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Mappings

MONDO

MONDO:0008710 RAB23-related Carpenter syndrome

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Affected individuals carry biallelic RAB23 variants. A founder nonsense allele, L145X, accounts for a substantial share of cases in patients of northern European descent, where it was found in the homozygous state in ten of the fifteen families in the original mapping study.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:17503333 SUPPORT Human Clinical

"Carpenter syndrome is a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects."

States the mode of inheritance and the cardinal features together.

PMID:17503333 SUPPORT Human Clinical

"In 10 patients, the disease was caused by homozygosity for the same nonsense mutation, L145X, that resides on a common haplotype, indicative of a founder effect in patients of northern European descent."

Documents the founder allele and the population in which it is enriched.

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Discussions and Knowledge Gaps

4

Why is homozygous RAB23 nonsense mutation embryonic lethal with neural tube defects in mouse but compatible with survival and a postnatal skeletal syndrome in humans, and what does that divergence imply for using mouse Rab23 models to study Carpenter syndrome?

HUMAN MODEL MISMATCH OPEN rab23_mouse_human_viability_mismatch

Attached to

pathophysiology#RAB23 Loss of Function animal_models#open brain (opb) spontaneous Rab23 nonsense mouse

This is not a difference of severity but of outcome: the same class of allele kills the mouse embryo and produces a viable developmental syndrome in humans. It has a direct methodological consequence, which the field has already had to work around - the mouse used to establish the FGF10-pERK1/2 suture mechanism had to be engineered specifically to survive to skeletal stages, because the classical null does not. Any claim carried from that model into the human disease therefore rests on a system that has been modified precisely at the point where the species diverge. Nothing in the cited literature explains the divergence; the original description labels it a species difference in the developmental requirement for RAB23, which names the problem without resolving it.

Proposed experiments

Compare RAB23 dependence in human and mouse neurulation-stage models

rab23_cross_species_neurulation

Determine whether the divergence lies in RAB23 itself or in pathway redundancy, by comparing Hedgehog pathway output and neural tube closure between human iPSC-derived neural models carrying patient RAB23 null alleles and the equivalent mouse system.

Perturbations

Biallelic RAB23 null allele

pathophysiology#RAB23 Loss of Function

Introduce a patient-equivalent RAB23 null genotype in both species' models.

Readouts

Hedgehog pathway output

pathophysiology#Hedgehog Signalling Dysregulation

Interpretation: Comparable de-repression in both species with divergent morphological outcome would locate the difference downstream of Hedgehog rather than in RAB23 itself.

Would support

pathophysiology#Hedgehog Signalling Dysregulation

Show evidence (3 references)

PMID:17503333 SUPPORT Model Organism

"Surprisingly, nonsense mutations of Rab23 in open brain mice cause recessive embryonic lethality with neural-tube defects"

The mouse phenotype that does not occur in humans.

PMID:29727300 SUPPORT Other

"It is unique amongst the Rabs in terms of its implicated role in mammalian development, as originally illustrated by the embryonic lethality and open neural tube phenotype of a spontaneous mouse mutant"

Confirms the mouse phenotype is the defining one for this gene, which is what makes the human divergence notable rather than incidental.

PMID:32662771 SUPPORT Model Organism

"we generated Rab23-deficient mice that survive to an age where skeletal development can be studied"

The workaround the mismatch forced on the field, and the reason model-derived mechanism in this disease needs the caveat attached.

Is the craniosynostosis of Carpenter syndrome primarily a Hedgehog de-repression phenotype, as inferred at gene discovery, or primarily an FGFR-ERK phenotype, as the interventional mouse work suggests?

OPEN QUESTION OPEN hedgehog_versus_fgf_arm

Attached to

pathophysiology#Hedgehog Signalling Dysregulation pathophysiology#Elevated FGF10-FGFR1-ERK Signalling in the Cranial Suture

The original inference from human genetics was that Hedgehog signalling must be involved in suture biogenesis, and the authors flagged this as unexpected because craniosynostosis is not usually caused by other Hedgehog pathway components. The later mouse work supplies a different emphasis: FGF10-FGFR1-pERK1/2 is elevated, and inhibiting it prevents the craniosynostosis, while Hedgehog appears as one arm of a broader imbalance. The two are not exclusive - RAB23 is proposed to restrain both pathways, and to regulate GLI1 non-canonically through pERK1/2 - but the pathograph currently records the FGF-ERK arm as the better-evidenced route to the suture phenotype, on the strength of the rescue experiment. That ordering rests on a single mouse study and should be revisited if the Hedgehog arm is tested by intervention.

Show evidence (3 references)

PMID:17503333 SUPPORT Human Clinical

"implicates HH signaling in cranial-suture biogenesis--an unexpected finding, given that craniosynostosis is not usually associated with mutations of other HH-pathway components"

The Hedgehog-first inference, together with the authors' own reason for doubting it is the whole account.

PMID:32662771 SUPPORT Model Organism

"Inhibition of elevated pERK1/2 signaling results in the normalization of osteoprogenitor proliferation with a concomitant reduction of osteogenic gene expression, and prevention of craniosynostosis."

The interventional result that gives the FGF-ERK arm its precedence in this pathograph.

PMID:32662771 SUPPORT Model Organism

"a novel role for RAB23 as an upstream negative regulator of both FGFR and canonical Hh-GLI1 signaling, and additionally in the non-canonical regulation of GLI1 through pERK1/2"

States that the two arms are connected rather than competing, which is why this is recorded as a question of emphasis and not a contradiction.

Does RAB23 loss raise or lower Hedgehog pathway output, and is the answer different in different cell types?

OPEN QUESTION OPEN hedgehog_direction_of_effect

Attached to

pathophysiology#Hedgehog Signalling Dysregulation pathophysiology#Impaired Ciliary Protein Trafficking

The classical genetics points one way: RAB23 is a Sonic hedgehog antagonist, mouse nulls have a ventralised neural tube, and losing an antagonist should de-repress the pathway. Two cell-biological results point the other way. Depleting RAB23 selectively lowers ciliary Smoothened - the transducer - while leaving control ciliary proteins alone. And RAB23-knockout neural progenitors respond less to cilium-dependent Hedgehog activation, not more. There is a proposed resolution, and it is better supported than "it depends on the cell type". Both directions were measured in the same cells: Rab23-depleted cerebellar granule cell precursors show a raised basal level of Shh pathway activity and, at the same time, a blunted response to Shh ligand and to a Smoothened agonist, together with reduced agonist-driven Smoothened localisation to the cilium. On that account RAB23 has two separable jobs - it represses basal pathway activity, and it facilitates cilium-dependent activation by ligand - so losing it raises the floor and lowers the ceiling. The classical genetics reports the floor; the ciliary trafficking work reports the ceiling; neither is wrong. Two things keep this open rather than settled. It rests on one study in one cell type, and that cell type is one where a second study found no ciliary abnormality at all - a discrepancy the two papers do not address, and which may come down to the different conditional drivers used. And no Hedgehog measurement of either kind has been made in a Carpenter suture or limb bud, so the direction is asserted in the tissues that define the disease and measured only in tissues that do not. Until that gap closes the node carries DYSREGULATED rather than a direction, which on the dual-function reading is not a hedge but the accurate description: the pathway is deranged in two directions at once.

Show evidence (6 references)

PMID:20375059 SUPPORT In Vitro

"Loss of Rab23 in mice recapitulates the HH phenotype but its function in HH signaling is unknown."

The authors state the gap this question is about: the genetic phenotype is established and the molecular direction of effect is not.

PMID:20375059 SUPPORT In Vitro

"Depletion of Rab23 or expression of dominant-negative Rab23 decreased the ciliary steady state specifically of Smoothened but not EB1 or Kim1"

The first of the two results pointing away from de-repression, with its own internal controls.

PMID:40825043 SUPPORT In Vitro

"Rab23-KO neural progenitor cells show perturbed ciliation and desensitized to primary cilium-dependent activation of the Hedgehog signaling pathway"

The second, in a disease-relevant cell type and from a study designed around this disorder.

+ 3 more references

Are overgrowth with advanced bone age, epileptiform EEG changes, autistic features and chronic kidney disease part of the RAB23 phenotype, or coincidental findings in single patients?

KNOWLEDGE GAP OPEN phenotype_expansion_single_cases

Attached to

phenotypes#Intellectual disability genetic#RAB23 pathogenic variants

Two recent reports propose extensions to the phenotype, each resting on one patient. One describes overgrowth with advanced bone age, epileptogenic EEG changes and autistic features in a patient with a novel missense allele, and attributes them to that allele. Another reports chronic kidney disease and calls the association unusual. None of these is curated as a phenotype here. Each rests on a single case; the overgrowth report explicitly contrasts its patient with a typical second patient from the same study, so the authors themselves treat it as atypical; and the disorder has no reported genotype-phenotype correlation, which makes attributing new features to a particular novel allele hard to sustain. Against that, the syndrome is rare enough that genuine features may only ever appear in single reports, so absence of replication is weak evidence of coincidence. What would settle it is systematic ascertainment - bone age, EEG and renal function in the assembled RAB23 cohort - rather than further case reports.

Show evidence (3 references)

PMID:34748996 SUPPORT Human Clinical

"overgrowth with advanced bone age, epileptogenic changes on electroencephalogram and autistic features"

The proposed new features, in the one patient they are reported in.

PMID:34748996 SUPPORT Human Clinical

"Patient 1 presented with an atypical clinical presentation of Carpenter syndrome"

The authors' own framing of the case as atypical, which is why this is held open rather than curated.

PMID:39040725 SUPPORT Human Clinical

"this case report highlights an unusual association of Carpenter syndrome with chronic kidney disease"

The renal claim, described by its own authors as unusual and as needing further exploration.

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Pathophysiology

6

RAB23 Loss of Function

Biallelic RAB23 variants abolish or impair a small GTPase that cycles between GDP-bound inactive and GTP-bound active states. The reported allele spectrum is dominated by truncating changes, with a recurrent founder nonsense allele; the point mutations that have been characterised structurally fall within the GTPase domain, and the Y79 deletion distorts the switch II region, which is the surface through which an activated Rab engages its effectors. The consequence is loss of function rather than a gain or a change of specificity. Three molecular routes to that loss have been demonstrated, and they are not variations on one theme. Most truncating alleles never make a protein at all: their transcripts are degraded by nonsense-mediated decay, shown experimentally rather than inferred from the premature stop codon. A frameshift late enough to escape that fate reaches the same endpoint differently, by deleting the C-terminal prenylatable cysteine, so a protein is made but cannot be lipid-anchored to the membranes it must work on. The missense and in-frame alleles leave a full-length, membrane-competent protein whose effector surface is distorted. All three converge on absent RAB23 activity, which is why the entry treats the allele spectrum as functionally uniform despite its structural variety - and is consistent with the absence of any reported genotype-phenotype correlation.

RAB23 hgnc:14263

RAB23 GTPase activity GO:0003924 ↓ DECREASED

Animal models

open brain (opb) spontaneous Rab23 nonsense mouse Mouse fails to recapitulate The same class of allele produces recessive embryonic lethality with an open neural tube in mouse, whereas human RAB23 null homozygotes survive and present with Carpenter syndrome. The model therefore does not reproduce the human consequence of RAB23 loss.

Downstream

Impaired Ciliary Protein Trafficking RAB23 is a membrane-trafficking GTPase implicated in delivery of protein to the primary cilium, so loss of its activity acts directly on that traffic.

Elevated FGF10-FGFR1-ERK Signalling in the Cranial Suture RAB23 restrains FGFR signalling as well as Hedgehog, so its loss raises FGF10-driven FGFR1 signalling in the suture.

Show evidence (6 references)

PMID:17503333 SUPPORT Human Clinical

"identified five different mutations (four truncating and one missense) in RAB23, which encodes a member of the RAB guanosine triphosphatase (GTPase) family of vesicle transport proteins and acts as a negative regulator of hedgehog (HH) signaling"

The gene discovery, the allele spectrum, and the protein's two relevant properties: it is a trafficking GTPase and a Hedgehog antagonist.

PMID:39615683 SUPPORT In Vitro

"we demonstrated that the Y79 deletion mutant exhibited structural distortions in the switch II region relative to that of the WT."

Crystallographic evidence for how a clinical point mutation impairs the protein.

PMID:39615683 SUPPORT In Vitro

"The structural changes potentially disrupted the binding of Rab23 Y79del to its interacting partners, thus leading to a loss-of-function and the development of Carpenter syndrome."

The authors' interpretation that the mechanism is loss of function. The hedge ("potentially") is theirs and is retained.

+ 3 more references

Impaired Ciliary Protein Trafficking

RAB23 participates in protein delivery to the primary cilium, the organelle in which vertebrate Hedgehog signal transduction is organised. This places Carpenter syndrome adjacent to the ciliopathies, which it partly resembles clinically, though RAB23 also has functions independent of cilia and of Hedgehog. Two ciliary cargoes have been identified, and the specificity of the first is the informative part. Depleting RAB23 lowers the ciliary steady-state level of Smoothened - the Hedgehog transducer - while leaving the control proteins EB1 and Kim1 untouched, so this is not a general collapse of ciliary import but a defect in turnover of a particular cargo. The second is Kif17, a kinesin-2 motor: RAB23 sits in a complex with Kif17 and importin beta-2, and Kif17 fails to reach the cilium in RAB23-depleted cells. Whether the cilium is affected at all depends on the cell type. Across a conditional knockout mouse, patient-derived iPSCs and zebrafish morphants, ciliary defects appear in chondrocytes, fibroblasts, neural progenitors and neocortical neurons but not in epithelial cells, cerebellar granule cells or hippocampal neurons - and the defect itself differs, being reduced ciliation frequency in patient-derived neurons but merely shortened cilia in the same patients' fibroblasts and progenitors. That cell-type dependence is a candidate explanation for why a lesion in a ubiquitous trafficking GTPase produces a phenotype concentrated in skull and limb.

protein localization to cilium GO:0061512 ↓ DECREASED cilium assembly GO:0060271 ↓ DECREASED

Experimental models

Carpenter syndrome patient-derived iPSC neural lineage IPSC DERIVED MODEL Patient cells carrying patient alleles, assayed for the ciliary phenotype this node asserts, with the cell-type dependence measured rather than assumed.

Animal models

Rab23 conditional knockout mouse Mouse recapitulates Reproduces ciliopathy-like developmental features in vivo and localises the ciliary defect to specific cell types.

Rab23 zebrafish morphant Zebrafish partially recapitulates Shows the same perturbation of primary cilium formation as the other two systems.

Downstream

Hedgehog Signalling Dysregulation Disrupted ciliary traffic is one route by which RAB23 loss reaches Hedgehog signal transduction; the cited work links the two without resolving each step.

Show evidence (6 references)

PMID:20375059 SUPPORT In Vitro

"Depletion of Rab23 or expression of dominant-negative Rab23 decreased the ciliary steady state specifically of Smoothened but not EB1 or Kim1, suggesting a role of Rab23 in protein turnover in the cilium."

The cargo-specific ciliary defect, with its own internal controls. The word "specifically" is what makes this more than a general trafficking observation.

PMID:26136363 SUPPORT In Vitro

"ciliary localization of the kinesin-2 motor protein Kif17 was disrupted in Rab23-depleted cells"

A second identified ciliary cargo, from a study that also places RAB23 in a complex with the motor and its import carrier.

PMID:40825043 SUPPORT Model Organism

"all three different vertebrate mutant models consistently show a perturbation of primary cilia formation, intriguingly, in a context-dependent manner"

Establishes the ciliary defect across three independent model systems, and its cell-type dependence. Graded MODEL_ORGANISM because the sentence reports the mutant animal systems; the human patient-cell measurements from the same study are quoted separately below.

