete ZRS duplications
      underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or
      without triphalangeal thumb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with
      unknown molecular etiology characterized by hypo- or aplasia of the tibiae
      in addition to the preaxial polydactyly (PPD) of the hands and feet and/or
      five-fingered hand with absence of thumbs.
    explanation: >-
      Documents the five-fingered hand with absent thumbs in the Werner branch.
  - reference: PMID:10869115
    reference_title: >-
      Are triphalangeal thumb-polysyndactyly syndrome (TPTPS) and tibial
      hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS) identical? A
      father with TPTPS and his daughter with THPTTS in a Thai family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His daughter was more severely affected, having complete syndactyly of
      five-fingered hands in rosebud fashion (Haas-type syndactyly), hypoplastic
      tibiae, absent patellae, thick and displaced fibulae, preaxial
      polysyndactyly of triphalangeal toes, and cutaneous syndactyly of some
      toes, the manifestations being consistent with THPTTS.
    explanation: >-
      Documents the five-fingered hand in the Haas-type configuration, in a
      patient whose father had TPT-PS.
- category: Musculoskeletal
  name: Tibial Hypoplasia or Aplasia
  subtypes:
  - Werner Mesomelic Syndrome
  description: >-
    Hypoplasia or complete absence of the tibia, unilateral or bilateral. The
    defining zeugopod feature of the Werner branch and the phenotype that takes
    this spectrum beyond the hands and feet.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the tibia
    term:
      id: HP:0005772
      label: Aplasia/Hypoplasia of the tibia
  evidence:
  - reference: PMID:19847792
    reference_title: >-
      A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS)
      causes Werner mesomelic syndrome (WMS) while complete ZRS duplications
      underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or
      without triphalangeal thumb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with
      unknown molecular etiology characterized by hypo- or aplasia of the tibiae
      in addition to the preaxial polydactyly (PPD) of the hands and feet and/or
      five-fingered hand with absence of thumbs.
    explanation: >-
      Directly defines tibial hypo- or aplasia as the characteristic Werner
      feature.
  - reference: PMID:10869115
    reference_title: >-
      Are triphalangeal thumb-polysyndactyly syndrome (TPTPS) and tibial
      hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS) identical? A
      father with TPTPS and his daughter with THPTTS in a Thai family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His daughter was more severely affected, having complete syndactyly of
      five-fingered hands in rosebud fashion (Haas-type syndactyly), hypoplastic
      tibiae, absent patellae, thick and displaced fibulae, preaxial
      polysyndactyly of triphalangeal toes, and cutaneous syndactyly of some
      toes, the manifestations being consistent with THPTTS.
    explanation: >-
      Documents hypoplastic tibiae in a daughter whose father had autopod-only
      TPT-PS, showing the zeugopod branch arising within one family.
- category: Musculoskeletal
  name: Fibular Duplication
  subtypes:
  - Laurin-Sandrow Syndrome
  description: >-
    Duplication of the fibula, accompanying the mirror-image foot phenotype and
    reflecting duplicated posterior positional identity in the hindlimb zeugopod.
    Reported alongside loss of identity between fibula and tibia.
  phenotype_term:
    preferred_term: Fibular duplication
    term:
      id: HP:0010503
      label: Fibular duplication
  evidence:
  - reference: PMID:24456159
    reference_title: >-
      Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are
      associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically, the patients show polysyndactyly phenotypes and various types
      of lower limb malformations ranging from syndactyly to mirror image
      polydactyly with duplications of the fibulae.
    explanation: >-
      Directly documents fibular duplication in ZRS-microduplication patients.
- category: Musculoskeletal
  name: Mesomelic Limb Shortening
  subtypes:
  - Werner Mesomelic Syndrome
  description: >-
    Shortening of the middle limb segment, involving the distal arm or leg bones.
    The feature the Werner eponym is named for, and the clearest marker that the
    patterning defect has extended proximally out of the autopod.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
  evidence:
  - reference: PMID:24777739
    reference_title: >-
      A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous
      form and Werner mesomelic syndrome in a homozygous form.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although most mutations cause preaxial polydactyly (PPD), triphalangeal
      thumb (TPT) or both, a mutation in position 404 of the ZRS causes more
      severe Werner mesomelic syndrome (WMS) for which malformations include the
      distal arm or leg bones in addition to the hands and/or feet.
    explanation: >-
      Identifies involvement of the distal long bones, the mesomelic segment, as
      the discriminating severe-branch feature.
