Heart defect-tongue hamartoma-polysyndactyly syndrome (congenital heart defects, hamartomas of tongue, and polysyndactyly; CHDTHP, OMIM 217085; also known as Orstavik-Lindemann-Solberg syndrome and orocardiodigital syndrome) is a rare autosomal recessive ciliopathy within the oral-facial-digital syndrome spectrum. It is caused by biallelic loss-of-function variants in WDPCP (the human homolog of Fritz, also known as the Bardet-Biedl syndrome 15 gene), which encodes a planar cell polarity (PCP) effector required for ciliogenesis. WDPCP localizes to the ciliary transition zone, where it recruits septins and other proteins essential for cilium assembly, and it also directly modulates the actin cytoskeleton to control PCP and directional cell migration. Loss of WDPCP function disrupts both cilium-dependent signaling and convergent-extension morphogenesis, producing the characteristic triad of tongue hamartomas, polysyndactyly, and congenital heart defects (notably coarctation of the aorta). Loss-of-function in WDPCP/Fritz has also been linked to the more severe Bardet-Biedl and Meckel-Gruber ciliopathy spectra.
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name: Heart Defect-Tongue Hamartoma-Polysyndactyly Syndrome
creation_date: "2026-06-22T00:00:00Z"
category: Mendelian
description: >-
Heart defect-tongue hamartoma-polysyndactyly syndrome (congenital heart
defects, hamartomas of tongue, and polysyndactyly; CHDTHP, OMIM 217085; also
known as Orstavik-Lindemann-Solberg syndrome and orocardiodigital syndrome) is
a rare autosomal recessive ciliopathy within the oral-facial-digital syndrome
spectrum. It is caused by biallelic loss-of-function variants in WDPCP (the
human homolog of Fritz, also known as the Bardet-Biedl syndrome 15 gene),
which encodes a planar cell polarity (PCP) effector required for ciliogenesis.
WDPCP localizes to the ciliary transition zone, where it recruits septins and
other proteins essential for cilium assembly, and it also directly modulates
the actin cytoskeleton to control PCP and directional cell migration. Loss of
WDPCP function disrupts both cilium-dependent signaling and convergent-extension
morphogenesis, producing the characteristic triad of tongue hamartomas,
polysyndactyly, and congenital heart defects (notably coarctation of the
aorta). Loss-of-function in WDPCP/Fritz has
also been linked to the more severe Bardet-Biedl and Meckel-Gruber ciliopathy
spectra.
disease_term:
preferred_term: heart defect-tongue hamartoma-polysyndactyly syndrome
term:
id: MONDO:0009008
label: heart defect - tongue hamartoma - polysyndactyly syndrome
parents:
- Ciliopathies
inheritance:
- name: Autosomal Recessive
description: >-
The syndrome is inherited in an autosomal recessive manner, caused by
biallelic (homozygous or compound heterozygous) loss-of-function variants in
WDPCP. The index case was a compound heterozygote, with segregation in the
family consistent with recessive inheritance.
evidence:
- reference: PMID:25427950
reference_title: "Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Results of genotyping in her parents and unaffected siblings were
consistent with autosomal recessive inheritance of the mutation and the
WDPCP variant.
explanation: >-
Establishes autosomal recessive inheritance of biallelic WDPCP variants
from segregation analysis in the index family.
mappings:
mondo_mappings:
- term:
id: MONDO:0009008
label: heart defect - tongue hamartoma - polysyndactyly syndrome
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
MONDO:0009008 is the disease term for this entry; it carries an
OMIM:217085 xref and is classified as a WDPCP-related ciliopathy
(is_a MONDO:0700378), matching the curated identity.
pathophysiology:
- name: WDPCP/Fritz Transition Zone Recruitment and Ciliogenesis Defect
conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
description: >-
WDPCP (Fritz) is a planar cell polarity effector that localizes to the
ciliary transition zone, where it is required to recruit septins (Sept2) and
other transition-zone proteins (Nphp1, Mks1) needed for cilium assembly.