+ 3 more references

Hedgehog Signalling Dysregulation

RAB23 antagonises Sonic hedgehog signalling, so its loss releases the pathway from negative regulation. This was the first mechanism proposed for Carpenter syndrome and was itself surprising, because craniosynostosis is not typically caused by variants in other Hedgehog pathway components. Mouse work later showed that the Hedgehog change in the suture is one arm of a broader signalling imbalance rather than the whole story. The classical genetics says de-repression, and the cell biology does not straightforwardly agree. Two results point the other way: depleting RAB23 lowers ciliary Smoothened, and RAB23-knockout neural progenitors are desensitized to cilium-dependent Hedgehog activation. Smoothened is the pathway's transducer, so less of it in the cilium and a blunted response to ligand are reduced output, not release from repression. This node is named for the dysregulation rather than for a direction because of that: an earlier name asserting de-repression would have contradicted the node's own modifier. The proposed reconciliation is that RAB23 does two separable things. It represses basal pathway activity, and it also facilitates activation by ligand through the cilium. Both were measured in one cell population: Rab23-depleted cerebellar granule cell precursors have a raised basal Shh signal and a blunted response to Shh ligand and to a Smoothened agonist. Losing RAB23 therefore raises the floor and lowers the ceiling, and the classical genetics and the trafficking work are each reporting one of those. This is why the pathway modifier is DYSREGULATED rather than INCREASED. On the dual-function reading that is not a refusal to commit but the accurate description: the pathway is deranged in two directions at once, and which one dominates in the cranial suture has not been measured.

negative regulation of smoothened signaling pathway GO:0045879 ↓ DECREASED smoothened signaling pathway GO:0007224 ↕ DYSREGULATED

Downstream

Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis Hedgehog-GLI1 signalling is one of the arms whose imbalance in the Rab23-null suture accompanies the excess osteogenesis.

Cryptorchidism Cryptorchidism is one of the three near-universal core features of Carpenter syndrome in males, so it is attributed to the shared Hedgehog de-repression rather than treated as incidental. No source cited here traces a route from the pathway to testicular descent, which is why the intermediates are marked unknown.

Intellectual disability Intellectual disability is part of the characterisation of the syndrome. Hedgehog signalling patterns the developing CNS, but nothing cited here connects the two in this disorder specifically.

Abnormal brain morphology Cerebral malformation is the one downstream feature here with independent support for the route as well as the association: the ciliopathy module this node conforms to carries its own edge from impaired Hedgehog transduction to CNS malformation, because Hedgehog patterns the neural tube and midbrain-hindbrain boundary. The steps between the two have still not been demonstrated in this disorder specifically.

Hydrocephalus Ventricular enlargement, attributed to the shared pathway lesion on the same basis as the other central-nervous-system features. Two mechanisms are plausible in a craniosynostosis syndrome - a Hedgehog-dependent developmental malformation, or a secondary consequence of the constrained skull and the abnormal venous drainage this entry records under surgical management - and no cited source distinguishes them.

Genu valgum A skeletal feature outside the digits. Hedgehog signalling patterns the limb skeleton beyond the autopod, but nothing cited here connects the pathway to knee alignment in this disorder.

Depressed nasal bridge Part of the characteristic midface appearance, attributed to the shared pathway lesion on the malformation-complex basis. Hedgehog signalling patterns the frontonasal process, but no cited source connects the pathway to this feature in this disorder.

Low-set ears Part of the same craniofacial complex, on the same basis and with the same limits.

Corneal anomaly An ocular finding reported without characterisation, attributed to the shared lesion on the malformation-complex basis rather than through any traced route.

Umbilical hernia A ventral body-wall defect, attributed to the shared pathway lesion on the same basis as cryptorchidism: it belongs to the malformation complex that defines the syndrome. No cited source connects Hedgehog signalling to umbilical closure in this disorder, and the source that records the feature predates the gene.

Obesity Obesity is a cardinal feature, and the gene-discovery paper proposed the Hedgehog connection as a route into obesity biology. That proposal is the whole of the support: no cited source traces a step between the pathway and adiposity in this disorder, and none reports a metabolic or hypothalamic measurement in a patient. The edge is drawn because the syndrome's own discoverers drew it, and it is marked with unknown intermediates because they did not fill it in.

Abnormal heart morphology Cardiac defects are a cardinal feature and are attributed here to the shared pathway lesion, on the same footing as cryptorchidism. There is one suggestive route rather than a demonstrated one: laterality defects are reported in RAB23 patients, and left-right patterning is Hedgehog- and Nodal-dependent. No cited source connects the pathway to a specific cardiac malformation in this disorder.

Limb Patterning Defect Hedgehog signalling patterns the anteroposterior axis of the limb bud, and the polysyndactyly of Carpenter syndrome is attributed to its de-repression. The intervening steps have not been demonstrated in this disorder.

Show evidence (6 references)

PMID:17503333 SUPPORT Human Clinical

"The discovery of RAB23 mutations in patients with Carpenter syndrome implicates HH signaling in cranial-suture biogenesis--an unexpected finding, given that craniosynostosis is not usually associated with mutations of other HH-pathway components"

The original inference, together with the authors' own reason for treating it as unexpected. That reservation is part of why a purely Hedgehog account of the craniosynostosis was later refined.

PMID:29727300 SUPPORT Other

"Rab23 was initially identified to act as an antagonist of Sonic hedgehog (Shh) signaling"

States the antagonist relationship this node depends on.

PMID:20375059 REFUTE In Vitro

"Depletion of Rab23 or expression of dominant-negative Rab23 decreased the ciliary steady state specifically of Smoothened but not EB1 or Kim1"

Cited as REFUTE against reading this node as uniformly increased Hedgehog output. Losing RAB23 removes Smoothened from the cilium, and Smoothened is what transduces the signal, so in this system the effect on pathway activity is negative.

+ 3 more references

Elevated FGF10-FGFR1-ERK Signalling in the Cranial Suture

In Rab23-null mouse sutures, FGF10-driven FGFR1 signalling is elevated, with downstream hyperactivation of the ERK1/2 arm of MAPK. This is the arm of the mechanism with the strongest causal evidence, because it was tested by intervention rather than only observed: inhibiting the raised pERK1/2 normalises osteoprogenitor proliferation and prevents the craniosynostosis.

fibroblast growth factor receptor signaling pathway GO:0008543 ↑ INCREASED ERK1 and ERK2 cascade GO:0070371 ↑ INCREASED

Animal models

Rab23-deficient mouse surviving to skeletal stages Mouse rescues Pharmacological inhibition of pERK1/2 in this model normalised osteoprogenitor proliferation, reduced osteogenic gene expression and prevented the craniosynostosis, which is the interventional evidence that the ERK arm is causal rather than correlated.

Downstream

Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis Raised pERK1/2 drives the osteoprogenitor proliferation and osteogenic gene expression; blocking it reverses both.

Show evidence (1 reference)

PMID:32662771 SUPPORT Model Organism

"FGF10-driven FGFR1 signaling is elevated in Rab23-/-sutures with a consequent imbalance in MAPK, Hedgehog signaling and RUNX2 expression."

The measured signalling change in the affected tissue.

Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis

Suture patency depends on mesenchymal cells at the centre of the suture remaining undifferentiated while progenitors at the osteogenic fronts proliferate and differentiate in a controlled way. In Rab23-null sutures that balance fails: osteoprogenitor proliferation is aberrant and osteogenesis in the suture is elevated, and multiple sutures fuse prematurely.

suture osteoprogenitor CL:0000062 suture mesenchymal cell CL:0000134

osteoblast differentiation GO:0001649 ↑ INCREASED

Animal models

Rab23-deficient mouse surviving to skeletal stages Mouse recapitulates The model reproduces multi-suture premature fusion arising from the same cellular lesion this node describes, and localises it to the suture.

Downstream

Craniosynostosis Premature fusion of the sutures is the direct consequence of the excess osteogenesis within them.

Proptosis Prominent eyes follow from the skull shape rather than from any ocular lesion: the altered calvarial growth that the suture fusion imposes leaves shallow orbits, and the globes sit forward in them. This is the one craniofacial feature in this entry with an intermediate that can be named, which is why it hangs off the osteogenic node rather than off the pathway node with the rest of the facies.

Show evidence (1 reference)

PMID:32662771 SUPPORT Model Organism

"Mesenchymal cells in the center of the suture must be kept in an undifferentiated state to maintain suture patency, while progenitor cells at the osteogenic fronts proliferate and differentiate to facilitate bone growth."

The normal cell biology of the suture that this node describes the failure of.

Limb Patterning Defect

Abnormal patterning of the developing limb produces the acral phenotype: polydactyly, cutaneous syndactyly and abnormalities of the middle phalanges. The syndactyly is near-universal in reported CRPT1 patients.

Downstream

Cutaneous syndactyly Failure of interdigital separation.

Polydactyly Supernumerary digits, part of the polysyndactyly that is a cardinal feature.

Talipes Club foot, reported as common in both Carpenter syndrome subtypes alongside the other acral findings, so it belongs with the limb patterning defect rather than standing alone.

Brachydactyly Shortening of the digits, reported as abnormalities of the middle phalanges.

Show evidence (1 reference)

PMID:32662771 SUPPORT Model Organism

"Along with polysyndactyly, these mice exhibit premature fusion of multiple sutures"

The limb phenotype is reproduced in the Rab23-null mouse alongside the skull phenotype, which is what links it to the same lesion.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

17

Cardiovascular 1

Abnormal heart morphology FREQUENT HP:0001627

Show evidence (5 references)

PMID:17503333 SUPPORT Human Clinical

"craniosynostosis, polysyndactyly, obesity, and cardiac defects"

Cardiac defects among the cardinal features.

PMID:21412941 SUPPORT Human Clinical

"but further evidence for laterality defects is reported"

Laterality defects do occur in RAB23 patients, which matters here because left-right patterning is Hedgehog- and Nodal-dependent and is one route by which a Hedgehog regulator could reach cardiac morphology. Rare in RAB23 and frequent in MEGF8, so it is also the discriminator between the two Carpenter genotypes.

PMID:23706836 SUPPORT Human Clinical

"We describe the anaesthetic management for caesarean section of a parturient with Carpenter syndrome and corrected Tetralogy of Fallot."

Names a specific cardiac lesion in a patient with this syndrome, rather than the generic "cardiac defects" of the cardinal-feature lists.

+ 2 more references

Digestive 1

Umbilical hernia OCCASIONAL HP:0001537

Show evidence (1 reference)

PMID:8352858 SUPPORT Human Clinical

"craniosynostosis, short fingers, soft tissue syndactyly, preaxial polydactyly, congenital heart disease, hypogenitalism, obesity, and umbilical hernia"

Umbilical hernia among the features defining the syndrome clinically. The source predates the gene, so it describes the clinical entity rather than the RAB23 genotype specifically.

Ear 1

Low-set ears FREQUENT HP:0000369

Show evidence (1 reference)

PMID:23599695 SUPPORT Human Clinical

"The eyes were prominent, furthermore there was a depressed nasal bridge, high arched palate and low set ears"

The finding in the second genotyped sibling, examined separately from the first.

Eye 2

Corneal anomaly OCCASIONAL Abnormal cornea morphology HP:0000481

Show evidence (1 reference)

PMID:20358613 SUPPORT Human Clinical

"abnormal genitalia (3/4), corneal anomaly (2/4)"

The finding as reported. The quote runs on from the neighbouring item in the same list so that it carries a full clause; only the corneal half is curated here, the genital findings being covered by the cryptorchidism phenotype. The source does not say what the corneal anomaly was, so this is the most specific binding the evidence carries.

Proptosis FREQUENT HP:0000520

Show evidence (2 references)

PMID:23599695 SUPPORT Human Clinical

"The eyes were prominent, furthermore there was a depressed nasal bridge, high arched palate and low set ears"

Prominent eyes in the second sibling; the first is described in the same paper with "prominent eyes" in the quote used on the nasal-bridge phenotype.

PMID:34244844 SUPPORT Human Clinical

"a trefoil-like skull, flattened and receding forehead, bulging of temporal bones, hypertelorism, exorbitism, and polysyndactyly"

The same finding in an unrelated patient, described as exorbitism, alongside the skull shape that produces it.

Genitourinary 1

Cryptorchidism VERY_FREQUENT HP:0000028

Show evidence (1 reference)

PMID:38760421 SUPPORT Human Clinical

"craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost universal in both CRPT1 and CRPT2"

"Almost universal" among males, which is the subgroup this band applies to.

Head and Neck 2

Craniosynostosis VERY_FREQUENT HP:0001363

Show evidence (2 references)

PMID:38760421 SUPPORT Human Clinical

"The core features of craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost universal in both CRPT1 and CRPT2."

"Almost universal" is the basis for the VERY_FREQUENT band.

PMID:38760421 SUPPORT Human Clinical

"Craniosynostosis in CRPT2 commonly involves a single midline suture in comparison to the multi-suture craniosynostosis characteristic of CRPT1."

The suture pattern that characterises this form, stated as the contrast with CRPT2.

Depressed nasal bridge FREQUENT HP:0005280

Show evidence (2 references)

PMID:23599695 SUPPORT Human Clinical

"Facial abnormalities include flat nasal bridge, broad cheeks and malformed and unevenly set ears."

A disease-level statement of the characteristic facies, not a single patient's findings, which is the basis for the FREQUENT band.

PMID:23599695 SUPPORT Human Clinical

"upward slanting of the palpebral fissures, prominent eyes, and depressed nasal bridge with low set ears"

The finding in the first of two genotyped siblings examined individually.

Limbs 5

Cutaneous syndactyly VERY_FREQUENT HP:0012725

Show evidence (1 reference)

PMID:38760421 SUPPORT Human Clinical

"Cutaneous syndactyly is a universal feature in all cases of MEGF8-associated CRPT2 to date (15/15 individuals, Supplementary Table 2) and is also near-universal in RAB23-associated CRPT1 (38/39 individuals)"

A counted frequency, 38 of 39, which places the band unambiguously.

Polydactyly VERY_FREQUENT HP:0010442

Show evidence (2 references)

PMID:38760421 SUPPORT Human Clinical

"The core features of craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost universal in both CRPT1 and CRPT2."

Polysyndactyly is among the almost universal core features.

PMID:8352858 SUPPORT Human Clinical

"craniosynostosis, short fingers, soft tissue syndactyly, preaxial polydactyly, congenital heart disease, hypogenitalism, obesity, and umbilical hernia"

Specifies the polydactyly as preaxial, which is the description this phenotype's text rests on. Bound to the general HP:0010442 rather than to HP:0100258 (Preaxial polydactyly) because the near-universal frequency band comes from sources that count "polysyndactyly" without splitting it by ray, so a preaxial-specific binding would carry a frequency it has not been shown to have.

Brachydactyly FREQUENT HP:0001156

Show evidence (1 reference)

PMID:38760421 SUPPORT Human Clinical

"with polydactyly, abnormalities of the middle phalanges and talipes also being common in both forms"

"Common" rather than "almost universal" is why this is banded below the core features.

Talipes FREQUENT HP:0001883

Show evidence (1 reference)

PMID:38760421 SUPPORT Human Clinical

"abnormalities of the middle phalanges and talipes also being common in both forms"

Talipes among the features described as common in both subtypes.

Genu valgum OCCASIONAL HP:0002857

Show evidence (1 reference)

PMID:20358613 SUPPORT Human Clinical

"additional features included genu valgum (2/4)"

Counted within the one family reporting it. Curated as a skeletal feature beyond the digits, which are otherwise where this entry's skeletal phenotype sits.

Nervous System 3

Hydrocephalus OCCASIONAL HP:0000238

Show evidence (2 references)

PMID:20358613 SUPPORT Human Clinical

"Brain imaging showed hydrocephalus in 2/4"

A counted proportion within one family, all four children homozygous for the same allele. The band is OCCASIONAL rather than derived from 2/4, because four siblings of one genotype is not a frequency estimate for the disease.

PMID:23599695 SUPPORT Human Clinical

"the affected child also had dilatation of the lateral ventricles which required a ventriculo-peritoneal shunt"

An independent family, and the one report in this entry where the hydrocephalus was severe enough to be shunted. Both siblings in that family had ventricular dilatation; only this one needed the operation.

Abnormal brain morphology OCCASIONAL HP:0012443

Show evidence (1 reference)

PMID:8352858 SUPPORT Human Clinical

"A patient is reported with the features of Carpenter syndrome who has profound developmental delay and cerebral malformations demonstrated by magnetic resonance imaging and computed tomography."

The documented finding, in the patient whose case established the association with cognitive outcome. A single case, hence the conservative band.

Intellectual disability FREQUENT HP:0001249

Show evidence (4 references)

PMID:29727300 SUPPORT Other

"causes the developmental disorder Carpenter's syndrome (CS), which is characterized by craniofacial malformations, polysyndactyly, obesity and intellectual disability"

Intellectual disability among the characterising features. The source is a review, so it is graded OTHER rather than as a primary clinical series.

PMID:8352858 SUPPORT Human Clinical

"As many as three-fourths of the patients have some degree of intellectual impairment."

The only proportion given for this feature in the cited literature, and the basis for the FREQUENT band.

PMID:8352858 REFUTE Human Clinical

"Because mental retardation is not an invariable feature of this syndrome or other craniosynostosis syndromes, neuroradiologic examination may help in predicting the intellectual outcome in these patients."