- category: Musculoskeletal
  name: Patellar Aplasia
  subtypes:
  - Werner Mesomelic Syndrome
  description: >-
    Absence of the patellae, reported together with tibial hypoplasia in the
    Werner branch and consistent with loss of the proximal tibial articulation
    that templates patellar formation.
  phenotype_term:
    preferred_term: Patellar aplasia
    term:
      id: HP:0006443
      label: Patellar aplasia
  evidence:
  - reference: PMID:10869115
    reference_title: >-
      Are triphalangeal thumb-polysyndactyly syndrome (TPTPS) and tibial
      hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS) identical? A
      father with TPTPS and his daughter with THPTTS in a Thai family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His daughter was more severely affected, having complete syndactyly of
      five-fingered hands in rosebud fashion (Haas-type syndactyly), hypoplastic
      tibiae, absent patellae, thick and displaced fibulae, preaxial
      polysyndactyly of triphalangeal toes, and cutaneous syndactyly of some
      toes, the manifestations being consistent with THPTTS.
    explanation: >-
      Directly documents absent patellae in the zeugopod-involving branch.
pathophysiology:
- name: ZRS or pZRS Regulatory Gain of Ectopic Expression
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    A heterozygous duplication encompassing ZRS or a pathogenic pZRS point
    variant changes the activity of the limb-specific SHH enhancer domain.
    This is a noncoding gain-of-ectopic-expression mechanism, not SHH protein
    loss of function and not a coding LMBR1 defect.
  genes:
  - preferred_term: LMBR1
    term:
      id: hgnc:13243
      label: LMBR1
  evidence:
  - reference: PMID:18417549
    reference_title: >-
      Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are
      caused by genomic duplications involving the long range, limb-specific
      SHH enhancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Point mutations in the ZRS and duplications encompassing the ZRS cause
      distinctive limb phenotypes.
    explanation: >-
      Establishes regulatory alteration of ZRS as a limb-patterning lesion and
      distinguishes variant-class-specific phenotypes.
  - reference: PMID:29543231
    reference_title: >-
      A point mutation in the pre-ZRS disrupts sonic hedgehog expression in
      the limb bud and results in triphalangeal thumb-polysyndactyly syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our work describes the first mutation in the pZRS to be associated with
      TPT-PS and provides functional evidence that this mutation leads to
      ectopic expression of this enhancer within the developing limb.
    explanation: >-
      Supports the rarer pZRS regulatory route to TPT-PS.
  downstream:
  - target: Ectopic Limb-Bud SHH Regulatory Activity
    causal_link_type: DIRECT
    description: >-
      Increased enhancer dosage or altered pZRS sequence directly changes the
      spatial activity of the limb-specific SHH regulatory domain.
    evidence:
    - reference: PMID:29543231
      reference_title: "A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb-polysyndactyly syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Functional characterization using a mouse transgenic enhancer essay
        showed extended ectopic expression dispersed throughout the entire
        limb bud (E11.5).
      explanation: >-
        The transgenic enhancer assay directly measures ectopic regulatory
        activity of the patient pZRS allele.
  - target: Altered SHH-LMBR1 Regulatory-Domain Contacts
    causal_link_type: UNKNOWN
    description: >-
      Patient fibroblasts carrying the pZRS variant show increased contacts
      across the SHH-LMBR1 TAD, but the causal path from the variant to this
      contact pattern is unresolved.
    evidence:
    - reference: PMID:35821352
      reference_title: "The pZRS non-coding regulatory mutation resulting in triphalangeal thumb-polysyndactyly syndrome changes the pattern of local interactions."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The results of 4C-seq experiments revealed increased interactions
        within the whole SHH regulatory domain (SHH-LMBR1 TAD) in the patient
        compared to controls.
      explanation: >-
        Supports the contact difference but not a complete causal mechanism or
        its fidelity to embryonic limb tissue.
- name: Ectopic Limb-Bud SHH Regulatory Activity
  conforms_to: >-
    limb_digit_patterning_serial_homology#Limb Patterning Signal Perturbation
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Mutant regulatory sequences activate a reporter outside the normal
    posterior zone of polarizing activity, extending activity across the limb
    bud. This establishes spatial gain of enhancer activity; it should not be
    overread as a measurement of endogenous human SHH protein abundance.
  biological_processes:
  - preferred_term: Smoothened signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: ABNORMAL
  locations:
  - preferred_term: limb bud
    term:
      id: UBERON:0004347
      label: limb bud
  evidence:
  - reference: PMID:29543231
    reference_title: >-
      A point mutation in the pre-ZRS disrupts sonic hedgehog expression in
      the limb bud and results in triphalangeal thumb-polysyndactyly syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Functional characterization using a mouse transgenic enhancer essay
      showed extended ectopic expression dispersed throughout the entire limb
      bud (E11.5).
    explanation: >-
      Direct functional evidence for ectopic limb-bud enhancer activity.
  downstream:
  - target: Disrupted Digit Number and Identity Specification
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered SHH morphogen distribution and GLI3 repressor gradient
    description: >-
      Spatially deregulated SHH regulatory activity perturbs the
      anterior-posterior information used to specify digit number and identity.
    evidence:
    - reference: PMID:18178630
      reference_title: "A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Point mutations within this non-coding regulatory region designated ZRS
        lead to ectopic expression of Shh in the anterior margin of the limb bud,
        as shown in mice, and cause the human triphalangeal thumb and
        polysyndactyly (TPT-PS) phenotype.
      explanation: >-
        Links anterior ectopic SHH activity to the human TPT-PS phenotype.