Loss of WDPCP function therefore disrupts ciliogenesis at the level of the
transition-zone gate, the upstream molecular lesion of this ciliopathy.
cell_types:
- preferred_term: ciliated cell
term:
id: CL:0000064
label: ciliated cell
biological_processes:
- preferred_term: cilium assembly
term:
id: GO:0060271
label: cilium assembly
modifier: ABNORMAL
- preferred_term: protein localization to cilium
term:
id: GO:0061512
label: protein localization to cilium
modifier: ABNORMAL
evidence:
- reference: PMID:24302887
reference_title: "Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We observed Wdpcp is localized to the transition zone, and in
Wdpcp-deficient cells, Sept2, Nphp1, and Mks1 were lost from the
transition zone, indicating Wdpcp is required for recruitment of proteins
essential for ciliogenesis.
explanation: >-
Localizes WDPCP to the ciliary transition zone and shows it is required to
recruit Sept2/Nphp1/Mks1 there, defining the transition-zone ciliogenesis
defect. Evidence source is IN_VITRO (cultured Wdpcp-deficient cells).
- reference: PMID:20671153
reference_title: "Planar cell polarity acts through septins to control collective cell movement and ciliogenesis."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
we identified control of septin localization by the PCP protein Fritz as a
crucial control point for both collective cell movement and ciliogenesis
in Xenopus embryos.
explanation: >-
Establishes that the PCP protein Fritz (WDPCP) controls septin
localization to govern ciliogenesis. Evidence source is MODEL_ORGANISM
(Xenopus embryos).
downstream:
- target: Planar Cell Polarity and Non-Canonical Wnt Disruption
description: >-
Failure of transition-zone protein recruitment and ciliogenesis
destabilizes the cilium-coupled planar cell polarity machinery.
- name: Planar Cell Polarity and Non-Canonical Wnt Disruption
conforms_to: "ciliopathy_dysfunction#Planar Cell Polarity and Non-Canonical Wnt Disruption"
description: >-
Beyond its ciliogenesis role, WDPCP is a planar cell polarity effector that
directly modulates the actin cytoskeleton to establish cell polarity and
directional (collective) cell migration during convergent-extension
morphogenesis. WDPCP deficiency disrupts non-canonical Wnt/PCP signaling and
actin organization, and notably the PCP defects are not solely a consequence
of lost cilia but reflect direct disruption of the actin cytoskeleton.
biological_processes:
- preferred_term: non-canonical Wnt signaling pathway
term:
id: GO:0035567
label: non-canonical Wnt signaling pathway
modifier: DYSREGULATED
- preferred_term: establishment of planar polarity
term:
id: GO:0001736
label: establishment of planar polarity
modifier: ABNORMAL
- preferred_term: actin cytoskeleton organization
term:
id: GO:0030036
label: actin cytoskeleton organization
modifier: ABNORMAL
- preferred_term: cell migration
term:
id: GO:0016477
label: cell migration
modifier: ABNORMAL
evidence:
- reference: PMID:24302887
reference_title: "Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These results suggest the PCP defects in Wdpcp mutants are not caused by
loss of cilia, but by direct disruption of the actin cytoskeleton.
explanation: >-
Shows WDPCP regulates planar cell polarity through direct modulation of
the actin cytoskeleton, independent of its ciliary role. Evidence source
is MODEL_ORGANISM (Wdpcp-mutant mouse).
- reference: PMID:20671153
reference_title: "Planar cell polarity acts through septins to control collective cell movement and ciliogenesis."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The planar cell polarity (PCP) signaling pathway governs collective cell
movements during vertebrate embryogenesis, and certain PCP proteins are
also implicated in the assembly of cilia.
explanation: >-
Frames the dual PCP/ciliogenesis role of the pathway that WDPCP/Fritz
effects, linking PCP disruption to morphogenetic failure. Evidence source
is MODEL_ORGANISM (vertebrate embryos).
- reference: PMID:25427950
reference_title: "Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These results suggest that disruption of planar cell polarity and
ciliogenesis may result in this unusual form of orofaciodigital syndrome.
explanation: >-
Directly attributes the human syndrome to disruption of planar cell
polarity and ciliogenesis, anchoring the central PCP effector node to
human disease.
downstream:
- target: Convergent-Extension and Outflow Tract Developmental Malformation
description: >-
Disrupted PCP/non-canonical Wnt signaling impairs convergent-extension
morphogenesis and oriented cell movement, producing structural
malformations of the heart, limbs, and craniofacial midline.