Cited as REFUTE against treating intellectual disability as a constant of the syndrome. The same sentence carries the prognostic point: imaging, not the diagnosis, is what indicates the likely outcome.

+ 1 more reference

Growth 1

Obesity FREQUENT HP:0001513

Show evidence (2 references)

PMID:17503333 SUPPORT Human Clinical

"the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects"

Obesity listed among the cardinal features. No source cited here gives a counted frequency, so the band reflects "cardinal feature" without claiming near-universality.

PMID:17503333 SUPPORT Human Clinical

"provides a new molecular target for studies of obesity"

The gene-discovery authors' proposal that this is a route into obesity biology. Quoted deliberately in its weak form: the paper offers a target for study, not a demonstrated mechanism, which is why the edge into this phenotype carries unknown intermediates.

🧬

Genetic Associations

1

RAB23 pathogenic variants (Causative)

Gene: RAB23 hgnc:14263 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:17503333 SUPPORT Human Clinical

"Using homozygosity mapping, we found linkage to chromosome 6p12.1-q12 and, in 15 independent families, identified five different mutations (four truncating and one missense) in RAB23"

The gene discovery and the allele spectrum in the founding series.

PMID:39615683 SUPPORT In Vitro

"Several clinical point mutations, for example, M12K, C85R, and Y79del, have been found to occur within the GTPase domain."

Locates the characterised point mutations within the functional domain.

PMID:39615683 SUPPORT In Vitro

"thus leading to a loss-of-function and the development of Carpenter syndrome"

The structural study's conclusion that the mechanism is loss of function.

Variants (6)

RAB23 p.Leu145X Pathogenic

Gene: RAB23 hgnc:14263 NONSENSE

The founder nonsense allele, homozygous in ten of the patients in the original mapping study and carried on a shared haplotype, indicating a founder effect in individuals of northern European descent. It is the single commonest cause of Carpenter syndrome.

Show evidence (1 reference)

PMID:17503333 SUPPORT Human Clinical

"In 10 patients, the disease was caused by homozygosity for the same nonsense mutation, L145X, that resides on a common haplotype, indicative of a founder effect in patients of northern European descent."

The allele, its recurrence, and the founder-effect interpretation.

RAB23 p.Tyr79del Pathogenic

Gene: RAB23 hgnc:14263 DELETION

An in-frame deletion within the GTPase domain and the only clinical allele solved crystallographically. It distorts the switch II region, the surface through which an activated Rab engages its effectors, which is how a single-residue deletion produces loss of function without removing the protein.

Functional effects

RAB23 effector binding

Structural distortion of the switch II region, predicted to disrupt binding to interacting partners.

Show evidence (1 reference)

PMID:39615683 SUPPORT In Vitro

"we demonstrated that the Y79 deletion mutant exhibited structural distortions in the switch II region relative to that of the WT."

The crystallographic result establishing how this allele impairs the protein.

RAB23 c.482-1G>A (p.Val161LeufsX3) Pathogenic

Gene: RAB23 hgnc:14263 SPLICE SITE

A splice-acceptor variant that activates a cryptic site inside exon 5, deleting eight nucleotides and shifting the frame. It is curated because of where the resulting stop falls: late enough that the transcript is not simply degraded, but early enough to remove the C-terminal prenylatable cysteine. The protein is made and cannot be lipid-anchored to the membranes a Rab GTPase works on, which is a different route to loss of function from the nonsense alleles.

Functional effects

RAB23 membrane association

Loss of the C-terminal prenylation site, so the truncated protein is predicted not to associate with target membranes.

Show evidence (1 reference)

PMID:23599695 SUPPORT In Vitro

"This mutation affects the authentic mRNA splicing and activates a cryptic acceptor site within exon 5."

The splicing consequence, demonstrated at the transcript level rather than predicted.

RAB23 c.481G>C (p.Val161Leufs*16) Pathogenic

Gene: RAB23 hgnc:14263 FRAMESHIFT

A substitution at the last base of exon 6 that causes the exon to be skipped, shifting the frame and creating a premature stop. It is curated as the allele of the one case with a documented prenatal picture, and as a second example of a coding substitution whose real consequence is on splicing rather than on the amino acid it appears to change.

Show evidence (1 reference)

PMID:25168863 SUPPORT Human Clinical

"Sequencing of RAB23 identified a homozygous mutation leading to skipping of exon 6 and premature termination codon"

The allele and its splicing consequence.

RAB23 c.82C>T (p.Arg28*) Pathogenic

Gene: RAB23 hgnc:14263 NONSENSE

A nonsense allele reported homozygous in the first molecularly confirmed case of Carpenter syndrome from continental Africa, with both parents shown to be carriers. It is curated as evidence that the disorder is not confined to the populations the founder allele comes from.

Show evidence (1 reference)

PMID:33368989 SUPPORT Human Clinical

"a previously described homozygous variant c.82C>T p.(Arg28*) was detected that results in a premature stop codon"

The allele and its homozygous state, with parental carrier testing reported in the same paper.

RAB23 c.86dupA Pathogenic

Gene: RAB23 hgnc:14263 FRAMESHIFT

A frameshift allele homozygous in four affected children of one Comorian family. This is the entry's clearest evidence that genotype does not fix phenotype here: with one allele held constant within a single family, craniosynostosis ranged from a cloverleaf skull to an isolated metopic ridge, hydrocephalus was present in two of four, and mental development was normal in all four.

Show evidence (2 references)

PMID:20358613 SUPPORT Human Clinical

"We report here on a RAB23 mutation (c.86dupA) present in the homozygote state in four relatives of Comorian origin with Carpenter syndrome."

The allele and the family it segregates in.

PMID:20358613 SUPPORT Human Clinical

"intrafamilial variability was observed with variable severity of craniosynostosis ranging from cloverleaf skull to predominant involvement of the metopic ridge"

Variable expressivity on an identical genotype in one family, which is stronger evidence for it than the absence of genotype-phenotype correlation across unrelated patients.

💊

Medical Actions

4

Craniofacial surgical management

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Surgical management of the craniosynostosis. No disease-modifying therapy exists for the underlying signalling defect, so this is the treatment of the disease in practice. There is no established management algorithm - the disorder is too rare for one - but two things are agreed. Early release of the fused sutures with fronto-orbital advancement is indicated, and particularly so where intracranial pressure is raised. And correction is usually safe within the first 6 to 12 months, which is early by the standards of craniofacial surgery generally. The operative planning carries a specific hazard worth recording as part of the treatment rather than as a complication of it: abnormal venous drainage and ectatic emissary veins can cause serious bleeding, and the skull may be weak enough to fragment when cranial flaps are raised. Both are why imaging before operating - 3D CT for the bone, MR angiography for the veins - changes what the surgeon does.

Mechanism Target:

Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis — Surgery acts on the product of this node rather than on the node itself. Releasing fused sutures and advancing the fronto-orbital segment undoes the anatomical consequence of the excess osteogenesis; it does not touch the FGF-ERK signalling that drove it, which is why the fusion can recur and why the pERK1/2 inhibition result is curated as a model rescue rather than as a therapy.

Show evidence (1 reference)

PMID:25162549 SUPPORT Other

"early release of craniosynostoses with fronto-orbital advancement is clearly indicated in the CS literature, particularly in cases of elevated intracranial pressure"

Names the intervention and the anatomical target it acts on.

Target Phenotypes: Craniosynostosis HP:0001363 Cutaneous syndactyly HP:0012725

Show evidence (5 references)

PMID:38760421 SUPPORT INDIRECT Human Clinical

"He had presented during infancy with polysyndactyly and craniosynostosis, both treated surgically, and had a clinical diagnosis of CRPTS."

Documents surgical management of both the craniosynostosis and the polysyndactyly in a patient with Carpenter syndrome. The individual described carries a MEGF8 variant, so this supports the surgical approach to the shared phenotype rather than a RAB23-specific practice.

PMID:25162549 SUPPORT Other

"early release of craniosynostoses with fronto-orbital advancement is clearly indicated in the CS literature, particularly in cases of elevated intracranial pressure"

The one clearly indicated intervention, from a review written for the surgeons who perform it. Graded OTHER because it is a synthesis of selected case literature rather than a series with its own outcomes.

PMID:25162549 SUPPORT Other

"Given the scarcity of CS cases, an algorithm for CS management has not been established."

States why this treatment entry describes agreed principles rather than a protocol: there are not enough patients to have built one.

+ 2 more references

Cardiac surgical correction

Action: cardiac surgical correction Ontology label: Cardiac Surgery NCIT:C157806

Platform: Surgery

Surgical repair of the congenital cardiac defect. The one lesion named in the cited literature is Tetralogy of Fallot, and the reported outcome is the reason this is curated separately rather than folded into supportive care: patients reach adulthood after correction, but residual lesions progress, and that progression was the principal difficulty in the one reported pregnancy in this syndrome. So the treatment is not a closed episode. It changes what the cardiac phenotype is - from a neonatal malformation to a lifelong one requiring follow-up - rather than ending it.

Target Phenotypes: Congenital heart defect HP:0001627

Show evidence (2 references)

PMID:23706836 SUPPORT Human Clinical

"We describe the anaesthetic management for caesarean section of a parturient with Carpenter syndrome and corrected Tetralogy of Fallot."

A patient with the syndrome whose cardiac defect had been surgically corrected and who survived to adulthood and pregnancy.

PMID:23706836 SUPPORT Human Clinical

"Even after surgical correction of cardiac abnormalities, intrapartum care of a parturient with this condition can be challenging because of progression of residual cardiac defects"

The limit of the intervention, stated by the authors: correction does not stop residual lesions progressing. This is why the treatment carries a follow-up implication rather than being recorded as definitive.

Ventriculoperitoneal shunt

Action: ventriculoperitoneal shunt placement Ontology label: Ventriculoperitoneal Shunt Placement NCIT:C168483

Platform: Surgery

Diversion of cerebrospinal fluid for hydrocephalus. It is curated because it is reported as actually performed in a patient with a confirmed RAB23 genotype, not because it is a general option for hydrocephalus: one of two siblings in the Emirati family had ventricular dilatation severe enough to require the shunt, while her brother had dilatation that did not. That pair is the useful part. The same allele, the same family, and one child shunted and the other not, which is a concrete instance of the variable expressivity this entry records elsewhere from craniosynostosis severity.

Target Phenotypes: Hydrocephalus HP:0000238

Show evidence (2 references)

PMID:23599695 SUPPORT Human Clinical

"the affected child also had dilatation of the lateral ventricles which required a ventriculo-peritoneal shunt"

The intervention as performed, in a genotyped patient.

PMID:23599695 SUPPORT Human Clinical

"There was dilatation of the lateral ventricles. Ophthalmological examination was normal."

The sibling with the same allele whose ventricular dilatation did not require shunting, which is why this treatment is not presented as a standard part of care.

Genetic counselling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counselling for an autosomal recessive disorder with a one-in-four recurrence risk for the parents of an affected child. It is curated because the genetics here make it unusually actionable rather than routine: the causal variants are known and homozygous, carrier testing of the parents has been done in reported families, and much of the literature is consanguineous families with several affected children. Prenatal recognition is possible but unreliable - see the prenatal-imaging entry in the diagnosis section, which records both the recommendation and its documented failure rate - so counselling based on a known familial variant is the stronger offering.

Show evidence (2 references)

PMID:33368989 SUPPORT Human Clinical

"Both parents were demonstrated to be heterozygous carriers of this variant."

Carrier testing of both parents, which is the concrete thing counselling rests on here: the recurrence risk is quantifiable because the variant is identified in the family.

PMID:20358613 SUPPORT Human Clinical

"four relatives of Comorian origin with Carpenter syndrome"

Four affected children in one family, which is the situation recurrence-risk counselling exists to address.

🔬

Diagnosis

2

Clinical recognition with RAB23 sequencing

Carpenter syndrome is recognised clinically from craniosynostosis with polysyndactyly. Distinguishing CRPT1 from CRPT2 requires gene testing, but two clinical features shift the prior towards RAB23: multi-suture rather than single midline suture craniosynostosis, and the absence of laterality defects, which are common in CRPT2 and rare in CRPT1.

Show evidence (1 reference)

PMID:38760421 SUPPORT Human Clinical

"However, laterality defects are present in nearly half of those with MEGF8-associated CRPT2, but are rare in RAB23-associated CRPT1."

The clinical discriminator, in the direction that favours RAB23 when laterality is normal.

Prenatal ultrasound recognition

Carpenter syndrome is hard to see before birth, and the cited experience says so plainly: in one fetus with a complex prenatal picture the diagnosis was still only made at birth, and it had been suggested on ultrasound in just one prior patient. Craniosynostosis and preaxial hexadactyly of the feet were visible on fetal CT only in retrospect. What the case yields is a prompt rather than a test. Bowed femora and a cardiac defect are both rare postnatal findings in this syndrome, so their appearance on a prenatal scan alongside an abnormal skull shape is a specific reason to consider the diagnosis. Cystic hygroma was also present in this fetus.

Show evidence (2 references)

PMID:25168863 SUPPORT Human Clinical

"The diagnosis of Carpenter syndrome should therefore be considered on prenatal imaging in cases of bowed femora and/or cardiac defect associated with abnormal skull shape."

The authors' recommendation, which is the substance of this diagnosis entry.

PMID:25168863 REFUTE Human Clinical

"This observation illustrates the difficulty of prenatal ultrasound diagnosis of Carpenter syndrome."

Cited as REFUTE against reading the entry above as a reliable prenatal test. The same paper that proposes the prompt records that the diagnosis was missed prenatally in this fetus and has been suggested on ultrasound in only one patient before.

📊

Prevalence

2

Global published literature

Cases In Literature Ultra Rare

A diagnosed-case count, not a population prevalence estimate. The 2024 comparative review tabulated 39 individuals with RAB23-associated CRPT1, against 15 with MEGF8-associated CRPT2; RAB23 is therefore the substantially more common cause of Carpenter syndrome, but both remain ultra-rare.

Show evidence (1 reference)

PMID:38760421 SUPPORT Human Clinical

"is also near-universal in RAB23-associated CRPT1 (38/39 individuals)"

The denominator in this feature count is the cumulative reported CRPT1 series as of 2024, which is what bounds the case count recorded here.

Worldwide

Birth Prevalence 0.1 per 100,000 <1 in 1,000,000 (births)

One in a million births, stated as an estimate in a case report rather than derived from a denominator-based study. It is recorded because it is the only population-rate figure in this literature, and it is consistent with the cumulative case count above; it should not be treated as a measured incidence. The figure is for Carpenter syndrome as a whole rather than for the RAB23 subtype specifically, which would be lower still.

Show evidence (1 reference)

PMID:39040725 SUPPORT Human Clinical

"This syndrome's rarity, with an estimated prevalence of one in a million births"

The only population-rate estimate cited in this entry, with the authors' own framing as an estimate preserved.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from RAB23-related Carpenter Syndrome:

🧫

Experimental Models

1

Carpenter syndrome patient-derived iPSC neural lineage IPSC_DERIVED_MODEL

Induced pluripotent stem cells from Carpenter syndrome patients, differentiated down the neural lineage. This is the only human-cell system in the entry, and it is what turns "Carpenter syndrome resembles a ciliopathy" into a measurement in patient cells rather than an inference from mouse work. Its most useful result is a dissociation within one genotype. Neurons differentiated from these lines show a marked drop in the proportion of ciliated cells, while the same patients' fibroblasts, undifferentiated iPSCs and neural progenitors keep a normal ciliation rate and show only shortened cilia. A study that had sampled fibroblasts alone would have concluded the ciliary defect was mild.

Pathograph links

Impaired Ciliary Protein Trafficking recapitulates fidelity: high Patient cells carrying patient alleles, assayed for the ciliary phenotype this node asserts, with the cell-type dependence measured rather than assumed.

Limitations: Differentiated cells in culture, not developing tissue. The lineages assayed are neural, so nothing here speaks to the cranial suture or limb bud, which are where the defining features of the disease arise.

Readouts

Ciliation frequency in iPSC-derived neurons

Direction: DECREASED

Interpretation: The proportion of ciliated cells falls in patient-derived neurons specifically.

Show evidence (1 reference)

PMID:40825043 SUPPORT In Vitro

"A profound reduction in ciliation frequency was observed specifically in neurons differentiated from CS patient iPSCs"

The measurement, in cells from patients with the disease this entry describes.

Cilium length in patient fibroblasts and neural progenitors

Direction: DECREASED

Interpretation: In the non-neuronal patient cells the defect is a shorter cilium at a normal ciliation rate, which is a milder and qualitatively different abnormality.