  - target: Disrupted Zeugopod Element Specification
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - strong ectopic SHH expression extending the patterning defect proximally from the autopod into the zeugopod
    description: >-
      Lesion class determines how far proximally the defect reaches. The ZRS
      position-404 point variants drive strong ectopic SHH expression and add
      zeugopod involvement, whereas complete ZRS duplications leave lower-limb
      development unaffected. This is the branch point that separates Werner
      mesomelic syndrome from the duplication phenotypes.
    evidence:
    - reference: PMID:19847792
      reference_title: "A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These data provide the first evidence that WMS is caused by a specific
        ZRS mutation, which leads to strong ectopic SHH expression.
      explanation: >-
        Attributes the more severe, zeugopod-involving branch to stronger ectopic
        expression from a specific ZRS allele.
    - reference: PMID:19847792
      reference_title: "A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In contrast, we show that complete duplications of the ZRS region lead to
        type Haas polysyndactyly or triphalangeal thumb-polysyndactyly syndrome,
        but do not affect lower limb development.
      explanation: >-
        The contrasting arm of the same study: duplications spare the zeugopod,
        establishing this edge as lesion-class dependent rather than universal.
- name: Altered SHH-LMBR1 Regulatory-Domain Contacts
  biological_scale: MOLECULAR
  role: modifier
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Circular chromatin-conformation capture in patient skin fibroblasts found
    increased contacts across the SHH-LMBR1 TAD. The observation is real, but
    its mechanistic relationship to ectopic embryonic limb expression is
    uncertain because fibroblasts are not limb-bud tissue and the authors did
    not resolve how the variant changes contacts.
  evidence:
  - reference: PMID:35821352
    reference_title: >-
      The pZRS non-coding regulatory mutation resulting in triphalangeal
      thumb-polysyndactyly syndrome changes the pattern of local interactions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The results of 4C-seq experiments revealed increased interactions within
      the whole SHH regulatory domain (SHH-LMBR1 TAD) in the patient compared
      to controls.
    explanation: >-
      Directly supports the measured chromatin-contact phenotype in patient
      fibroblasts.
- name: Disrupted Digit Number and Identity Specification
  conforms_to: >-
    limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity
    Specification
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The abnormal spatial SHH signal perturbs anterior-posterior digit-number,
    digit-identity, and phalangeal-segmentation programs in the developing
    autopod.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Anterior/posterior pattern specification
    term:
      id: GO:0009952
      label: anterior/posterior pattern specification
    modifier: ABNORMAL
  - preferred_term: Embryonic limb morphogenesis
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:18417549
    reference_title: >-
      Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are
      caused by genomic duplications involving the long range, limb-specific
      SHH enhancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Sonic hedgehog (SHH) protein produced in the zone of polarising
      activity (ZPA) is a major determinant of the identity and numbers of
      digits in early limb development.
    explanation: >-
      Establishes SHH-dependent digit-number and identity specification as the
      affected developmental program.
  downstream:
  - target: Serially Homologous Autopod Malformation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - abnormal digit condensation and phalangeal segmentation
    description: >-
      Altered digit specification produces the coordinated triphalangism,
      polydactyly, and syndactyly phenotype across the hands and feet.
    evidence:
    - reference: PMID:10594878
      reference_title: "Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome linked to chromosome 7q36."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Triphalangeal thumb-polysyndactyly (TPT-PS) is an isolated limb
        malformation consisting of pre- and postaxial polysyndactyly of hands
        and feet.
      explanation: >-
        Documents the serially repeated hand-foot outcome in human TPT-PS.
- name: Serially Homologous Autopod Malformation
  conforms_to: >-
    limb_digit_patterning_serial_homology#Serially Homologous Autopod
    Malformation
  biological_scale: TISSUE
  role: consequence
  description: >-
    Because homologous digit-patterning programs operate in the forelimb and
    hindlimb autopods, the single cis-regulatory lesion can produce a variable
    bundle of triphalangeal thumbs, preaxial and postaxial polydactyly, and
    finger or foot syndactyly rather than an isolated single-element defect.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Limb morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:10594878
    reference_title: >-
      Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome
      linked to chromosome 7q36.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The characteristic findings in this family are triphalangeal thumb,
      webbing between 3rd, 4th, and 5th fingers associated with bony synostosis
      in the distal phalanges of the same fingers, and pre- and postaxial
      polysyndactyly of feet.
    explanation: >-
      Directly supports the coordinated hand-foot malformation bundle.