- name: Convergent-Extension and Outflow Tract Developmental Malformation
role: consequence
description: >-
Loss of PCP-controlled convergent extension and directional cell migration
disrupts morphogenesis of the cardiac outflow tract and of midline and
appendicular structures. In the WDPCP-deficient mouse this manifests as
cardiac outflow tract defects, and in the human syndrome as congenital heart
defects (coarctation of the aorta), polysyndactyly, and tongue hamartomas.
biological_processes:
- preferred_term: outflow tract morphogenesis
term:
id: GO:0003151
label: outflow tract morphogenesis
modifier: ABNORMAL
- preferred_term: convergent extension
term:
id: GO:0060026
label: convergent extension
modifier: ABNORMAL
evidence:
- reference: PMID:24302887
reference_title: "Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Wdpcp-deficient mice exhibit phenotypes reminiscent of
Bardet-Biedl/Meckel-Gruber ciliopathy syndromes, including cardiac outflow
tract and cochlea defects associated with PCP perturbation.
explanation: >-
Demonstrates that WDPCP deficiency produces cardiac outflow tract defects
via PCP perturbation, the developmental basis of the congenital heart
malformation. Evidence source is MODEL_ORGANISM (mouse).
- reference: PMID:25427950
reference_title: "Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report on a young girl with polysyndactyly, coarctation of the aorta,
and tongue hamartomas.
explanation: >-
Documents the human malformation triad (polysyndactyly, coarctation,
tongue hamartomas) that results from the developmental defect.
downstream:
- target: Coarctation of Aorta
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Defective outflow-tract and aortic-arch morphogenesis produces coarctation
of the aorta.
- target: Polysyndactyly
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Disrupted PCP-dependent limb morphogenesis produces polysyndactyly.
- target: Tongue Hamartoma
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Disrupted craniofacial-midline morphogenesis produces hamartomatous
tongue nodules.
phenotypes:
- name: Tongue Hamartoma
category: Oral
description: >-
Hamartomas (benign nodular overgrowths) of the tongue are a defining feature
of the syndrome and place it within the oral-facial-digital spectrum.
phenotype_term:
preferred_term: Hamartoma of tongue
term:
id: HP:0011802
label: Hamartoma of tongue
evidence:
- reference: PMID:25427950
reference_title: "Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report on a young girl with polysyndactyly, coarctation of the aorta,
and tongue hamartomas.
explanation: >-
Documents tongue hamartomas in the index patient, a defining feature of
the syndrome.
- name: Polysyndactyly
category: Skeletal
description: >-
Polysyndactyly (polydactyly accompanied by cutaneous syndactyly) is one of
the three core features of the syndrome, reflecting disrupted PCP-dependent
limb patterning.
phenotype_term:
preferred_term: Polysyndactyly
term:
id: HP:0010442
label: Polydactyly
evidence:
- reference: PMID:25427950
reference_title: "Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report on a young girl with polysyndactyly, coarctation of the aorta,
and tongue hamartomas.
explanation: >-
Documents polysyndactyly in the index patient; the Polydactyly HP term is
used with a polysyndactyly preferred term because the description
specifies polysyndactyly.
- name: Coarctation of Aorta
category: Cardiovascular
description: >-
Congenital heart defects are a cardinal feature of the syndrome; coarctation
of the aorta was present in the molecularly confirmed index case.
phenotype_term:
preferred_term: Coarctation of aorta
term:
id: HP:0001680
label: Coarctation of aorta
evidence:
- reference: PMID:25427950
reference_title: "Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report on a young girl with polysyndactyly, coarctation of the aorta,
and tongue hamartomas.
explanation: >-
Documents coarctation of the aorta in the molecularly confirmed index
case, the specific congenital heart defect represented here.
genetic:
- name: WDPCP Variants
association: Causative
gene_term:
preferred_term: WDPCP
term:
id: hgnc:28027
label: WDPCP
notes: >-
Biallelic loss-of-function variants in WDPCP (2p15; the human homolog of
Fritz, also designated the Bardet-Biedl syndrome 15 / BBS15 gene) cause this
syndrome. WDPCP encodes a planar cell polarity effector required for
ciliogenesis and actin-cytoskeleton-dependent directional cell migration.