Show evidence (1 reference)

PMID:40825043 SUPPORT In Vitro

"the patients' fibroblasts, iPSCs and neural progenitor cells maintained normal ciliation percentages but shortened cilia length"

The contrasting result in the same patients' other cell types, which is what establishes the dependence on cell type rather than on genotype.

Show evidence (1 reference)

PMID:40825043 SUPPORT In Vitro

"Through the use of patient-derived iPSCs differentiated cells, we present direct evidence of primary cilia anomalies in CS, thereby confirming CS as a ciliopathy disorder."

The authors' statement of what this system establishes: that the ciliary defect is present in human patient cells and not only in animal models.

🐁

Animal Models

4

Rab23 conditional knockout mouse

A conditional knockout that avoids the embryonic lethality of the classical null and was used to ask where in the body RAB23 loss actually disturbs the cilium. The answer is that it depends on the cell: chondrocytes, embryonic fibroblasts, neural progenitors and neocortical neurons are affected, while epithelial cells, cerebellar granule cells and hippocampal neurons are not. This is the model behind the entry's context-dependence claim, and it is also why the Hedgehog node's direction is left unasserted: Rab23-knockout neural progenitors respond less to Hedgehog rather than more.

Species

Mouse

Genotype

Rab23 conditional knockout

Publication

PMID:40825043

Pathograph links

Impaired Ciliary Protein Trafficking recapitulates fidelity: high Reproduces ciliopathy-like developmental features in vivo and localises the ciliary defect to specific cell types.

Limitations: Murine, and conditional, so which cells lose Rab23 depends on the driver used. The species difference that dominates this entry still applies: mouse nulls are embryo-lethal where human nulls survive.

Readouts

Hedgehog pathway responsiveness in neural progenitor cells

Direction: DECREASED

Interpretation: Rab23-null progenitors are less responsive to cilium-dependent Hedgehog activation, which is the opposite direction to simple de-repression.

Show evidence (1 reference)

PMID:40825043 SUPPORT In Vitro

"Rab23-KO neural progenitor cells show perturbed ciliation and desensitized to primary cilium-dependent activation of the Hedgehog signaling pathway"

The measured pathway response, in the cell type where it was assayed.

Show evidence (1 reference)

PMID:40825043 SUPPORT Model Organism

"The Rab23-CKO mutants exhibit multiple developmental and phenotypical traits recapitulating the clinical features of human ciliopathies and CS, indicating a causal link between the loss of Rab23 and ciliopathy."

Establishes the model as informative for this disease, in the authors' own terms.

Rab23 zebrafish morphant

The third of the three vertebrate systems in which RAB23 loss was tested in parallel. Its value here is corroborative rather than independent: it is reported in the same study as the mouse and iPSC arms, and it is what allows the ciliary defect to be called consistent across vertebrates.

Species

Zebrafish

Genotype

rab23 morpholino knockdown

Publication

PMID:40825043

Pathograph links

Impaired Ciliary Protein Trafficking partially recapitulates fidelity: moderate Shows the same perturbation of primary cilium formation as the other two systems.

Limitations: A morpholino knockdown rather than a genetic null, so residual protein and off-target effects are not excluded, and no Carpenter-specific skeletal readout is reported for this arm.

Show evidence (1 reference)

PMID:40825043 SUPPORT Model Organism

"all three different vertebrate mutant models consistently show a perturbation of primary cilia formation"

The consistency across systems that this arm contributes to. The same sentence's "context-dependent" qualifier is quoted on the trafficking node.

Rab23-deficient mouse surviving to skeletal stages

A Rab23-deficient mouse engineered to survive past the embryonic lethality of the classical null, allowing skeletal development to be studied. It is the model in which the FGF10-pERK1/2 mechanism was established and pharmacologically tested.

Species

Mouse

Genotype

Rab23-/-

Publication

PMID:32662771

Pathograph links

Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis recapitulates fidelity: high The model reproduces multi-suture premature fusion arising from the same cellular lesion this node describes, and localises it to the suture.

Limitations: The cellular measurements are murine; no equivalent suture histology or signalling measurement from a RAB23 patient is cited.

Readouts

Osteoprogenitor proliferation in the cranial suture

Direction: INCREASED

Interpretation: The proliferative excess that drives the premature fusion.

Show evidence (1 reference)

PMID:32662771 SUPPORT Model Organism

"these mice exhibit premature fusion of multiple sutures resultant from aberrant osteoprogenitor proliferation and elevated osteogenesis in the suture"

Reports the proliferation and osteogenesis measurements behind this readout.

Show evidence (1 reference)

PMID:32662771 SUPPORT Model Organism

"To understand how RAB23 regulates skull development, we generated Rab23-deficient mice that survive to an age where skeletal development can be studied."

States the purpose and the design feature that makes this model informative for the skull phenotype at all.

Elevated FGF10-FGFR1-ERK Signalling in the Cranial Suture rescues fidelity: high Pharmacological inhibition of pERK1/2 in this model normalised osteoprogenitor proliferation, reduced osteogenic gene expression and prevented the craniosynostosis, which is the interventional evidence that the ERK arm is causal rather than correlated.

Limitations: The rescue is preclinical and prophylactic in a mouse. Nothing is reported about whether the same inhibition would help after sutures have fused, and no corresponding human intervention exists.

Readouts

Suture patency after pERK1/2 inhibition

Direction: RESTORED

Interpretation: Prevention of craniosynostosis on inhibition of the raised ERK signal.

Show evidence (1 reference)

PMID:32662771 SUPPORT Model Organism

"Inhibition of elevated pERK1/2 signaling results in the normalization of osteoprogenitor proliferation with a concomitant reduction of osteogenic gene expression, and prevention of craniosynostosis."

The rescue result behind this readout.

Show evidence (1 reference)

PMID:32662771 SUPPORT Model Organism

"FGF10-driven FGFR1 signaling is elevated in Rab23-/-sutures with a consequent imbalance in MAPK, Hedgehog signaling and RUNX2 expression."

Establishes that the pathway being rescued is the one elevated in the model.

open brain (opb) spontaneous Rab23 nonsense mouse

The classical spontaneous mouse mutant that first identified Rab23 as a Hedgehog antagonist. It is recorded here as a negative result: homozygotes die as embryos with neural tube defects, a phenotype humans with equivalent alleles do not have.

Species

Mouse

Genotype

Rab23 nonsense (open brain), homozygous

Publication

PMID:17503333

Pathograph links

RAB23 Loss of Function fails to recapitulate fidelity: low The same class of allele produces recessive embryonic lethality with an open neural tube in mouse, whereas human RAB23 null homozygotes survive and present with Carpenter syndrome. The model therefore does not reproduce the human consequence of RAB23 loss.

Limitations: The divergence is at the level of viability, so this model cannot be used to study the postnatal skeletal, adipose or cognitive phenotypes of Carpenter syndrome at all. The reason for the species difference is unknown; the original authors described it as a species difference in the requirement for RAB23 during early development, which is a restatement of the observation rather than an explanation.

Show evidence (2 references)

PMID:17503333 SUPPORT Model Organism

"Surprisingly, nonsense mutations of Rab23 in open brain mice cause recessive embryonic lethality with neural-tube defects, suggesting a species difference in the requirement for RAB23 during early development."

The discrepant model phenotype, and the authors' own reading of it as a species difference.

+ 1 more reference

{ }

Source YAML

click to show

name: RAB23-related Carpenter Syndrome
creation_date: "2026-09-01T14:07:00Z"
description: >-
  RAB23-related Carpenter syndrome (Carpenter syndrome 1, CRPT1, acrocephalopolysyndactyly
  type II) is an autosomal recessive developmental disorder caused by biallelic
  loss-of-function variants in RAB23, a small GTPase that acts as a negative regulator
  of Hedgehog signalling and participates in protein traffic to the primary cilium. It
  is the common form of Carpenter syndrome; the rarer CRPT2 is caused by MEGF8, the
  other negative regulator of the same pathway. The cardinal features are multi-suture
  craniosynostosis, polysyndactyly, obesity, cardiac defects and intellectual
  disability. Mouse work locates the craniosynostosis mechanism more precisely than
  Hedgehog de-repression alone: Rab23-null sutures show elevated FGF10-driven FGFR1
  signalling with a consequent imbalance in MAPK, Hedgehog signalling and RUNX2
  expression, and pharmacological inhibition of the raised pERK1/2 normalises
  osteoprogenitor proliferation and prevents the craniosynostosis. A striking species
  difference frames the interpretation of any model: nonsense Rab23 alleles in mice
  are embryonic lethal with neural tube defects, whereas human RAB23 null homozygotes
  survive to present with Carpenter syndrome.

  Two further findings complicate the simple account. The ciliary defect is real but
  conditional: across a conditional knockout mouse, patient-derived iPSCs and zebrafish,
  cilia are disturbed in chondrocytes, fibroblasts, neural progenitors and neocortical
  neurons but not in epithelial cells, cerebellar granule cells or hippocampal neurons,
  and within one patient the neurons lose cilia while the fibroblasts merely have shorter
  ones. And the direction of the Hedgehog effect is unsettled: RAB23 depletion lowers
  ciliary Smoothened, and RAB23-null progenitors respond less to Hedgehog, not more. Both
  are reduced pathway output rather than release from repression, so this entry records
  the pathway as dysregulated instead of asserting a direction.
synonyms:
- Carpenter syndrome 1
- CRPT1
- Carpenter syndrome
- acrocephalopolysyndactyly type II
- RAB23-associated Carpenter syndrome
category: Mendelian
disease_term:
  preferred_term: RAB23-related Carpenter syndrome
  term:
    id: MONDO:0008710
    label: RAB23-related Carpenter syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008710
      label: RAB23-related Carpenter syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- Carpenter syndrome
- Craniosynostosis syndrome
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry biallelic RAB23 variants. A founder nonsense allele,
    L145X, accounts for a substantial share of cases in patients of northern European
    descent, where it was found in the homozygous state in ten of the fifteen families
    in the original mapping study.
  evidence:
  - reference: PMID:17503333
    reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carpenter syndrome is a pleiotropic disorder with autosomal recessive
      inheritance, the cardinal features of which include craniosynostosis,
      polysyndactyly, obesity, and cardiac defects.
    explanation: >-
      States the mode of inheritance and the cardinal features together.
  - reference: PMID:17503333
    reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 10 patients, the disease was caused by homozygosity for the same nonsense
      mutation, L145X, that resides on a common haplotype, indicative of a founder
      effect in patients of northern European descent.
    explanation: >-
      Documents the founder allele and the population in which it is enriched.
prevalence:
- population: Global published literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A diagnosed-case count, not a population prevalence estimate. The 2024 comparative
    review tabulated 39 individuals with RAB23-associated CRPT1, against 15 with
    MEGF8-associated CRPT2; RAB23 is therefore the substantially more common cause of
    Carpenter syndrome, but both remain ultra-rare.
  evidence:
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is also near-universal in RAB23-associated CRPT1 (38/39 individuals)
    explanation: >-
      The denominator in this feature count is the cumulative reported CRPT1 series as
      of 2024, which is what bounds the case count recorded here.
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.1
  notes: >-
    One in a million births, stated as an estimate in a case report rather than derived
    from a denominator-based study. It is recorded because it is the only population-rate
    figure in this literature, and it is consistent with the cumulative case count above;
    it should not be treated as a measured incidence. The figure is for Carpenter syndrome
    as a whole rather than for the RAB23 subtype specifically, which would be lower still.
  evidence:
  - reference: PMID:39040725
    reference_title: A Rare Case of Carpenter Syndrome and Its Unique Association With Chronic Kidney Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This syndrome's rarity, with an estimated prevalence of one in a million births
    explanation: >-
      The only population-rate estimate cited in this entry, with the authors' own framing
      as an estimate preserved.
pathophysiology:
- name: RAB23 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic RAB23 variants abolish or impair a small GTPase that cycles between
    GDP-bound inactive and GTP-bound active states. The reported allele spectrum is
    dominated by truncating changes, with a recurrent founder nonsense allele; the
    point mutations that have been characterised structurally fall within the GTPase
    domain, and the Y79 deletion distorts the switch II region, which is the surface
    through which an activated Rab engages its effectors. The consequence is loss of
    function rather than a gain or a change of specificity.

    Three molecular routes to that loss have been demonstrated, and they are not
    variations on one theme. Most truncating alleles never make a protein at all: their
    transcripts are degraded by nonsense-mediated decay, shown experimentally rather than
    inferred from the premature stop codon. A frameshift late enough to escape that fate
    reaches the same endpoint differently, by deleting the C-terminal prenylatable
    cysteine, so a protein is made but cannot be lipid-anchored to the membranes it must
    work on. The missense and in-frame alleles leave a full-length, membrane-competent
    protein whose effector surface is distorted. All three converge on absent RAB23
    activity, which is why the entry treats the allele spectrum as functionally uniform
    despite its structural variety - and is consistent with the absence of any reported
    genotype-phenotype correlation.
  genes:
  - preferred_term: RAB23
    term:
      id: hgnc:14263
      label: RAB23
  molecular_functions:
  - preferred_term: RAB23 GTPase activity
    term:
      id: GO:0003924
      label: GTPase activity
    modifier: DECREASED
  downstream:
  - target: Impaired Ciliary Protein Trafficking
    causal_link_type: DIRECT
    description: >-
      RAB23 is a membrane-trafficking GTPase implicated in delivery of protein to the
      primary cilium, so loss of its activity acts directly on that traffic.
    evidence:
    - reference: PMID:29727300
      reference_title: Rab23 and developmental disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Recent findings have in fact implicated Rab23 in protein traffic to the primary
        cilium, thus linking it with the primary cellular locale of Shh signaling.
      explanation: >-
        States the trafficking role and why it is the relevant one for Hedgehog
        signalling. This is a review summarising other groups' findings, hence OTHER.
  - target: Elevated FGF10-FGFR1-ERK Signalling in the Cranial Suture
    causal_link_type: DIRECT
    description: >-
      RAB23 restrains FGFR signalling as well as Hedgehog, so its loss raises
      FGF10-driven FGFR1 signalling in the suture.
    evidence:
    - reference: PMID:32662771
      reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results suggest a novel role for RAB23 as an upstream negative regulator of
        both FGFR and canonical Hh-GLI1 signaling, and additionally in the non-canonical
        regulation of GLI1 through pERK1/2.
      explanation: >-
        Establishes RAB23 as an upstream negative regulator of FGFR signalling, which is
        what this edge asserts.
  evidence:
  - reference: PMID:17503333
    reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified five different mutations (four truncating and one missense) in RAB23,
      which encodes a member of the RAB guanosine triphosphatase (GTPase) family of
      vesicle transport proteins and acts as a negative regulator of hedgehog (HH)
      signaling
    explanation: >-
      The gene discovery, the allele spectrum, and the protein's two relevant
      properties: it is a trafficking GTPase and a Hedgehog antagonist.
  - reference: PMID:39615683
    reference_title: Structural basis for Rab23 activation and a loss-of-function mutation in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrated that the Y79 deletion mutant exhibited structural distortions in
      the switch II region relative to that of the WT.
    explanation: >-
      Crystallographic evidence for how a clinical point mutation impairs the protein.
  - reference: PMID:39615683
    reference_title: Structural basis for Rab23 activation and a loss-of-function mutation in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The structural changes potentially disrupted the binding of Rab23 Y79del to its
      interacting partners, thus leading to a loss-of-function and the development of
      Carpenter syndrome.
    explanation: >-
      The authors' interpretation that the mechanism is loss of function. The hedge
      ("potentially") is theirs and is retained.
  - reference: PMID:21412941
    reference_title: "Carpenter syndrome: extended RAB23 mutation spectrum and analysis of nonsense-mediated mRNA decay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We provide experimental evidence that transcripts encoding truncating mutations
      are subject to nonsense-mediated decay, and that this plays an important role in
      the pathogenesis of many RAB23 mutations.
    explanation: >-
      The first molecular route: truncating alleles are degraded at the transcript level
      rather than producing a truncated protein. Measured, not inferred from the stop
      codon position.
  - reference: PMID:23599695
    reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Due to the loss of the C-terminally prenylatable cysteine residue, the truncated
      protein will probably fail to associate with the target cellular membranes due to
      the absence of the necessary lipid modification.
    explanation: >-
      The second route, in a frameshift allele that does produce a protein: without the
      prenylation site it cannot reach the membranes where a Rab GTPase functions. The
      authors' hedge ("probably") is retained - this is inferred from the sequence, not
      a membrane-association assay.
  - reference: PMID:21412941
    reference_title: "Carpenter syndrome: extended RAB23 mutation spectrum and analysis of nonsense-mediated mRNA decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No genotype-phenotype correlations are apparent.
    explanation: >-
      Across the largest assembled mutation series, allele class does not predict
      presentation. This is what licenses treating the three molecular routes above as
      one functional lesion.
- name: Impaired Ciliary Protein Trafficking
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  biological_scale: CELLULAR
  description: >-
    RAB23 participates in protein delivery to the primary cilium, the organelle in
    which vertebrate Hedgehog signal transduction is organised. This places Carpenter
    syndrome adjacent to the ciliopathies, which it partly resembles clinically, though
    RAB23 also has functions independent of cilia and of Hedgehog.