  downstream:
  - target: Triphalangeal Thumb
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - abnormal thumb phalangeal segmentation
  - target: Preaxial Hand Polydactyly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - supernumerary preaxial digit specification
  - target: Postaxial Hand Polydactyly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - supernumerary postaxial digit specification
  - target: Finger Syndactyly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - incomplete interdigital separation and phalangeal synostosis
  - target: Preaxial Foot Polydactyly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - supernumerary preaxial digit specification
  - target: Postaxial Foot Polydactyly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - supernumerary postaxial digit specification
  - target: Mirror Image Foot Polydactyly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - duplication of posterior positional identity across the anteroposterior axis of the hindlimb autopod
  - target: Absent Thumb
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of thumb positional identity with transformation of digit 1 towards a finger-like identity
- name: Disrupted Zeugopod Element Specification
  biological_scale: TISSUE
  role: consequence
  description: >-
    In the strong-ectopic-expression branch the patterning defect is not confined
    to the autopod: specification of the zeugopod elements is also disturbed,
    producing tibial hypoplasia or aplasia, abnormal or duplicated fibulae, and
    mesomelic shortening of the limb. This node is what distinguishes Werner
    mesomelic syndrome and the fibular phenotype of Laurin-Sandrow syndrome from
    the autopod-only branches of the spectrum, and it is engaged in a
    lesion-class-dependent way rather than by every ZRS alteration.
  biological_processes:
  - preferred_term: Embryonic limb morphogenesis
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19847792
    reference_title: >-
      A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS)
      causes Werner mesomelic syndrome (WMS) while complete ZRS duplications
      underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or
      without triphalangeal thumb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with
      unknown molecular etiology characterized by hypo- or aplasia of the tibiae
      in addition to the preaxial polydactyly (PPD) of the hands and feet and/or
      five-fingered hand with absence of thumbs.
    explanation: >-
      Establishes zeugopod involvement as an addition to, not a replacement for,
      the shared autopod phenotype.
  - reference: PMID:24777739
    reference_title: >-
      A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous
      form and Werner mesomelic syndrome in a homozygous form.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although most mutations cause preaxial polydactyly (PPD), triphalangeal
      thumb (TPT) or both, a mutation in position 404 of the ZRS causes more
      severe Werner mesomelic syndrome (WMS) for which malformations include the
      distal arm or leg bones in addition to the hands and/or feet.
    explanation: >-
      States the proximal extension of the defect into the distal long bones as
      the feature that marks the severe branch.
  downstream:
  - target: Tibial Hypoplasia or Aplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - failure of anterior zeugopod element specification and outgrowth
  - target: Fibular Duplication
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - duplication of posterior zeugopod positional identity
  - target: Mesomelic Limb Shortening
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced growth of the mispatterned zeugopod segment
  - target: Patellar Aplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - absent or malformed proximal tibial articulation removing the template for patellar formation
diagnosis:
- name: ZRS copy-number analysis with pZRS sequencing
  description: >-
    Molecular evaluation should be able to detect copy-number gains spanning
    ZRS and point variants in the adjacent pZRS. A coding-only gene panel or
    exome may miss both regulatory variant classes.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:35821352
    reference_title: >-
      The pZRS non-coding regulatory mutation resulting in triphalangeal
      thumb-polysyndactyly syndrome changes the pattern of local interactions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study expands the number of TPT-PS families carrying a pathogenic
      alteration of the pZRS and underlines the importance of routine pZRS
      sequencing in the genetic diagnostics of patients with TPT-PS or similar
      phenotypes.
    explanation: >-
      Directly supports pZRS sequencing after routine approaches do not find a
      ZRS alteration.
  - reference: PMID:18417549
    reference_title: >-
      Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are
      caused by genomic duplications involving the long range, limb-specific
      SHH enhancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We designed 17 additional qPCR assays and defined the minimum
      duplications in all six families, ranging from 131kb to 398kb.
    explanation: >-
      Supports copy-number-sensitive analysis for the common
      ZRS-encompassing duplication class.
treatments:
- name: Individualized triphalangeal-thumb and polydactyly reconstruction
  description: >-
    Hand surgery may remove an accessory/delta phalanx, reconstruct ligaments,
    perform osteotomy, or rebalance soft tissues according to the individual's
    anatomy and functional goals. It corrects established anatomy and does not
    reverse the embryonic SHH-patterning lesion.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic hand surgery
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Triphalangeal thumb
    term:
      id: HP:0001199
      label: Triphalangeal thumb
  - preferred_term: Preaxial hand polydactyly
    term:
      id: HP:0001177
      label: Preaxial hand polydactyly
  evidence:
  - reference: PMID:30223699
    reference_title: "Triphalangeal thumb: clinical features and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The aim of surgical treatment is to reconstruct or correct the anatomic
      anomalies to obtain greater function and a more acceptable appearance.
    explanation: >-
      Supports individualized reconstructive surgery for the triphalangeal
      thumb phenotype.