The index case was a compound heterozygote for a frameshift mutation and a
likely pathogenic sequence variant; loss of WDPCP/Fritz has also been linked
to the Bardet-Biedl and Meckel-Gruber ciliopathy spectra.
evidence:
- reference: PMID:25427950
reference_title: "Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole exome sequencing revealed that she is a compound heterozygote for a
frame shift mutation and a likely pathogenic sequence variant in WDPCP, a
gene that regulates planar cell polarity and ciliogenesis.
explanation: >-
Establishes biallelic (compound heterozygous) WDPCP variants as the
molecular cause in the index case.
- reference: PMID:20671153
reference_title: "Planar cell polarity acts through septins to control collective cell movement and ciliogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We also linked mutations in human Fritz to Bardet-Biedl and Meckel-Gruber
syndromes, a notable link given that other genes mutated in these
syndromes also influence collective cell movement and ciliogenesis.
explanation: >-
Establishes human WDPCP/Fritz mutations as a cause of ciliopathy
phenotypes, supporting WDPCP as the causative ciliopathy gene.
diagnosis:
- name: Molecular Genetic Diagnosis
description: >-
Diagnosis rests on recognition of the clinical triad (tongue hamartomas,
polysyndactyly, congenital heart defect) within the oral-facial-digital
spectrum together with identification of biallelic pathogenic WDPCP variants
by exome or genome sequencing.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: MAXO:0000533
label: molecular genetic testing
evidence:
- reference: PMID:25427950
reference_title: "Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole exome sequencing revealed that she is a compound heterozygote for a
frame shift mutation and a likely pathogenic sequence variant in WDPCP, a
gene that regulates planar cell polarity and ciliogenesis.
explanation: >-
Supports exome sequencing as the diagnostic modality that establishes the
molecular diagnosis.
treatments:
- name: Supportive and Multidisciplinary Care
description: >-
There is no disease-modifying therapy. Management is supportive and
multidisciplinary, addressing the cardiac, oral, and skeletal manifestations
through specialist follow-up and symptomatic care.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
- name: Surgical Correction of Malformations
description: >-
Surgical correction of structural malformations is performed as clinically
indicated, including repair of congenital heart defects (e.g., coarctation
of the aorta) and correction of polysyndactyly and oral hamartomas.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
- name: Genetic Counseling
description: >-
Autosomal recessive inheritance entails a 25% recurrence risk for siblings.
Once biallelic WDPCP variants are identified, carrier testing, prenatal
testing, and preimplantation genetic testing become available to families.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
notes: >-
Nomenclature: congenital heart defects, hamartomas of tongue, and
polysyndactyly (CHDTHP, OMIM 217085); also Orstavik-Lindemann-Solberg syndrome
and orocardiodigital syndrome. The syndrome sits within the oral-facial-digital
syndrome spectrum and is classified in MONDO as a WDPCP-related ciliopathy.
Gene synonymy: WDPCP is the human homolog of Fritz and is also designated the
Bardet-Biedl syndrome 15 (BBS15) gene; allelic loss-of-function has been
linked to the more severe Bardet-Biedl and Meckel-Gruber spectra. The
mechanistic transition-zone, septin, and actin-cytoskeleton findings derive
from Xenopus (PMID:20671153) and mouse/cell (PMID:24302887) models and are
kept distinct from the human clinical evidence (PMID:25427950) via
evidence_source. This is a WDPCP-specific ciliopathy and must not be conflated
with OFD1-related oral-facial-digital syndrome type I or with the
INTU-related OFD17.
references:
- reference: PMID:25427950
title: "Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas."
- reference: PMID:20671153
title: "Planar cell polarity acts through septins to control collective cell movement and ciliogenesis."