    Two ciliary cargoes have been identified, and the specificity of the first is the
    informative part. Depleting RAB23 lowers the ciliary steady-state level of Smoothened
    - the Hedgehog transducer - while leaving the control proteins EB1 and Kim1
    untouched, so this is not a general collapse of ciliary import but a defect in
    turnover of a particular cargo. The second is Kif17, a kinesin-2 motor: RAB23 sits in
    a complex with Kif17 and importin beta-2, and Kif17 fails to reach the cilium in
    RAB23-depleted cells.

    Whether the cilium is affected at all depends on the cell type. Across a conditional
    knockout mouse, patient-derived iPSCs and zebrafish morphants, ciliary defects appear
    in chondrocytes, fibroblasts, neural progenitors and neocortical neurons but not in
    epithelial cells, cerebellar granule cells or hippocampal neurons - and the defect
    itself differs, being reduced ciliation frequency in patient-derived neurons but
    merely shortened cilia in the same patients' fibroblasts and progenitors. That
    cell-type dependence is a candidate explanation for why a lesion in a ubiquitous
    trafficking GTPase produces a phenotype concentrated in skull and limb.
  biological_processes:
  - preferred_term: protein localization to cilium
    term:
      id: GO:0061512
      label: protein localization to cilium
    modifier: DECREASED
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  downstream:
  - target: Hedgehog Signalling Dysregulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Disrupted ciliary traffic is one route by which RAB23 loss reaches Hedgehog
      signal transduction; the cited work links the two without resolving each step.
    evidence:
    - reference: PMID:31465935
      reference_title: "Small GTPases in hedgehog signalling: emerging insights into the disease mechanisms of Rab23-mediated and Arl13b-mediated ciliopathies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Notably, Rab23 and Arl13b have been implicated in ciliopathy-associated human
        diseases and could regulate Hh signalling cascade in multifaceted manners.
      explanation: >-
        Connects the ciliary role to Hedgehog regulation. The review's own hedging
        ("could", "multifaceted") is why the link carries known but unresolved
        intermediates rather than being asserted as direct.
      directness: INDIRECT
  evidence:
  - reference: PMID:20375059
    reference_title: "Differential role of Rab proteins in ciliary trafficking: Rab23 regulates smoothened levels."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of Rab23 or expression of dominant-negative Rab23 decreased the ciliary
      steady state specifically of Smoothened but not EB1 or Kim1, suggesting a role of
      Rab23 in protein turnover in the cilium.
    explanation: >-
      The cargo-specific ciliary defect, with its own internal controls. The word
      "specifically" is what makes this more than a general trafficking observation.
  - reference: PMID:26136363
    reference_title: A role for Rab23 in the trafficking of Kif17 to the primary cilium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ciliary localization of the kinesin-2 motor protein Kif17 was disrupted in
      Rab23-depleted cells
    explanation: >-
      A second identified ciliary cargo, from a study that also places RAB23 in a
      complex with the motor and its import carrier.
  - reference: PMID:40825043
    reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      all three different vertebrate mutant models consistently show a perturbation of
      primary cilia formation, intriguingly, in a context-dependent manner
    explanation: >-
      Establishes the ciliary defect across three independent model systems, and its
      cell-type dependence. Graded MODEL_ORGANISM because the sentence reports the mutant
      animal systems; the human patient-cell measurements from the same study are quoted
      separately below.
  - reference: PMID:40825043
    reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A profound reduction in ciliation frequency was observed specifically in neurons
      differentiated from CS patient iPSCs, whereas the patients' fibroblasts, iPSCs and
      neural progenitor cells maintained normal ciliation percentages but shortened cilia
      length.
    explanation: >-
      Human patient-derived evidence that the ciliary phenotype differs by cell type
      within the same individual, which is the strongest support in this entry for the
      node being cell-type conditional rather than uniform.
  - reference: PMID:29727300
    reference_title: Rab23 and developmental disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CS bears some phenotypic resemblance to a spectrum of hereditary defects
      associated with the primary cilium, or the ciliopathies.
    explanation: >-
      The clinical observation that motivates treating ciliary traffic as part of this
      mechanism.
  - reference: PMID:29727300
    reference_title: Rab23 and developmental disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rab23 also has Shh and cilia-independent functions.
    explanation: >-
      An explicit caution against reducing the disease to a ciliary Hedgehog defect;
      recorded here so the node is not read as the whole mechanism.
- name: Hedgehog Signalling Dysregulation
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  biological_scale: CELLULAR
  description: >-
    RAB23 antagonises Sonic hedgehog signalling, so its loss releases the pathway from
    negative regulation. This was the first mechanism proposed for Carpenter syndrome
    and was itself surprising, because craniosynostosis is not typically caused by
    variants in other Hedgehog pathway components. Mouse work later showed that the
    Hedgehog change in the suture is one arm of a broader signalling imbalance rather
    than the whole story.

    The classical genetics says de-repression, and the cell biology does not
    straightforwardly agree. Two results point the other way: depleting RAB23 lowers
    ciliary Smoothened, and RAB23-knockout neural progenitors are desensitized to
    cilium-dependent Hedgehog activation. Smoothened is the pathway's transducer, so less
    of it in the cilium and a blunted response to ligand are reduced output, not release
    from repression. This node is named for the dysregulation rather than for a direction
    because of that: an earlier name asserting de-repression would have contradicted the
    node's own modifier.

    The proposed reconciliation is that RAB23 does two separable things. It represses
    basal pathway activity, and it also facilitates activation by ligand through the
    cilium. Both were measured in one cell population: Rab23-depleted cerebellar granule
    cell precursors have a raised basal Shh signal and a blunted response to Shh ligand
    and to a Smoothened agonist. Losing RAB23 therefore raises the floor and lowers the
    ceiling, and the classical genetics and the trafficking work are each reporting one of
    those.