  - reference: PMID:30223699
    reference_title: "Triphalangeal thumb: clinical features and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our series, operations varied from removal of the delta phalanx with
      ligament reconstruction to multiple osteotomies and rebalancing of soft
      tissues.
    explanation: >-
      Documents the range of anatomy-directed reconstructive procedures.
experimental_models:
- name: Patient-skin-fibroblast SHH-LMBR1 4C-seq model
  description: >-
    Circular chromatin-conformation capture compared skin fibroblasts from one
    affected pZRS-variant carrier with controls and measured increased contacts
    across the SHH-LMBR1 TAD.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Skin fibroblasts from one affected family member and controls
  culture_system: Primary fibroblast monolayer analyzed by 4C-seq
  publication: PMID:35821352
  modeled_mechanisms:
  - target: Altered SHH-LMBR1 Regulatory-Domain Contacts
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      The primary cells reproduce the patient-associated chromatin-contact
      phenotype measured in the study.
    limitations: >-
      One affected donor was studied, the cells were skin fibroblasts rather
      than embryonic limb-bud mesenchyme, and the contact change was not linked
      experimentally to endogenous SHH expression.
    readouts:
    - name: SHH-LMBR1 TAD contact frequency by 4C-seq
      target: Altered SHH-LMBR1 Regulatory-Domain Contacts
      direction: INCREASED
      interpretation: >-
        Increased local interaction frequency is the molecular phenotype
        measured in patient fibroblasts.
      evidence:
      - reference: PMID:35821352
        reference_title: "The pZRS non-coding regulatory mutation resulting in triphalangeal thumb-polysyndactyly syndrome changes the pattern of local interactions."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          The results of 4C-seq experiments revealed increased interactions
          within the whole SHH regulatory domain (SHH-LMBR1 TAD) in the patient
          compared to controls.
        explanation: >-
          Directly reports the readout and direction.
    evidence:
    - reference: PMID:35821352
      reference_title: "The pZRS non-coding regulatory mutation resulting in triphalangeal thumb-polysyndactyly syndrome changes the pattern of local interactions."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Finally, we performed a circular chromatin conformation
        capture-sequencing (4C-seq) assay on skin fibroblasts of one affected
        family member and control samples to examine potential alterations in
        the SHH regulatory domain and functionally characterize the identified
        variant.
      explanation: >-
        Establishes the patient-derived primary-cell model and its purpose.
  evidence:
  - reference: PMID:35821352
    reference_title: "The pZRS non-coding regulatory mutation resulting in triphalangeal thumb-polysyndactyly syndrome changes the pattern of local interactions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, we performed a circular chromatin conformation
      capture-sequencing (4C-seq) assay on skin fibroblasts of one affected
      family member and control samples to examine potential alterations in the
      SHH regulatory domain and functionally characterize the identified
      variant.
    explanation: >-
      Directly describes the primary-fibroblast 4C-seq system.
animal_models:
- name: Human pZRS mutant transgenic mouse enhancer-reporter assay
  species: Mus musculus
  genotype: >-
    Transgenic reporter carrying the human TPT-PS-associated pZRS
    chr7:156585476G>C allele
  publication: PMID:29543231
  description: >-
    A mouse transgenic enhancer assay tested the human patient pZRS allele at
    embryonic day 11.5 and showed extended ectopic reporter expression across
    the developing limb bud.
  modeled_mechanisms:
  - target: Ectopic Limb-Bud SHH Regulatory Activity
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The reporter assay directly reproduces the spatial gain of enhancer
      activity caused by the patient allele.
    limitations: >-
      The assay uses an isolated human regulatory construct and reporter in a
      mouse embryo; it does not reproduce the full human SHH-LMBR1 locus,
      endogenous SHH transcription, or the mature hand-foot phenotype.
    readouts:
    - name: Limb-bud enhancer-reporter expression at E11.5
      target: Ectopic Limb-Bud SHH Regulatory Activity
      direction: INCREASED
      interpretation: >-
        Spatially extended reporter expression is the direct readout of ectopic
        pZRS enhancer activity.
      evidence:
      - reference: PMID:29543231
        reference_title: "A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb-polysyndactyly syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Functional characterization using a mouse transgenic enhancer essay
          showed extended ectopic expression dispersed throughout the entire
          limb bud (E11.5).
        explanation: >-
          Directly reports the model readout and developmental time point.
    evidence:
    - reference: PMID:29543231
      reference_title: "A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb-polysyndactyly syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Functional characterization using a mouse transgenic enhancer essay
        showed extended ectopic expression dispersed throughout the entire
        limb bud (E11.5).
      explanation: >-
        Supports using the assay as a model of the ectopic regulatory-activity
        node.
  evidence:
  - reference: PMID:29543231
    reference_title: "A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb-polysyndactyly syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      METHODS: We used linkage analysis, whole-exome sequencing, Sanger
      sequencing, fluorescence in situ hybridization, multiplex
      ligation-dependent probe amplification, single-nucleotide polymorphism
      array, and a mouse transgenic enhancer assay.
    explanation: >-
      Directly identifies the transgenic mouse enhancer model used in the
      study.
datasets: []
discussions:
- discussion_id: mondo_no_zrs_spectrum_class
  prompt: >-
    Which disease term should ground a locus-level entry when the ontology has
    classes for every member of a spectrum but none for the spectrum itself?