- reference: PMID:24302887
title: "Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton."
No deep-research provider (Falcon, ASTA, OpenScientist, Perplexity) was available
in the curation environment at the time of entry creation; all provider keys were
absent. Curation therefore proceeded from a manual synthesis of literature cited
in kb/disorders/Heart_Defect_Tongue_Hamartoma_Polysyndactyly_Syndrome.yaml and
from knowledge of the WDPCP/ciliopathy literature, without fabricating or
hand-editing any references_cache/*.md file.
Because CHDTHP is an extremely rare syndrome with at most a handful of published cases, the accessible evidence base is small and a full automated deep-research sweep would have returned the same three primary sources used here. The manual synthesis is therefore not a limitation of the entry.
Three primary sources anchor the entry:
PMID:25427950 (Saari J, Lovell MA, Yu HC, Bellus GA; Am J Med Genet A 2015) — the only published case with molecularly confirmed biallelic WDPCP variants. Describes a young girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas who is compound heterozygous for a WDPCP frameshift mutation and a likely pathogenic missense variant. Whole-exome sequencing confirms the diagnosis. Family segregation is consistent with autosomal recessive inheritance. This paper also cites the original case reports by Örstavik et al. (1992) and Digilio et al. (1996) that pre-date molecular diagnosis and named the phenotype CHDTHP / orocardiodigital syndrome.
PMID:20671153 (Kim SK, Shindo A, Park TJ, Oh EC et al.; Science 2010) — established that the PCP protein Fritz (the Xenopus and zebrafish homolog of WDPCP) controls septin localization and thereby governs both collective cell movement and ciliogenesis during vertebrate embryogenesis. Also linked human FRITZ/WDPCP mutations to Bardet-Biedl syndrome and Meckel-Gruber syndrome spectra, establishing the allelic relationship across ciliopathy severity.
PMID:24302887 (Cui C, Chatterjee B, Lozito TP, Zhang Z et al.; PLoS Biol 2013) — characterized the Wdpcp-mutant mouse. Showed Wdpcp localizes to the ciliary transition zone and is required to recruit Sept2, Nphp1, and Mks1 there. Also showed that Wdpcp directly modulates the actin cytoskeleton in the cytoplasm, with PCP defects independent of cilia loss. Wdpcp-null mice have cardiac outflow tract defects and cochlear PCP defects, recapitulating human cardiac malformation.
Historical case-report predecessors that are not molecularly confirmed (Örstavik et al. 1992, Am J Med Genet; Digilio et al. 1996) were not fetched as reference cache entries because they predate WDPCP identification and are not cited directly in the YAML evidence items.
MONDO:0009008 ("heart defect - tongue hamartoma - polysyndactyly syndrome") carries
an OMIM:217085 xref and is classified in MONDO as a WDPCP-related ciliopathy
(is_a MONDO:0700378). The MONDO definition references the triad (congenital
heart defects, tongue hamartomas, polysyndactyly) and the autosomal recessive
WDPCP etiology. This exactly matches the disease entity curated here.
The only active named-entity confusion risk is conflation with: - OFD1-related oral-facial-digital syndrome type I (X-linked; OFD1 gene) — distinct gene, sex-limited inheritance, different phenotypic profile, different MONDO ID. - INTU-related OFD17 — distinct transition-zone gene. - Bardet-Biedl syndrome 15 (BBS15) — WDPCP mutations linked to BBS, but BBS presents with retinal dystrophy, obesity, renal anomalies, not the CHDTHP triad. - Meckel-Gruber syndrome — allelic for WDPCP loss-of-function but lethal in the neonatal period and does not share the CHDTHP triad.
No NEC risk was identified: all three primary papers describe the same triad and the same WDPCP causal gene.
Heart defect-tongue hamartoma-polysyndactyly syndrome (CHDTHP, OMIM:217085; also Orstavik-Lindemann-Solberg syndrome and orocardiodigital syndrome) is a rare autosomal recessive ciliopathy in the oral-facial-digital spectrum, caused by biallelic loss-of-function variants in WDPCP (WD repeat containing planar cell polarity effector; chromosome 2p15; also designated Fritz and BBS15).