    This is why the pathway modifier is DYSREGULATED rather than INCREASED. On the
    dual-function reading that is not a refusal to commit but the accurate description:
    the pathway is deranged in two directions at once, and which one dominates in the
    cranial suture has not been measured.
  biological_processes:
  - preferred_term: negative regulation of smoothened signaling pathway
    term:
      id: GO:0045879
      label: negative regulation of smoothened signaling pathway
    modifier: DECREASED
  - preferred_term: smoothened signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DYSREGULATED
  downstream:
  - target: Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Hedgehog-GLI1 signalling is one of the arms whose imbalance in the Rab23-null
      suture accompanies the excess osteogenesis.
    evidence:
    - reference: PMID:32662771
      reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        FGF10-driven FGFR1 signaling is elevated in Rab23-/-sutures with a consequent
        imbalance in MAPK, Hedgehog signaling and RUNX2 expression.
      explanation: >-
        Places the Hedgehog change alongside MAPK and RUNX2 as part of one imbalance in
        the affected tissue, rather than as an independent cause.
      directness: INDIRECT
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cryptorchidism is one of the three near-universal core features of Carpenter
      syndrome in males, so it is attributed to the shared Hedgehog de-repression rather
      than treated as incidental. No source cited here traces a route from the pathway to
      testicular descent, which is why the intermediates are marked unknown.
    evidence:
    - reference: PMID:38760421
      reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The core features of craniosynostosis, polysyndactyly and (in males)
        cryptorchidism are almost universal in both CRPT1 and CRPT2.
      explanation: >-
        Places cryptorchidism among the core features shared by both Hedgehog-regulator
        genotypes, which is the basis for attributing it to the shared pathway defect.
      directness: INDIRECT
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Intellectual disability is part of the characterisation of the syndrome. Hedgehog
      signalling patterns the developing CNS, but nothing cited here connects the two in
      this disorder specifically.
    evidence:
    - reference: PMID:29727300
      reference_title: Rab23 and developmental disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        causes the developmental disorder Carpenter's syndrome (CS), which is
        characterized by craniofacial malformations, polysyndactyly, obesity and
        intellectual disability
      explanation: >-
        Establishes intellectual disability as a defining feature of the RAB23 disorder.
        The mechanism is not addressed by any cited source.
      directness: INDIRECT
  - target: Abnormal brain morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cerebral malformation is the one downstream feature here with independent support
      for the route as well as the association: the ciliopathy module this node conforms
      to carries its own edge from impaired Hedgehog transduction to CNS malformation,
      because Hedgehog patterns the neural tube and midbrain-hindbrain boundary. The steps
      between the two have still not been demonstrated in this disorder specifically.
    evidence:
    - reference: PMID:8352858
      reference_title: Cerebral malformations in Carpenter syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        cerebral malformations demonstrated by magnetic resonance imaging and computed
        tomography
      explanation: >-
        The malformation in a patient with the syndrome. The Hedgehog route is inferred
        from the pathway's known role in neural patterning, not traced in this disease,
        which is why the intermediates are unknown.
      directness: INDIRECT
  - target: Hydrocephalus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Ventricular enlargement, attributed to the shared pathway lesion on the same basis
      as the other central-nervous-system features. Two mechanisms are plausible in a
      craniosynostosis syndrome - a Hedgehog-dependent developmental malformation, or a
      secondary consequence of the constrained skull and the abnormal venous drainage this
      entry records under surgical management - and no cited source distinguishes them.
    evidence:
    - reference: PMID:20358613
      reference_title: RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Brain imaging showed hydrocephalus in 2/4
      explanation: >-
        Establishes hydrocephalus in patients with a confirmed RAB23 genotype. The route
        is not addressed by the source.
      directness: INDIRECT
  - target: Genu valgum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A skeletal feature outside the digits. Hedgehog signalling patterns the limb
      skeleton beyond the autopod, but nothing cited here connects the pathway to knee
      alignment in this disorder.
    evidence:
    - reference: PMID:20358613
      reference_title: RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        additional features included genu valgum (2/4)
      explanation: >-
        The feature in genotyped patients, with no mechanism proposed.
      directness: INDIRECT
  - target: Depressed nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the characteristic midface appearance, attributed to the shared pathway
      lesion on the malformation-complex basis. Hedgehog signalling patterns the
      frontonasal process, but no cited source connects the pathway to this feature in
      this disorder.
    evidence:
    - reference: PMID:23599695
      reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Facial abnormalities include flat nasal bridge, broad cheeks and malformed and
        unevenly set ears.
      explanation: >-
        Establishes the facies as a feature of the disease rather than of one patient.
      directness: INDIRECT
  - target: Low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the same craniofacial complex, on the same basis and with the same limits.
    evidence:
    - reference: PMID:23599695
      reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Facial abnormalities include flat nasal bridge, broad cheeks and malformed and
        unevenly set ears.
      explanation: >-
        The ears named in the disease-level statement of the facies.
      directness: INDIRECT
  - target: Corneal anomaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      An ocular finding reported without characterisation, attributed to the shared lesion
      on the malformation-complex basis rather than through any traced route.
    evidence:
    - reference: PMID:20358613
      reference_title: RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        abnormal genitalia (3/4), corneal anomaly (2/4)
      explanation: >-
        The finding in genotyped patients, quoted with the preceding list item so the
        snippet carries a full clause. Nothing more specific about the cornea is reported.
      directness: INDIRECT
  - target: Umbilical hernia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A ventral body-wall defect, attributed to the shared pathway lesion on the same
      basis as cryptorchidism: it belongs to the malformation complex that defines the
      syndrome. No cited source connects Hedgehog signalling to umbilical closure in this
      disorder, and the source that records the feature predates the gene.
    evidence:
    - reference: PMID:8352858
      reference_title: Cerebral malformations in Carpenter syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Acrocephalopolysyndactyly or Carpenter syndrome consists of craniosynostosis,
        short fingers, soft tissue syndactyly, preaxial polydactyly, congenital heart
        disease, hypogenitalism, obesity, and umbilical hernia.
      explanation: >-
        Establishes umbilical hernia as part of the defined syndrome, which is the whole
        basis for this edge.
      directness: INDIRECT
  - target: Obesity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Obesity is a cardinal feature, and the gene-discovery paper proposed the Hedgehog
      connection as a route into obesity biology. That proposal is the whole of the
      support: no cited source traces a step between the pathway and adiposity in this
      disorder, and none reports a metabolic or hypothalamic measurement in a patient.
      The edge is drawn because the syndrome's own discoverers drew it, and it is marked
      with unknown intermediates because they did not fill it in.
    evidence:
    - reference: PMID:17503333
      reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        provides a new molecular target for studies of obesity
      explanation: >-
        The proposal, in the authors' own deliberately weak phrasing. A target for study
        is not a mechanism, which is what this edge's link type records.
      directness: INDIRECT
  - target: Abnormal heart morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cardiac defects are a cardinal feature and are attributed here to the shared
      pathway lesion, on the same footing as cryptorchidism. There is one suggestive
      route rather than a demonstrated one: laterality defects are reported in RAB23
      patients, and left-right patterning is Hedgehog- and Nodal-dependent. No cited
      source connects the pathway to a specific cardiac malformation in this disorder.
    evidence:
    - reference: PMID:17503333
      reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the cardinal features of which include craniosynostosis, polysyndactyly, obesity,
        and cardiac defects
      explanation: >-
        Places cardiac defects among the cardinal features of the disorder whose cause is
        this pathway lesion.
      directness: INDIRECT
    - reference: PMID:21412941
      reference_title: "Carpenter syndrome: extended RAB23 mutation spectrum and analysis of nonsense-mediated mRNA decay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        but further evidence for laterality defects is reported
      explanation: >-
        The one mechanistically suggestive observation: RAB23 loss can disturb left-right
        patterning, which is a Hedgehog-dependent process and a recognised route to
        cardiac malformation.
      directness: INDIRECT
  - target: Limb Patterning Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hedgehog signalling patterns the anteroposterior axis of the limb bud, and the
      polysyndactyly of Carpenter syndrome is attributed to its de-repression. The
      intervening steps have not been demonstrated in this disorder.
    evidence:
    - reference: PMID:38760421
      reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Carpenter syndrome (CRPTS) is a rare autosomal recessive condition caused by
        biallelic variants in genes that encode negative regulators of hedgehog
        signalling
      explanation: >-
        Establishes that both Carpenter syndrome genes are Hedgehog negative regulators,
        which is the basis for attributing the limb phenotype to pathway de-repression.
        No source cited here measures Hedgehog activity in a patient limb bud.
      directness: INDIRECT
  evidence:
  - reference: PMID:17503333
    reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The discovery of RAB23 mutations in patients with Carpenter syndrome implicates
      HH signaling in cranial-suture biogenesis--an unexpected finding, given that
      craniosynostosis is not usually associated with mutations of other HH-pathway
      components
    explanation: >-
      The original inference, together with the authors' own reason for treating it as
      unexpected. That reservation is part of why a purely Hedgehog account of the
      craniosynostosis was later refined.
  - reference: PMID:29727300
    reference_title: Rab23 and developmental disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rab23 was initially identified to act as an antagonist of Sonic hedgehog (Shh)
      signaling
    explanation: >-
      States the antagonist relationship this node depends on.
  - reference: PMID:20375059
    reference_title: "Differential role of Rab proteins in ciliary trafficking: Rab23 regulates smoothened levels."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of Rab23 or expression of dominant-negative Rab23 decreased the ciliary
      steady state specifically of Smoothened but not EB1 or Kim1
    explanation: >-
      Cited as REFUTE against reading this node as uniformly increased Hedgehog output.
      Losing RAB23 removes Smoothened from the cilium, and Smoothened is what transduces
      the signal, so in this system the effect on pathway activity is negative.
  - reference: PMID:40825043
    reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      Rab23-KO neural progenitor cells show perturbed ciliation and desensitized to
      primary cilium-dependent activation of the Hedgehog signaling pathway
    explanation: >-
      A second result in the same direction and in a disease-relevant cell type:
      RAB23-null progenitors respond less to Hedgehog, not more. Together with the
      Smoothened result this is why the pathway modifier on this node is DYSREGULATED.
  - reference: PMID:34210780
    reference_title: Multifaceted Functions of Rab23 on Primary Cilium-Mediated and Hedgehog Signaling-Mediated Cerebellar Granule Cell Proliferation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rab23 represses the basal level of Shh signaling, while facilitating primary
      cilium-dependent extrinsic Shh signaling activation.
    explanation: >-
      The dual-function account that reconciles the de-repression evidence with the
      reduced-responsiveness evidence, rather than choosing between them. This is the
      claim the node's description now rests on.
  - reference: PMID:34210780
    reference_title: Multifaceted Functions of Rab23 on Primary Cilium-Mediated and Hedgehog Signaling-Mediated Cerebellar Granule Cell Proliferation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rab23-depleted GCPs were desensitized against Hh pathway activity stimulations by
      Shh ligand and Smoothened (Smo) agonist-SAG, and exhibited attenuated stimulation
      of Smo-localization on the primary cilium in response to SAG
    explanation: >-
      Ties the blunted ligand response directly to failed Smoothened delivery to the
      cilium, which is the link between this node and the trafficking node upstream of
      it.
- name: Elevated FGF10-FGFR1-ERK Signalling in the Cranial Suture
  biological_scale: CELLULAR
  description: >-
    In Rab23-null mouse sutures, FGF10-driven FGFR1 signalling is elevated, with
    downstream hyperactivation of the ERK1/2 arm of MAPK. This is the arm of the
    mechanism with the strongest causal evidence, because it was tested by
    intervention rather than only observed: inhibiting the raised pERK1/2 normalises
    osteoprogenitor proliferation and prevents the craniosynostosis.
  biological_processes:
  - preferred_term: fibroblast growth factor receptor signaling pathway
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
    modifier: INCREASED
  - preferred_term: ERK1 and ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    modifier: INCREASED
  downstream:
  - target: Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis
    causal_link_type: DIRECT
    description: >-
      Raised pERK1/2 drives the osteoprogenitor proliferation and osteogenic gene
      expression; blocking it reverses both.
    evidence:
    - reference: PMID:32662771
      reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Inhibition of elevated pERK1/2 signaling results in the normalization of
        osteoprogenitor proliferation with a concomitant reduction of osteogenic gene
        expression, and prevention of craniosynostosis.
      explanation: >-
        An interventional result, which is what makes this the best-supported causal
        step in the pathograph. It is a mouse experiment, so it establishes the
        mechanism in the model rather than in patients.
  evidence:
  - reference: PMID:32662771
    reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      FGF10-driven FGFR1 signaling is elevated in Rab23-/-sutures with a consequent
      imbalance in MAPK, Hedgehog signaling and RUNX2 expression.
    explanation: >-
      The measured signalling change in the affected tissue.
- name: Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis
  biological_scale: TISSUE
  description: >-
    Suture patency depends on mesenchymal cells at the centre of the suture remaining
    undifferentiated while progenitors at the osteogenic fronts proliferate and
    differentiate in a controlled way. In Rab23-null sutures that balance fails:
    osteoprogenitor proliferation is aberrant and osteogenesis in the suture is
    elevated, and multiple sutures fuse prematurely.
  cell_types:
  - preferred_term: suture osteoprogenitor
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: suture mesenchymal cell
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: INCREASED
  downstream:
  - target: Craniosynostosis
    causal_link_type: DIRECT
    description: >-
      Premature fusion of the sutures is the direct consequence of the excess
      osteogenesis within them.
    evidence:
    - reference: PMID:32662771
      reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        these mice exhibit premature fusion of multiple sutures resultant from aberrant
        osteoprogenitor proliferation and elevated osteogenesis in the suture
      explanation: >-
        States the cellular cause of the suture fusion, in the model.
  - target: Proptosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Prominent eyes follow from the skull shape rather than from any ocular lesion: the
      altered calvarial growth that the suture fusion imposes leaves shallow orbits, and
      the globes sit forward in them. This is the one craniofacial feature in this entry
      with an intermediate that can be named, which is why it hangs off the osteogenic
      node rather than off the pathway node with the rest of the facies.
    evidence:
    - reference: PMID:34244844
      reference_title: "Complex craniosynostosis in the context of Carpenter's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a trefoil-like skull, flattened and receding forehead, bulging of temporal bones,
        hypertelorism, exorbitism, and polysyndactyly
      explanation: >-
        Lists the exorbitism in the same breath as the skull deformity that produces it,
        in one patient. The intermediate step - shallow orbits - is standard
        craniosynostosis anatomy rather than something this source measures, so the link
        is indirect with known rather than demonstrated intermediates.
      directness: INDIRECT
  evidence:
  - reference: PMID:32662771
    reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mesenchymal cells in the center of the suture must be kept in an undifferentiated
      state to maintain suture patency, while progenitor cells at the osteogenic fronts
      proliferate and differentiate to facilitate bone growth.
    explanation: >-
      The normal cell biology of the suture that this node describes the failure of.
- name: Limb Patterning Defect
  conforms_to: "limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity Specification"
  biological_scale: TISSUE
  description: >-
    Abnormal patterning of the developing limb produces the acral phenotype:
    polydactyly, cutaneous syndactyly and abnormalities of the middle phalanges. The
    syndactyly is near-universal in reported CRPT1 patients.
  downstream:
  - target: Cutaneous syndactyly
    causal_link_type: DIRECT
    description: >-
      Failure of interdigital separation.
    evidence:
    - reference: PMID:38760421
      reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        is also near-universal in RAB23-associated CRPT1 (38/39 individuals)
      explanation: >-
        The counted frequency of cutaneous syndactyly in the cumulative CRPT1 series.
  - target: Polydactyly
    causal_link_type: DIRECT
    description: >-
      Supernumerary digits, part of the polysyndactyly that is a cardinal feature.
    evidence:
    - reference: PMID:38760421
      reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        with polydactyly, abnormalities of the middle phalanges and talipes also being
        common in both forms
      explanation: >-
        Establishes polydactyly as common in both Carpenter syndrome subtypes.
  - target: Talipes
    causal_link_type: DIRECT
    description: >-
      Club foot, reported as common in both Carpenter syndrome subtypes alongside the
      other acral findings, so it belongs with the limb patterning defect rather than
      standing alone.
    evidence:
    - reference: PMID:38760421
      reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        with polydactyly, abnormalities of the middle phalanges and talipes also being
        common in both forms
      explanation: >-
        Groups talipes with the other limb findings as common in both subtypes.
  - target: Brachydactyly
    causal_link_type: DIRECT
    description: >-
      Shortening of the digits, reported as abnormalities of the middle phalanges.
    evidence:
    - reference: PMID:38760421
      reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        abnormalities of the middle phalanges and talipes also being common in both
        forms
      explanation: >-
        Middle phalangeal abnormality is the reported form of the brachydactyly.
  evidence:
  - reference: PMID:32662771
    reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Along with polysyndactyly, these mice exhibit premature fusion of multiple
      sutures
    explanation: >-
      The limb phenotype is reproduced in the Rab23-null mouse alongside the skull
      phenotype, which is what links it to the same lesion.
phenotypes:
- name: Craniosynostosis
  category: Clinical
  description: >-
    Premature fusion of cranial sutures, characteristically involving multiple sutures.
    The multi-suture pattern is one of the two features that clinically separates CRPT1
    from MEGF8-related CRPT2, in which a single midline suture is typical.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The core features of craniosynostosis, polysyndactyly and (in males)
      cryptorchidism are almost universal in both CRPT1 and CRPT2.
    explanation: >-
      "Almost universal" is the basis for the VERY_FREQUENT band.
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Craniosynostosis in CRPT2 commonly involves a single midline suture in comparison
      to the multi-suture craniosynostosis characteristic of CRPT1.
    explanation: >-
      The suture pattern that characterises this form, stated as the contrast with
      CRPT2.
- name: Cutaneous syndactyly
  category: Clinical
  description: >-
    Soft-tissue fusion of the digits, present in all but one of the reported CRPT1
    patients.
  phenotype_term:
    preferred_term: Cutaneous syndactyly
    term:
      id: HP:0012725
      label: Cutaneous syndactyly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cutaneous syndactyly is a universal feature in all cases of MEGF8-associated CRPT2
      to date (15/15 individuals, Supplementary Table 2) and is also near-universal in
      RAB23-associated CRPT1 (38/39 individuals)
    explanation: >-
      A counted frequency, 38 of 39, which places the band unambiguously.
- name: Polydactyly
  category: Clinical
  description: >-
    Supernumerary digits, typically preaxial in the feet, combining with the syndactyly
    to give the polysyndactyly that names the older designation acrocephalopolysyndactyly.
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The core features of craniosynostosis, polysyndactyly and (in males)
      cryptorchidism are almost universal in both CRPT1 and CRPT2.
    explanation: >-
      Polysyndactyly is among the almost universal core features.
  - reference: PMID:8352858
    reference_title: Cerebral malformations in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      craniosynostosis, short fingers, soft tissue syndactyly, preaxial polydactyly,
      congenital heart disease, hypogenitalism, obesity, and umbilical hernia
    explanation: >-
      Specifies the polydactyly as preaxial, which is the description this phenotype's
      text rests on. Bound to the general HP:0010442 rather than to HP:0100258 (Preaxial
      polydactyly) because the near-universal frequency band comes from sources that
      count "polysyndactyly" without splitting it by ray, so a preaxial-specific binding
      would carry a frequency it has not been shown to have.
- name: Brachydactyly
  category: Clinical
  description: >-
    Shortened digits from abnormalities of the middle phalanges.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  frequency: FREQUENT
  evidence:
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with polydactyly, abnormalities of the middle phalanges and talipes also being
      common in both forms
    explanation: >-
      "Common" rather than "almost universal" is why this is banded below the core
      features.
- name: Talipes
  category: Clinical
  description: >-
    Club foot, reported as a common feature of both forms of Carpenter syndrome.
  phenotype_term:
    preferred_term: Talipes
    term:
      id: HP:0001883
      label: Talipes
  frequency: FREQUENT
  evidence:
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormalities of the middle phalanges and talipes also being common in both forms
    explanation: >-
      Talipes among the features described as common in both subtypes.
- name: Umbilical hernia
  category: Clinical
  description: >-
    Protrusion at the umbilicus, part of the malformation complex catalogued under the
    older name acrocephalopolysyndactyly. It is listed in the clinical descriptions of
    the syndrome but is not counted in any of the cited series, so the band reflects
    membership in the described phenotype rather than a measured frequency.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:8352858
    reference_title: Cerebral malformations in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      craniosynostosis, short fingers, soft tissue syndactyly, preaxial polydactyly,
      congenital heart disease, hypogenitalism, obesity, and umbilical hernia
    explanation: >-
      Umbilical hernia among the features defining the syndrome clinically. The source
      predates the gene, so it describes the clinical entity rather than the RAB23
      genotype specifically.
- name: Cryptorchidism
  category: Clinical
  description: >-
    Undescended testes, near-universal in affected males and one of the three core
    features shared by both Carpenter syndrome subtypes.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost
      universal in both CRPT1 and CRPT2
    explanation: >-
      "Almost universal" among males, which is the subgroup this band applies to.
- name: Obesity
  category: Clinical
  description: >-
    Obesity is one of the cardinal features and was, at gene discovery, the finding
    that made RAB23 a proposed molecular entry point into obesity biology.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  frequency: FREQUENT
  evidence:
  - reference: PMID:17503333
    reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the cardinal features of which include craniosynostosis, polysyndactyly, obesity,
      and cardiac defects
    explanation: >-
      Obesity listed among the cardinal features. No source cited here gives a counted
      frequency, so the band reflects "cardinal feature" without claiming near-universality.
  - reference: PMID:17503333
    reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      provides a new molecular target for studies of obesity
    explanation: >-
      The gene-discovery authors' proposal that this is a route into obesity biology.
      Quoted deliberately in its weak form: the paper offers a target for study, not a
      demonstrated mechanism, which is why the edge into this phenotype carries unknown
      intermediates.
- name: Abnormal heart morphology
  category: Clinical
  description: >-
    Congenital cardiac defects, listed among the cardinal features of the syndrome. Where
    a specific lesion is named in the cited literature it is Tetralogy of Fallot, and a
    complex heart defect has also been seen prenatally on ultrasound.

    The defects are surgically correctable and patients reach adulthood, but they are not
    thereby finished with: residual lesions progress, and in one reported pregnancy the
    combination of that progression with the haemodynamic load of pregnancy was the main
    difficulty in care. The phenotype is therefore lifelong rather than neonatal.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:17503333
    reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      craniosynostosis, polysyndactyly, obesity, and cardiac defects
    explanation: >-
      Cardiac defects among the cardinal features.
  - reference: PMID:21412941
    reference_title: "Carpenter syndrome: extended RAB23 mutation spectrum and analysis of nonsense-mediated mRNA decay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      but further evidence for laterality defects is reported
    explanation: >-
      Laterality defects do occur in RAB23 patients, which matters here because
      left-right patterning is Hedgehog- and Nodal-dependent and is one route by which a
      Hedgehog regulator could reach cardiac morphology. Rare in RAB23 and frequent in
      MEGF8, so it is also the discriminator between the two Carpenter genotypes.
  - reference: PMID:23706836
    reference_title: Caesarean section in a parturient with Carpenter syndrome and corrected Tetralogy of Fallot.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe the anaesthetic management for caesarean section of a parturient with
      Carpenter syndrome and corrected Tetralogy of Fallot.
    explanation: >-
      Names a specific cardiac lesion in a patient with this syndrome, rather than the
      generic "cardiac defects" of the cardinal-feature lists.
  - reference: PMID:23706836
    reference_title: Caesarean section in a parturient with Carpenter syndrome and corrected Tetralogy of Fallot.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Even after surgical correction of cardiac abnormalities, intrapartum care of a
      parturient with this condition can be challenging because of progression of
      residual cardiac defects
    explanation: >-
      Establishes that the cardiac phenotype progresses after correction, which is why it
      is described here as lifelong rather than as a neonatal malformation that surgery
      closes out.
  - reference: PMID:25168863
    reference_title: Prenatal findings in carpenter syndrome and a novel mutation in RAB23.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cystic hygroma, bowed femora, abnormal skull shape and a complex heart defect were
      seen on ultrasound scan
    explanation: >-
      A complex cardiac defect detectable before birth, which is also the basis for the
      prenatal-imaging entry in this entry's diagnosis section.
- name: Hydrocephalus
  category: Clinical
  description: >-
    Enlargement of the cerebral ventricles, present in two of four affected siblings in
    the one family where brain imaging was reported for every child. It is the finding
    with the most direct management consequence in this entry, since it is what a
    ventriculoperitoneal shunt is placed for, and it also bears on the interpretation of
    the intracranial pressure that drives the timing of craniofacial surgery.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20358613
    reference_title: RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging showed hydrocephalus in 2/4
    explanation: >-
      A counted proportion within one family, all four children homozygous for the same
      allele. The band is OCCASIONAL rather than derived from 2/4, because four siblings
      of one genotype is not a frequency estimate for the disease.
  - reference: PMID:23599695
    reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the affected child also had dilatation of the lateral ventricles which required a
      ventriculo-peritoneal shunt
    explanation: >-
      An independent family, and the one report in this entry where the hydrocephalus was
      severe enough to be shunted. Both siblings in that family had ventricular
      dilatation; only this one needed the operation.
- name: Abnormal brain morphology
  category: Clinical
  description: >-
    Structural malformation of the brain on MRI or CT. This is curated as its own
    phenotype because of the role it plays in prognosis rather than for its own sake: the
    most profound developmental delay in this syndrome goes with demonstrable cerebral
    malformation, which is what makes neuroimaging predictive of cognitive outcome where
    the external craniofacial appearance is not.
  phenotype_term:
    preferred_term: Cerebral malformation
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:8352858
    reference_title: Cerebral malformations in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A patient is reported with the features of Carpenter syndrome who has profound
      developmental delay and cerebral malformations demonstrated by magnetic resonance
      imaging and computed tomography.
    explanation: >-
      The documented finding, in the patient whose case established the association with
      cognitive outcome. A single case, hence the conservative band.
- name: Genu valgum
  category: Clinical
  description: >-
    Knock-knee deformity, reported in two of the four siblings in the Comorian family.
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20358613
    reference_title: RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      additional features included genu valgum (2/4)
    explanation: >-
      Counted within the one family reporting it. Curated as a skeletal feature beyond the
      digits, which are otherwise where this entry's skeletal phenotype sits.
- name: Corneal anomaly
  category: Clinical
  description: >-
    Corneal abnormality reported in two of four siblings in the Comorian family. The source
    records "corneal anomaly" and nothing more, so this is bound to the general
    cornea-morphology term rather than to any specific corneal finding. An earlier version
    of this entry bound it to HP:0007957 Corneal opacity, which asserts an opacity the
    source never reports.
  phenotype_term:
    preferred_term: Corneal anomaly
    term:
      id: HP:0000481
      label: Abnormal cornea morphology
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20358613
    reference_title: RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal genitalia (3/4), corneal anomaly (2/4)
    explanation: >-
      The finding as reported. The quote runs on from the neighbouring item in the same
      list so that it carries a full clause; only the corneal half is curated here, the
      genital findings being covered by the cryptorchidism phenotype. The source does not
      say what the corneal anomaly was, so this is the most specific binding the evidence
      carries.
- name: Depressed nasal bridge
  category: Clinical
  description: >-
    Flattening of the nasal bridge, part of the characteristic facial appearance. It is
    named both at disease level in a review of the syndrome's features and individually in
    two siblings examined separately, which is why it is curated rather than treated as a
    single-case observation.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  frequency: FREQUENT
  evidence:
  - reference: PMID:23599695
    reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial abnormalities include flat nasal bridge, broad cheeks and malformed and
      unevenly set ears.
    explanation: >-
      A disease-level statement of the characteristic facies, not a single patient's
      findings, which is the basis for the FREQUENT band.
  - reference: PMID:23599695
    reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      upward slanting of the palpebral fissures, prominent eyes, and depressed nasal
      bridge with low set ears
    explanation: >-
      The finding in the first of two genotyped siblings examined individually.
- name: Low-set ears
  category: Clinical
  description: >-
    Ears set below the normal level, described at disease level as malformed and unevenly
    set, and recorded in both siblings of the Emirati family.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  frequency: FREQUENT
  evidence:
  - reference: PMID:23599695
    reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The eyes were prominent, furthermore there was a depressed nasal bridge, high arched
      palate and low set ears
    explanation: >-
      The finding in the second genotyped sibling, examined separately from the first.
- name: Proptosis
  category: Clinical
  description: >-
    Prominent or protruding eyes, recorded in both siblings of the Emirati family and, as
    exorbitism, in an unrelated case. In a craniosynostosis syndrome this is a consequence
    of shallow orbits rather than an independent ocular finding.
  phenotype_term:
    preferred_term: Prominent eyes
    term:
      id: HP:0000520
      label: Proptosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:23599695
    reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The eyes were prominent, furthermore there was a depressed nasal bridge, high arched
      palate and low set ears
    explanation: >-
      Prominent eyes in the second sibling; the first is described in the same paper with
      "prominent eyes" in the quote used on the nasal-bridge phenotype.
  - reference: PMID:34244844
    reference_title: "Complex craniosynostosis in the context of Carpenter's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a trefoil-like skull, flattened and receding forehead, bulging of temporal bones,
      hypertelorism, exorbitism, and polysyndactyly
    explanation: >-
      The same finding in an unrelated patient, described as exorbitism, alongside the
      skull shape that produces it.
- name: Intellectual disability
  category: Clinical
  description: >-
    Intellectual impairment affects up to three-quarters of patients, but it is expressly
    not invariable, and the entry bands it accordingly rather than treating it as a
    defining feature.