  kind: CURATION_TODO
  status: OPEN
  attaches_to:
  - has_subtypes#Preaxial Polydactyly Type 2
  - has_subtypes#Triphalangeal Thumb-Polysyndactyly Syndrome
  - has_subtypes#Werner Mesomelic Syndrome
  rationale: >-
    MONDO has classes for all six members curated here, and they are grounded
    individually via subtype_term, but no class covers the ZRS gain-of-function
    spectrum as a whole. The members are scattered across unrelated branches:
    PPD2 sits under preaxial polydactyly of fingers, TPT-PS under congenital limb
    malformation, syndactyly type IV under non-syndromic syndactyly, and Werner
    under dysostosis and non-syndromic limb reduction defect, so there is no
    existing common ancestor below the level of developmental disorders. MONDO's
    natural construct for this would be a gene-anchored disease series, which is
    unavailable because ZRS has no HGNC identifier. Rather than ground the entry
    on the narrowest available member class, which is how this file previously
    came to be scoped as TPT-PS alone, disease_term is omitted so the gap is
    recorded. Resolving it needs either a new MONDO grouping class for the
    spectrum or an agreed convention for locus-level entries with no ontology
    counterpart. Note also that Orphanet has already partially lumped: ORPHA:2950
    (TPT-PS) and ORPHA:3332 are both moved into ORPHA:988, the Werner
    mesomelic spectrum; ORPHA:2950 is additionally flagged "Deprecated entity"
    in Orphanet's own record.
  evidence:
  - reference: ORPHA:988
    reference_title: "Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ORPHA:2950 | Triphalangeal thumb-polysyndactyly syndrome | Moved to |
      ORPHA:988 | Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome
    explanation: >-
      Orphanet's own disorder-disorder association list for ORPHA:988 records
      ORPHA:2950 (TPT-PS) as "Moved to" this entry, directly documenting half
      of the lumping this discussion notes.
  - reference: ORPHA:988
    reference_title: "Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ORPHA:3332 | Hypoplastic tibiae-postaxial polydactyly syndrome | Moved to
      | ORPHA:988 | Tibial hemimelia-polysyndactyly-triphalangeal thumb
      syndrome
    explanation: >-
      The same association list also records ORPHA:3332 as "Moved to"
      ORPHA:988, documenting the other half of the lumping this discussion
      notes.
  - reference: PMID:19847792
    reference_title: >-
      A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS)
      causes Werner mesomelic syndrome (WMS) while complete ZRS duplications
      underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or
      without triphalangeal thumb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest the term "ZRS-associated syndromes" and a clinical
      subclassification for the continuum of limb malformations caused by
      different molecular alterations of the ZRS.
    explanation: >-
      The literature proposes a cover term for exactly the grouping that no
      ontology class currently provides.
  - reference: PMID:10869115
    reference_title: >-
      Are triphalangeal thumb-polysyndactyly syndrome (TPTPS) and tibial
      hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS) identical? A
      father with TPTPS and his daughter with THPTTS in a Thai family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Having two different syndromes in the same family suggests that they are
      actually the same disorder.
    explanation: >-
      The single-family observation underlying Orphanet's deprecation of
      ORPHA:2950 into ORPHA:988, and the clearest statement that the named
      entities of this spectrum are not separable.
- discussion_id: zrs_regulatory_element_not_groundable
  prompt: >-
    How should a disease entry ground its causal entity when that entity is a
    cis-regulatory element rather than a gene?
  kind: CURATION_TODO
  status: OPEN
  attaches_to:
  - genetic#ZRS/pZRS cis-regulatory locus controlling limb-specific SHH expression
  - pathophysiology#ZRS or pZRS Regulatory Gain of Ectopic Expression
  rationale: >-
    The causal entity for this spectrum is the ZRS enhancer. The LMBR1 protein is
    a bystander - no LMBR1 coding variant causes any branch - and OMIM records
    this by maintaining a separate locus entry for the enhancer (OMIM:620738,
    NCBI Gene 105804841, Homo sapiens chromosome 7). The schema cannot express
    that. The gene slot binds to the GeneTerm enum, which is HGNC-only, and HGNC
    has no entry for ZRS because HGNC names genes; a lookup by NCBI Gene ID
    returns nothing, and a search for the symbol returns LMBR1 as an alias. There
    is no regulatory-element or genomic-feature descriptor in the schema:
    regulatory_element_type records that an ENHANCER was disrupted but has no
    companion slot for which enhancer. The entry is therefore grounded on
    hgnc:13243 LMBR1, which reproduces the gene-centric conflation OMIM moved away
    from. A regulatory_element_term slot alongside gene_term, rangeable over NCBI
    Gene or OMIM locus entries, would fix this; ZRS is the canonical test case
    because here the element is the disease locus and the gene is incidental.
    Note also that the schema is internally inconsistent on this point:
    GeneDescriptor is documented as "bindable to HGNC or other gene databases",
    while the gene_term slot is documented as "The HGNC term for this gene" and
    the enum admits HGNC alone.