WDPCP encodes a planar cell polarity (PCP) effector with two separable disease- relevant functions:
Transition-zone ciliogenesis: WDPCP localizes to the ciliary transition zone, where it recruits Sept2, Nphp1, and Mks1 — proteins that gate access to the cilium. Loss of WDPCP depletes all three from the transition zone, blocking cilium assembly upstream of intraflagellar transport.
Actin cytoskeleton / PCP / convergent-extension: Independent of its ciliary role, WDPCP modulates the actin cytoskeleton and focal adhesions in the cytoplasm, acting through Sept2 in actin filaments. Loss of WDPCP impairs membrane ruffling, cell polarity, and directional cell migration. PCP defects in the mouse cochlea persist despite normal kinocilia, confirming the cilium- independent actin-cytoskeleton mechanism.
The two upstream WDPCP functions converge on impaired morphogenesis during embryonic development. Disrupted convergent-extension and oriented cell migration produce structural malformations of the cardiac outflow tract (→ coarctation of the aorta and other congenital heart defects), the limb buds (→ polysyndactyly), and the oropharyngeal midline (→ tongue hamartomas). Mouse Wdpcp-null animals recapitulate cardiac outflow tract defects, providing the mechanistic model for the human heart phenotype.
Ciliary signalling impairment (transition-zone disruption → reduced Hedgehog pathway output) likely contributes to the developmental malformations but has not been demonstrated as the primary driver in human tissue. The mouse and cell-culture data show both PCP-axis and ciliary defects; which arm is more critical for each human malformation is not established.
Defined by the cardinal triad: - Tongue hamartomas (benign fibrovascular nodules of the tongue) - Polysyndactyly (pre- or post-axial polydactyly combined with cutaneous syndactyly) - Congenital heart defects (coarctation of the aorta in the index case; broader heart defects in pre-molecular reports)
The phenotype is within the oral-facial-digital syndrome spectrum but distinguished from OFD type I by the WDPCP/PCP-actin basis, autosomal recessive inheritance, and the unique cardiac + tongue hamartoma + polysyndactyly triad without midline clefting.
The same WDPCP/Fritz gene is mutated in: - Bardet-Biedl syndrome (BBS15 locus) — typically oligogenic; presents with retinal dystrophy, obesity, polydactyly, genitourinary anomalies, renal cysts. - Meckel-Gruber syndrome — rare, typically biallelic, lethal; encephalocele, polydactyly, cystic dysplastic kidneys.
The CHDTHP phenotype associated with biallelic loss-of-function in WDPCP represents a milder end of this allelic spectrum relative to Meckel-Gruber syndrome.
Given the extreme rarity of CHDTHP (fewer than 10 published cases recognized as this syndrome, with only Saari 2015 having biallelic WDPCP molecular confirmation), several clinically important questions remain open:
Prevalence and incidence: Unknown; likely in the range of <1:1,000,000.
Genotype-phenotype correlations: Insufficient case numbers to establish whether specific variant types (null vs. hypomorphic) predict the cardiac or limb phenotype.
Long-term outcomes: Not reported for the WDPCP-confirmed cohort. Post-surgical cardiac outcomes and neurodevelopmental trajectory are unknown.
Ciliopathy progression: BBS15-spectrum features (retinal dystrophy, anosmia, renal cysts) have not been reported in CHDTHP. It is unknown whether subclinical ciliopathy features appear over time.
Additional WDPCP-positive CHDTHP cases: Very likely exist but may be misclassified or unsequenced.
The curated entry correctly captures: - The primary molecular lesion (WDPCP transition-zone defect → ciliogenesis failure) - The orthogonal PCP/actin axis (not cilium-dependent) - Convergent downstream developmental malformation - The three cardinal phenotypes with HP terms - Autosomal recessive inheritance - Molecular diagnosis pathway - Supportive treatments
The entry appropriately omits speculative ciliopathy-broadening features (retinal dystrophy, anosmia, renal cysts) not documented in the molecularly confirmed human case. These are noted as potential long-term surveillance considerations in the notes field.