    Its severity has a reported structural correlate: the most profound delay goes with
    cerebral malformations visible on MRI or CT, which makes neuroimaging prognostically
    informative rather than merely confirmatory. That relationship is not mirrored on the
    outside of the head - degree of craniofacial dysmorphology does not track brain
    dysmorphology - so the face does not predict the outcome.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:29727300
    reference_title: Rab23 and developmental disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      causes the developmental disorder Carpenter's syndrome (CS), which is
      characterized by craniofacial malformations, polysyndactyly, obesity and
      intellectual disability
    explanation: >-
      Intellectual disability among the characterising features. The source is a review,
      so it is graded OTHER rather than as a primary clinical series.
  - reference: PMID:8352858
    reference_title: Cerebral malformations in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As many as three-fourths of the patients have some degree of intellectual
      impairment.
    explanation: >-
      The only proportion given for this feature in the cited literature, and the basis
      for the FREQUENT band.
  - reference: PMID:8352858
    reference_title: Cerebral malformations in Carpenter syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because mental retardation is not an invariable feature of this syndrome or other
      craniosynostosis syndromes, neuroradiologic examination may help in predicting the
      intellectual outcome in these patients.
    explanation: >-
      Cited as REFUTE against treating intellectual disability as a constant of the
      syndrome. The same sentence carries the prognostic point: imaging, not the
      diagnosis, is what indicates the likely outcome.
  - reference: PMID:20358613
    reference_title: RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mental development was normal in all four children
    explanation: >-
      Four affected siblings homozygous for one allele, none with intellectual
      disability. The strongest single counterexample in this literature, because it
      holds genotype constant.
genetic:
- name: RAB23 pathogenic variants
  gene_term:
    preferred_term: RAB23
    term:
      id: hgnc:14263
      label: RAB23
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic variants, predominantly truncating. The original mapping study found five
    distinct alleles across fifteen families, four truncating and one missense, with the
    nonsense allele L145X homozygous in ten patients on a shared haplotype - a founder
    effect in individuals of northern European descent. Point mutations characterised
    since (M12K, C85R, Y79del) fall within the GTPase domain. Y79del has been solved
    crystallographically and distorts the switch II region, supporting loss of function
    as the mechanism for missense and in-frame alleles as well as for the truncating
    ones. No `functional_impact_category` is recorded on this entry because the schema
    places that slot on variant-level genetic context rather than on the gene-level
    record; the loss-of-function conclusion is stated here and evidenced below.
  evidence:
  - reference: PMID:17503333
    reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using homozygosity mapping, we found linkage to chromosome 6p12.1-q12 and, in 15
      independent families, identified five different mutations (four truncating and one
      missense) in RAB23
    explanation: >-
      The gene discovery and the allele spectrum in the founding series.
  - reference: PMID:39615683
    reference_title: Structural basis for Rab23 activation and a loss-of-function mutation in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Several clinical point mutations, for example, M12K, C85R, and Y79del, have been
      found to occur within the GTPase domain.
    explanation: >-
      Locates the characterised point mutations within the functional domain.
  - reference: PMID:39615683
    reference_title: Structural basis for Rab23 activation and a loss-of-function mutation in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      thus leading to a loss-of-function and the development of Carpenter syndrome
    explanation: >-
      The structural study's conclusion that the mechanism is loss of function.
  variants:
  - name: RAB23 p.Leu145X
    description: >-
      The founder nonsense allele, homozygous in ten of the patients in the original
      mapping study and carried on a shared haplotype, indicating a founder effect in
      individuals of northern European descent. It is the single commonest cause of
      Carpenter syndrome.
    gene:
      preferred_term: RAB23
      term:
        id: hgnc:14263
        label: RAB23
    type: NONSENSE
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:17503333
      reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In 10 patients, the disease was caused by homozygosity for the same nonsense
        mutation, L145X, that resides on a common haplotype, indicative of a founder
        effect in patients of northern European descent.
      explanation: >-
        The allele, its recurrence, and the founder-effect interpretation.
  - name: RAB23 p.Tyr79del
    description: >-
      An in-frame deletion within the GTPase domain and the only clinical allele solved
      crystallographically. It distorts the switch II region, the surface through which an
      activated Rab engages its effectors, which is how a single-residue deletion produces
      loss of function without removing the protein.
    gene:
      preferred_term: RAB23
      term:
        id: hgnc:14263
        label: RAB23
    type: DELETION
    clinical_significance: PATHOGENIC
    functional_effects:
    - function: RAB23 effector binding
      description: >-
        Structural distortion of the switch II region, predicted to disrupt binding to
        interacting partners.
    evidence:
    - reference: PMID:39615683
      reference_title: Structural basis for Rab23 activation and a loss-of-function mutation in Carpenter syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we demonstrated that the Y79 deletion mutant exhibited structural distortions in
        the switch II region relative to that of the WT.
      explanation: >-
        The crystallographic result establishing how this allele impairs the protein.
  - name: RAB23 c.482-1G>A (p.Val161LeufsX3)
    description: >-
      A splice-acceptor variant that activates a cryptic site inside exon 5, deleting
      eight nucleotides and shifting the frame. It is curated because of where the
      resulting stop falls: late enough that the transcript is not simply degraded, but
      early enough to remove the C-terminal prenylatable cysteine. The protein is made and
      cannot be lipid-anchored to the membranes a Rab GTPase works on, which is a
      different route to loss of function from the nonsense alleles.
    gene:
      preferred_term: RAB23
      term:
        id: hgnc:14263
        label: RAB23
    type: SPLICE_SITE
    clinical_significance: PATHOGENIC
    functional_effects:
    - function: RAB23 membrane association
      description: >-
        Loss of the C-terminal prenylation site, so the truncated protein is predicted not
        to associate with target membranes.
    evidence:
    - reference: PMID:23599695
      reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This mutation affects the authentic mRNA splicing and activates a cryptic acceptor
        site within exon 5.
      explanation: >-
        The splicing consequence, demonstrated at the transcript level rather than
        predicted.
  - name: RAB23 c.481G>C (p.Val161Leufs*16)
    description: >-
      A substitution at the last base of exon 6 that causes the exon to be skipped,
      shifting the frame and creating a premature stop. It is curated as the allele of the
      one case with a documented prenatal picture, and as a second example of a coding
      substitution whose real consequence is on splicing rather than on the amino acid it
      appears to change.
    gene:
      preferred_term: RAB23
      term:
        id: hgnc:14263
        label: RAB23
    type: FRAMESHIFT
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:25168863
      reference_title: Prenatal findings in carpenter syndrome and a novel mutation in RAB23.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sequencing of RAB23 identified a homozygous mutation leading to skipping of exon 6
        and premature termination codon
      explanation: >-
        The allele and its splicing consequence.
  - name: RAB23 c.82C>T (p.Arg28*)
    description: >-
      A nonsense allele reported homozygous in the first molecularly confirmed case of
      Carpenter syndrome from continental Africa, with both parents shown to be carriers.
      It is curated as evidence that the disorder is not confined to the populations the
      founder allele comes from.
    gene:
      preferred_term: RAB23
      term:
        id: hgnc:14263
        label: RAB23
    type: NONSENSE
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:33368989
      reference_title: Carpenter syndrome in a patient from Tanzania.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a previously described homozygous variant c.82C>T p.(Arg28*) was detected that
        results in a premature stop codon
      explanation: >-
        The allele and its homozygous state, with parental carrier testing reported in the
        same paper.
  - name: RAB23 c.86dupA
    description: >-
      A frameshift allele homozygous in four affected children of one Comorian family.
      This is the entry's clearest evidence that genotype does not fix phenotype here:
      with one allele held constant within a single family, craniosynostosis ranged from a
      cloverleaf skull to an isolated metopic ridge, hydrocephalus was present in two of
      four, and mental development was normal in all four.
    gene:
      preferred_term: RAB23
      term:
        id: hgnc:14263
        label: RAB23
    type: FRAMESHIFT
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:20358613
      reference_title: RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report here on a RAB23 mutation (c.86dupA) present in the homozygote state in
        four relatives of Comorian origin with Carpenter syndrome.
      explanation: >-
        The allele and the family it segregates in.
    - reference: PMID:20358613
      reference_title: RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        intrafamilial variability was observed with variable severity of craniosynostosis
        ranging from cloverleaf skull to predominant involvement of the metopic ridge
      explanation: >-
        Variable expressivity on an identical genotype in one family, which is stronger
        evidence for it than the absence of genotype-phenotype correlation across
        unrelated patients.
diagnosis:
- name: Clinical recognition with RAB23 sequencing
  description: >-
    Carpenter syndrome is recognised clinically from craniosynostosis with
    polysyndactyly. Distinguishing CRPT1 from CRPT2 requires gene testing, but two
    clinical features shift the prior towards RAB23: multi-suture rather than single
    midline suture craniosynostosis, and the absence of laterality defects, which are
    common in CRPT2 and rare in CRPT1.
  evidence:
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, laterality defects are present in nearly half of those with
      MEGF8-associated CRPT2, but are rare in RAB23-associated CRPT1.
    explanation: >-
      The clinical discriminator, in the direction that favours RAB23 when laterality is
      normal.
- name: Prenatal ultrasound recognition
  description: >-
    Carpenter syndrome is hard to see before birth, and the cited experience says so
    plainly: in one fetus with a complex prenatal picture the diagnosis was still only
    made at birth, and it had been suggested on ultrasound in just one prior patient.
    Craniosynostosis and preaxial hexadactyly of the feet were visible on fetal CT only in
    retrospect.

    What the case yields is a prompt rather than a test. Bowed femora and a cardiac defect
    are both rare postnatal findings in this syndrome, so their appearance on a prenatal
    scan alongside an abnormal skull shape is a specific reason to consider the diagnosis.
    Cystic hygroma was also present in this fetus.
  evidence:
  - reference: PMID:25168863
    reference_title: Prenatal findings in carpenter syndrome and a novel mutation in RAB23.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Carpenter syndrome should therefore be considered on prenatal
      imaging in cases of bowed femora and/or cardiac defect associated with abnormal
      skull shape.
    explanation: >-
      The authors' recommendation, which is the substance of this diagnosis entry.
  - reference: PMID:25168863
    reference_title: Prenatal findings in carpenter syndrome and a novel mutation in RAB23.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This observation illustrates the difficulty of prenatal ultrasound diagnosis of
      Carpenter syndrome.
    explanation: >-
      Cited as REFUTE against reading the entry above as a reliable prenatal test. The
      same paper that proposes the prompt records that the diagnosis was missed
      prenatally in this fetus and has been suggested on ultrasound in only one patient
      before.
treatments:
- name: Craniofacial surgical management
  description: >-
    Surgical management of the craniosynostosis. No disease-modifying therapy exists for
    the underlying signalling defect, so this is the treatment of the disease in practice.

    There is no established management algorithm - the disorder is too rare for one - but
    two things are agreed. Early release of the fused sutures with fronto-orbital
    advancement is indicated, and particularly so where intracranial pressure is raised.
    And correction is usually safe within the first 6 to 12 months, which is early by the
    standards of craniofacial surgery generally.

    The operative planning carries a specific hazard worth recording as part of the
    treatment rather than as a complication of it: abnormal venous drainage and ectatic
    emissary veins can cause serious bleeding, and the skull may be weak enough to
    fragment when cranial flaps are raised. Both are why imaging before operating - 3D CT
    for the bone, MR angiography for the veins - changes what the surgeon does.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  - preferred_term: Cutaneous syndactyly
    term:
      id: HP:0012725
      label: Cutaneous syndactyly
  target_mechanisms:
  - target: Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis
    description: >-
      Surgery acts on the product of this node rather than on the node itself. Releasing
      fused sutures and advancing the fronto-orbital segment undoes the anatomical
      consequence of the excess osteogenesis; it does not touch the FGF-ERK signalling
      that drove it, which is why the fusion can recur and why the pERK1/2 inhibition
      result is curated as a model rescue rather than as a therapy.
    evidence:
    - reference: PMID:25162549
      reference_title: "Carpenter syndrome: a review for the craniofacial surgeon."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        early release of craniosynostoses with fronto-orbital advancement is clearly
        indicated in the CS literature, particularly in cases of elevated intracranial
        pressure
      explanation: >-
        Names the intervention and the anatomical target it acts on.
  evidence:
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had presented during infancy with polysyndactyly and craniosynostosis, both
      treated surgically, and had a clinical diagnosis of CRPTS.
    explanation: >-
      Documents surgical management of both the craniosynostosis and the polysyndactyly
      in a patient with Carpenter syndrome. The individual described carries a MEGF8
      variant, so this supports the surgical approach to the shared phenotype rather
      than a RAB23-specific practice.
    directness: INDIRECT
  - reference: PMID:25162549
    reference_title: "Carpenter syndrome: a review for the craniofacial surgeon."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      early release of craniosynostoses with fronto-orbital advancement is clearly
      indicated in the CS literature, particularly in cases of elevated intracranial
      pressure
    explanation: >-
      The one clearly indicated intervention, from a review written for the surgeons who
      perform it. Graded OTHER because it is a synthesis of selected case literature
      rather than a series with its own outcomes.
  - reference: PMID:25162549
    reference_title: "Carpenter syndrome: a review for the craniofacial surgeon."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Given the scarcity of CS cases, an algorithm for CS management has not been
      established.
    explanation: >-
      States why this treatment entry describes agreed principles rather than a protocol:
      there are not enough patients to have built one.
  - reference: PMID:34244844
    reference_title: "Complex craniosynostosis in the context of Carpenter's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early correction of craniofacial deformity in Carpenter's syndrome is usually safe
      within 6 to 12 months.
    explanation: >-
      The timing, from a case with two years of follow-up after correction.
  - reference: PMID:34244844
    reference_title: "Complex craniosynostosis in the context of Carpenter's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Venous drainage abnormalities and ectatic emissary veins can lead to significant
      bleeding and may be detected on MR angiography.
    explanation: >-
      The operative hazard and the imaging that detects it beforehand. Recorded because
      it changes preoperative planning rather than being a general surgical caution.
- name: Cardiac surgical correction
  description: >-
    Surgical repair of the congenital cardiac defect. The one lesion named in the cited
    literature is Tetralogy of Fallot, and the reported outcome is the reason this is
    curated separately rather than folded into supportive care: patients reach adulthood
    after correction, but residual lesions progress, and that progression was the
    principal difficulty in the one reported pregnancy in this syndrome.