- discussion_id: lss_nasal_defects_outside_limb_enhancer_scope
  prompt: >-
    How does a limb-specific enhancer produce the nasal defects reported in
    Laurin-Sandrow syndrome?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - has_subtypes#Laurin-Sandrow Syndrome
  - pathophysiology#Ectopic Limb-Bud SHH Regulatory Activity
  rationale: >-
    Nasal defects are part of the clinical definition of Laurin-Sandrow syndrome,
    but every mechanism curated in this entry is limb-restricted. ZRS drives SHH
    expression specifically in the limb bud, and the pathograph runs from ectopic
    limb-bud enhancer activity to autopod and zeugopod patterning; there is no
    curated route from that lesion to the developing face. The nasal phenotype is
    therefore recorded in the Laurin-Sandrow subtype description but is
    deliberately not curated as a phenotype record, because doing so would attach
    a disconnected node asserting a causal path the evidence does not support.
    Candidate explanations that would need testing: the smaller (<80 kb)
    duplications associated with Laurin-Sandrow may disturb regulatory elements or
    topological boundaries beyond ZRS itself, giving a craniofacial effect that
    larger duplications and point variants do not; alternatively the nasal finding
    may be a variable or coincidental association in a small reported series.
    Distinguishing these matters for the spectrum's boundaries, since it is the
    one curated feature that a purely limb-specific mechanism cannot explain.
  evidence:
  - reference: PMID:24456159
    reference_title: >-
      Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are
      associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laurin-Sandrow syndrome (LSS) is a rare autosomal dominant disorder
      characterized by polysyndactyly of hands and/or feet, mirror image
      duplication of the feet, nasal defects, and loss of identity between fibula
      and tibia.
    explanation: >-
      Establishes nasal defects as part of the syndrome definition, which is what
      makes their absence from the limb-restricted mechanism a gap.
- discussion_id: pzrs_fibroblast_mouse_limb_bud_model_mismatch
  prompt: >-
    Are the pZRS-associated contact changes measured in patient skin
    fibroblasts and the ectopic reporter activity measured in transgenic mouse
    limbs faithful to endogenous regulation in the human embryonic limb bud?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - experimental_models#Patient-skin-fibroblast SHH-LMBR1 4C-seq model
  - animal_models#Human pZRS mutant transgenic mouse enhancer-reporter assay
  - pathophysiology#Altered SHH-LMBR1 Regulatory-Domain Contacts
  - pathophysiology#Ectopic Limb-Bud SHH Regulatory Activity
  rationale: >-
    Existing model evidence is informative but not anatomically equivalent to
    the human embryonic limb. The 4C-seq result comes from one affected donor's
    skin fibroblasts, while the mouse assay measures an isolated human
    regulatory construct and reporter rather than the intact human SHH-LMBR1
    locus or endogenous SHH transcription. Their fidelity to the
    disease-relevant human developmental cell state therefore remains open.
  proposed_experiments:
  - experiment_id: pzrs_isogenic_limb_bud_context_fidelity
    name: Isogenic pZRS human limb-bud context-fidelity study
    description: >-
      Introduce and correct the recurrent pZRS variant in isogenic human
      iPSC-derived limb-bud mesenchymal models, then jointly measure enhancer
      accessibility, SHH-LMBR1 contacts, endogenous SHH expression, and
      Hedgehog-response gradients across the developmental time course. Compare
      those readouts directly with the fibroblast 4C-seq and mouse-reporter
      observations to establish which model findings translate to human
      limb-bud biology.
    readouts:
    - name: Difference in SHH-LMBR1 contact frequency
      target: pathophysiology#Altered SHH-LMBR1 Regulatory-Domain Contacts
    - name: Spatial and temporal endogenous SHH expression
      target: pathophysiology#Ectopic Limb-Bud SHH Regulatory Activity
  evidence:
  - reference: PMID:35821352
    reference_title: "The pZRS non-coding regulatory mutation resulting in triphalangeal thumb-polysyndactyly syndrome changes the pattern of local interactions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, we performed a circular chromatin conformation
      capture-sequencing (4C-seq) assay on skin fibroblasts of one affected
      family member and control samples to examine potential alterations in
      the SHH regulatory domain and functionally characterize the identified
      variant.
    explanation: >-
      Confirms the 4C-seq model is a single-donor skin-fibroblast system, the
      basis for the fibroblast side of the human-model-fidelity mismatch.
  - reference: PMID:29543231
    reference_title: "A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb-polysyndactyly syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Functional characterization using a mouse transgenic enhancer essay
      showed extended ectopic expression dispersed throughout the entire
      limb bud (E11.5).
    explanation: >-
      Identifies the mouse readout as a transgenic enhancer assay and reports
      its ectopic-expression result, the basis for the mouse-model side of the
      fidelity mismatch. That such an assay scores a reporter construct rather
      than endogenous SHH transcription is domain knowledge about the assay
      type, not a claim the quote itself makes.
- discussion_id: pzrs_chromatin_contact_causality
  prompt: >-
    Do altered SHH-LMBR1 chromatin contacts causally mediate pZRS-dependent
    ectopic endogenous SHH expression?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#ZRS or pZRS Regulatory Gain of Ectopic Expression
  - pathophysiology#Altered SHH-LMBR1 Regulatory-Domain Contacts
  - pathophysiology#Ectopic Limb-Bud SHH Regulatory Activity
  rationale: >-
    The patient-fibroblast study associates the pZRS variant with increased TAD
    contacts, and the mouse reporter assay separately shows ectopic regulatory
    activity. Neither study perturbs chromatin contacts independently of pZRS
    genotype, so they do not establish that the contact change causes
    endogenous SHH misexpression. The source explicitly states that the contact
    change arose by an unknown mechanism.
  proposed_experiments:
  - experiment_id: pzrs_contact_causality_perturbation
    name: Orthogonal SHH-LMBR1 contact-causality test
    description: >-
      In pZRS-mutant and corrected human iPSC-derived limb-bud mesenchyme,
      disrupt or restore the relevant regulatory-domain contacts while holding
      pZRS genotype constant. Jointly measure contact frequency, endogenous SHH
      transcription, and Hedgehog-response output to test whether expression
      follows contact manipulation independently of the sequence variant.
    readouts:
    - name: SHH-LMBR1 contact frequency under orthogonal perturbation
      target: pathophysiology#Altered SHH-LMBR1 Regulatory-Domain Contacts
    - name: Endogenous SHH transcription at fixed pZRS genotype
      target: pathophysiology#Ectopic Limb-Bud SHH Regulatory Activity
  evidence:
  - reference: PMID:35821352
    reference_title: "The pZRS non-coding regulatory mutation resulting in triphalangeal thumb-polysyndactyly syndrome changes the pattern of local interactions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The pathogenic mutation causative for TPT-PS in our patient gave rise to
      increased interactions within the SHH regulatory domain in yet unknown
      mechanism.
    explanation: >-
      The authors explicitly identify the mechanism connecting the pZRS variant
      to altered contacts as unresolved.
notes: >-
  Entry scope: this file was retargeted from the single TPT-PS entity
  (MONDO:0017454 / OMIM:190605) to the locus-level ZRS gain-of-function spectrum.
  The earlier narrow scoping produced two artefacts that this revision reverses.
  First, the ZRS dosage-effect content from PMID:24777739 - one allele giving PPD2
  when heterozygous and Werner mesomelic syndrome when homozygous - had been
  deleted as "crossing this entry's disease boundary"; under the locus-level scope
  it is core evidence and is restored as an inheritance entry and in the Werner
  subtype. Second, TPT-PS and syndactyly type IV were noted as a reported
  phenotypic continuum (PMID:23793141) but held apart as separate entities; both
  are now subtypes.
  There is no top-level disease_term. No MONDO class covers the ZRS
  gain-of-function spectrum: the six member entities exist as separate MONDO
  classes and are grounded individually via subtype_term, but MONDO has no
  grouping class over them, and the natural construct (a gene-anchored disease
  series) is unavailable because ZRS has no HGNC identifier. Omitting the slot
  records that gap rather than resolving it by picking the narrowest available
  member class; 22 other disorder entries omit disease_term for comparable
  reasons. See the mondo_no_zrs_spectrum_class discussion.
  Acheiropodia (OMIM:200500; MONDO:0008700) is deliberately out of scope. It maps
  to the same locus but arises from deletion, and its pathograph is loss of
  enhancer-promoter contact producing limb reduction - the opposite direction of
  travel from the gain-of-ectopic-expression mechanism curated here.
  PPD3 (OMIM:174600) is noted in the genetic section but not curated as a
  subtype: Kantaputra and Chalidapong place it in this spectrum (PMID:10869115),
  but OMIM assigns the entry no gene or locus and Orphanet records no literature
  description since 1962.
  No disease-specific GeneReviews article was located. GEO discovery returned
  GSE44325 as a lexical polydactyly hit, but it studies Sost/Sostdc1-Gli3
  digit-number biology rather than a ZRS/pZRS model, so no dataset accession was
  curated. No spectrum-specific clinical trial was identified.
  Phenotype coverage spans both limb segments. The six autopod phenotypes
  inherited from the TPT-PS scoping are joined by mirror-image foot polydactyly
  and absent thumb in the autopod, and by tibial hypoplasia or aplasia, fibular
  duplication, mesomelic shortening and patellar aplasia in the zeugopod. The
  zeugopod group hangs off a separate pathograph node, Disrupted Zeugopod Element
  Specification, because it is engaged in a lesion-class-dependent way: ZRS
  position-404 point variants drive strong ectopic expression that reaches the
  zeugopod, while complete duplications leave lower-limb development unaffected
  (PMID:19847792). That contrast is the branch point separating Werner mesomelic
  syndrome from the duplication phenotypes, so it is modelled as an edge condition
  rather than a universal consequence.
  One Laurin-Sandrow feature is deliberately uncurated. Nasal defects are part of
  that syndrome's definition but no limb-specific enhancer mechanism reaches the
  face, so recording them as a phenotype would create a node asserting a causal
  path the evidence does not support. They are described in the subtype entry and
  raised as the lss_nasal_defects_outside_limb_enhancer_scope discussion instead.