    So the treatment is not a closed episode. It changes what the cardiac phenotype is -
    from a neonatal malformation to a lifelong one requiring follow-up - rather than
    ending it.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac surgical correction
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_phenotypes:
  - preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:23706836
    reference_title: Caesarean section in a parturient with Carpenter syndrome and corrected Tetralogy of Fallot.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe the anaesthetic management for caesarean section of a parturient with
      Carpenter syndrome and corrected Tetralogy of Fallot.
    explanation: >-
      A patient with the syndrome whose cardiac defect had been surgically corrected and
      who survived to adulthood and pregnancy.
  - reference: PMID:23706836
    reference_title: Caesarean section in a parturient with Carpenter syndrome and corrected Tetralogy of Fallot.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Even after surgical correction of cardiac abnormalities, intrapartum care of a
      parturient with this condition can be challenging because of progression of
      residual cardiac defects
    explanation: >-
      The limit of the intervention, stated by the authors: correction does not stop
      residual lesions progressing. This is why the treatment carries a follow-up
      implication rather than being recorded as definitive.
- name: Ventriculoperitoneal shunt
  description: >-
    Diversion of cerebrospinal fluid for hydrocephalus. It is curated because it is
    reported as actually performed in a patient with a confirmed RAB23 genotype, not
    because it is a general option for hydrocephalus: one of two siblings in the Emirati
    family had ventricular dilatation severe enough to require the shunt, while her
    brother had dilatation that did not.

    That pair is the useful part. The same allele, the same family, and one child shunted
    and the other not, which is a concrete instance of the variable expressivity this
    entry records elsewhere from craniosynostosis severity.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: ventriculoperitoneal shunt placement
    term:
      id: NCIT:C168483
      label: Ventriculoperitoneal Shunt Placement
  target_phenotypes:
  - preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:23599695
    reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the affected child also had dilatation of the lateral ventricles which required a
      ventriculo-peritoneal shunt
    explanation: >-
      The intervention as performed, in a genotyped patient.
  - reference: PMID:23599695
    reference_title: A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was dilatation of the lateral ventricles. Ophthalmological examination was
      normal.
    explanation: >-
      The sibling with the same allele whose ventricular dilatation did not require
      shunting, which is why this treatment is not presented as a standard part of care.
- name: Genetic counselling
  description: >-
    Counselling for an autosomal recessive disorder with a one-in-four recurrence risk for
    the parents of an affected child. It is curated because the genetics here make it
    unusually actionable rather than routine: the causal variants are known and
    homozygous, carrier testing of the parents has been done in reported families, and
    much of the literature is consanguineous families with several affected children.

    Prenatal recognition is possible but unreliable - see the prenatal-imaging entry in
    the diagnosis section, which records both the recommendation and its documented
    failure rate - so counselling based on a known familial variant is the stronger
    offering.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33368989
    reference_title: Carpenter syndrome in a patient from Tanzania.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both parents were demonstrated to be heterozygous carriers of this variant.
    explanation: >-
      Carrier testing of both parents, which is the concrete thing counselling rests on
      here: the recurrence risk is quantifiable because the variant is identified in the
      family.
  - reference: PMID:20358613
    reference_title: RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      four relatives of Comorian origin with Carpenter syndrome
    explanation: >-
      Four affected children in one family, which is the situation recurrence-risk
      counselling exists to address.
experimental_models:
- name: Carpenter syndrome patient-derived iPSC neural lineage
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Induced pluripotent stem cells from Carpenter syndrome patients, differentiated down
    the neural lineage. This is the only human-cell system in the entry, and it is what
    turns "Carpenter syndrome resembles a ciliopathy" into a measurement in patient cells
    rather than an inference from mouse work.

    Its most useful result is a dissociation within one genotype. Neurons differentiated
    from these lines show a marked drop in the proportion of ciliated cells, while the
    same patients' fibroblasts, undifferentiated iPSCs and neural progenitors keep a
    normal ciliation rate and show only shortened cilia. A study that had sampled
    fibroblasts alone would have concluded the ciliary defect was mild.
  modeled_mechanisms:
  - target: Impaired Ciliary Protein Trafficking
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Patient cells carrying patient alleles, assayed for the ciliary phenotype this node
      asserts, with the cell-type dependence measured rather than assumed.
    limitations: >-
      Differentiated cells in culture, not developing tissue. The lineages assayed are
      neural, so nothing here speaks to the cranial suture or limb bud, which are where
      the defining features of the disease arise.
    readouts:
    - name: Ciliation frequency in iPSC-derived neurons
      target: Impaired Ciliary Protein Trafficking
      direction: DECREASED
      interpretation: >-
        The proportion of ciliated cells falls in patient-derived neurons specifically.
      evidence:
      - reference: PMID:40825043
        reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          A profound reduction in ciliation frequency was observed specifically in neurons
          differentiated from CS patient iPSCs
        explanation: >-
          The measurement, in cells from patients with the disease this entry describes.
    - name: Cilium length in patient fibroblasts and neural progenitors
      target: Impaired Ciliary Protein Trafficking
      direction: DECREASED
      interpretation: >-
        In the non-neuronal patient cells the defect is a shorter cilium at a normal
        ciliation rate, which is a milder and qualitatively different abnormality.
      evidence:
      - reference: PMID:40825043
        reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          the patients' fibroblasts, iPSCs and neural progenitor cells maintained normal
          ciliation percentages but shortened cilia length
        explanation: >-
          The contrasting result in the same patients' other cell types, which is what
          establishes the dependence on cell type rather than on genotype.
    evidence:
    - reference: PMID:40825043
      reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Through the use of patient-derived iPSCs differentiated cells, we present direct
        evidence of primary cilia anomalies in CS, thereby confirming CS as a ciliopathy
        disorder.
      explanation: >-
        The authors' statement of what this system establishes: that the ciliary defect is
        present in human patient cells and not only in animal models.
animal_models:
- name: Rab23 conditional knockout mouse
  species: Mouse
  genotype: Rab23 conditional knockout
  publication: PMID:40825043
  description: >-
    A conditional knockout that avoids the embryonic lethality of the classical null and
    was used to ask where in the body RAB23 loss actually disturbs the cilium. The answer
    is that it depends on the cell: chondrocytes, embryonic fibroblasts, neural
    progenitors and neocortical neurons are affected, while epithelial cells, cerebellar
    granule cells and hippocampal neurons are not.

    This is the model behind the entry's context-dependence claim, and it is also why the
    Hedgehog node's direction is left unasserted: Rab23-knockout neural progenitors
    respond less to Hedgehog rather than more.
  modeled_mechanisms:
  - target: Impaired Ciliary Protein Trafficking
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces ciliopathy-like developmental features in vivo and localises the ciliary
      defect to specific cell types.
    limitations: >-
      Murine, and conditional, so which cells lose Rab23 depends on the driver used. The
      species difference that dominates this entry still applies: mouse nulls are
      embryo-lethal where human nulls survive.
    readouts:
    - name: Hedgehog pathway responsiveness in neural progenitor cells
      target: Impaired Ciliary Protein Trafficking
      direction: DECREASED
      interpretation: >-
        Rab23-null progenitors are less responsive to cilium-dependent Hedgehog
        activation, which is the opposite direction to simple de-repression.
      evidence:
      - reference: PMID:40825043
        reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Rab23-KO neural progenitor cells show perturbed ciliation and desensitized to
          primary cilium-dependent activation of the Hedgehog signaling pathway
        explanation: >-
          The measured pathway response, in the cell type where it was assayed.
    evidence:
    - reference: PMID:40825043
      reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The Rab23-CKO mutants exhibit multiple developmental and phenotypical traits
        recapitulating the clinical features of human ciliopathies and CS, indicating a
        causal link between the loss of Rab23 and ciliopathy.
      explanation: >-
        Establishes the model as informative for this disease, in the authors' own terms.
- name: Rab23 zebrafish morphant
  species: Zebrafish
  genotype: rab23 morpholino knockdown
  publication: PMID:40825043
  description: >-
    The third of the three vertebrate systems in which RAB23 loss was tested in parallel.
    Its value here is corroborative rather than independent: it is reported in the same
    study as the mouse and iPSC arms, and it is what allows the ciliary defect to be
    called consistent across vertebrates.
  modeled_mechanisms:
  - target: Impaired Ciliary Protein Trafficking
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Shows the same perturbation of primary cilium formation as the other two systems.
    limitations: >-
      A morpholino knockdown rather than a genetic null, so residual protein and
      off-target effects are not excluded, and no Carpenter-specific skeletal readout is
      reported for this arm.
    evidence:
    - reference: PMID:40825043
      reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        all three different vertebrate mutant models consistently show a perturbation of
        primary cilia formation
      explanation: >-
        The consistency across systems that this arm contributes to. The same sentence's
        "context-dependent" qualifier is quoted on the trafficking node.
- name: Rab23-deficient mouse surviving to skeletal stages
  species: Mouse
  genotype: Rab23-/-
  publication: PMID:32662771
  description: >-
    A Rab23-deficient mouse engineered to survive past the embryonic lethality of the
    classical null, allowing skeletal development to be studied. It is the model in
    which the FGF10-pERK1/2 mechanism was established and pharmacologically tested.
  modeled_mechanisms:
  - target: Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The model reproduces multi-suture premature fusion arising from the same cellular
      lesion this node describes, and localises it to the suture.
    limitations: >-
      The cellular measurements are murine; no equivalent suture histology or signalling
      measurement from a RAB23 patient is cited.
    readouts:
    - name: Osteoprogenitor proliferation in the cranial suture
      target: Aberrant Osteoprogenitor Proliferation and Premature Osteogenesis
      direction: INCREASED
      interpretation: >-
        The proliferative excess that drives the premature fusion.
      evidence:
      - reference: PMID:32662771
        reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          these mice exhibit premature fusion of multiple sutures resultant from aberrant
          osteoprogenitor proliferation and elevated osteogenesis in the suture
        explanation: >-
          Reports the proliferation and osteogenesis measurements behind this readout.
    evidence:
    - reference: PMID:32662771
      reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        To understand how RAB23 regulates skull development, we generated Rab23-deficient
        mice that survive to an age where skeletal development can be studied.
      explanation: >-
        States the purpose and the design feature that makes this model informative for
        the skull phenotype at all.
  - target: Elevated FGF10-FGFR1-ERK Signalling in the Cranial Suture
    relationship: RESCUES
    fidelity: HIGH
    description: >-
      Pharmacological inhibition of pERK1/2 in this model normalised osteoprogenitor
      proliferation, reduced osteogenic gene expression and prevented the
      craniosynostosis, which is the interventional evidence that the ERK arm is causal
      rather than correlated.
    limitations: >-
      The rescue is preclinical and prophylactic in a mouse. Nothing is reported about
      whether the same inhibition would help after sutures have fused, and no
      corresponding human intervention exists.
    readouts:
    - name: Suture patency after pERK1/2 inhibition
      target: Elevated FGF10-FGFR1-ERK Signalling in the Cranial Suture
      direction: RESTORED
      interpretation: >-
        Prevention of craniosynostosis on inhibition of the raised ERK signal.
      evidence:
      - reference: PMID:32662771
        reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Inhibition of elevated pERK1/2 signaling results in the normalization of
          osteoprogenitor proliferation with a concomitant reduction of osteogenic gene
          expression, and prevention of craniosynostosis.
        explanation: >-
          The rescue result behind this readout.
    evidence:
    - reference: PMID:32662771
      reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        FGF10-driven FGFR1 signaling is elevated in Rab23-/-sutures with a consequent
        imbalance in MAPK, Hedgehog signaling and RUNX2 expression.
      explanation: >-
        Establishes that the pathway being rescued is the one elevated in the model.
- name: open brain (opb) spontaneous Rab23 nonsense mouse
  species: Mouse
  genotype: Rab23 nonsense (open brain), homozygous
  publication: PMID:17503333
  description: >-
    The classical spontaneous mouse mutant that first identified Rab23 as a Hedgehog
    antagonist. It is recorded here as a negative result: homozygotes die as embryos
    with neural tube defects, a phenotype humans with equivalent alleles do not have.
  modeled_mechanisms:
  - target: RAB23 Loss of Function
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The same class of allele produces recessive embryonic lethality with an open
      neural tube in mouse, whereas human RAB23 null homozygotes survive and present
      with Carpenter syndrome. The model therefore does not reproduce the human
      consequence of RAB23 loss.
    limitations: >-
      The divergence is at the level of viability, so this model cannot be used to study
      the postnatal skeletal, adipose or cognitive phenotypes of Carpenter syndrome at
      all. The reason for the species difference is unknown; the original authors
      described it as a species difference in the requirement for RAB23 during early
      development, which is a restatement of the observation rather than an explanation.
    evidence:
    - reference: PMID:17503333
      reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Surprisingly, nonsense mutations of Rab23 in open brain mice cause recessive
        embryonic lethality with neural-tube defects, suggesting a species difference in
        the requirement for RAB23 during early development.
      explanation: >-
        The discrepant model phenotype, and the authors' own reading of it as a species
        difference.
    - reference: PMID:29727300
      reference_title: Rab23 and developmental disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Interestingly, RAB23 null allele homozygosity in humans is not lethal, but
        instead causes the developmental disorder Carpenter's syndrome (CS)
      explanation: >-
        The human side of the same contrast, stated explicitly.
differential_diagnoses:
- name: MEGF8-related Carpenter syndrome
  description: >-
    Carpenter syndrome 2, the rarer form, caused by biallelic variants in the other
    Hedgehog negative regulator. The two share the core craniosynostosis,
    polysyndactyly and cryptorchidism, and are separated clinically by laterality
    defects (common in CRPT2, rare here) and by suture pattern (single midline in CRPT2,
    multi-suture here). They are curated as separate entries because the two proteins
    diverge mechanistically downstream, MEGF8 acting through BMP-SMAD and RAB23 through
    FGF-ERK.
  evidence:
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carpenter syndrome (CRPTS) is a rare autosomal recessive condition caused by
      biallelic variants in genes that encode negative regulators of hedgehog signalling
    explanation: >-
      Establishes that the two subtypes are defined by two genes in the same regulatory
      role.
  - reference: PMID:38760421
    reference_title: The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the most common form of CRPTS (CRPT1; OMIM 201000) was shown in 2007 to be caused
      by biallelic pathogenic variants in RAB23
    explanation: >-
      Identifies this entry's disease as the common form, and dates the gene discovery.
discussions:
- discussion_id: rab23_mouse_human_viability_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why is homozygous RAB23 nonsense mutation embryonic lethal with neural tube defects
    in mouse but compatible with survival and a postnatal skeletal syndrome in humans,
    and what does that divergence imply for using mouse Rab23 models to study Carpenter
    syndrome?
  attaches_to:
  - pathophysiology#RAB23 Loss of Function
  - animal_models#open brain (opb) spontaneous Rab23 nonsense mouse
  rationale: >-
    This is not a difference of severity but of outcome: the same class of allele kills
    the mouse embryo and produces a viable developmental syndrome in humans. It has a
    direct methodological consequence, which the field has already had to work around -
    the mouse used to establish the FGF10-pERK1/2 suture mechanism had to be engineered
    specifically to survive to skeletal stages, because the classical null does not. Any
    claim carried from that model into the human disease therefore rests on a system
    that has been modified precisely at the point where the species diverge. Nothing in
    the cited literature explains the divergence; the original description labels it a
    species difference in the developmental requirement for RAB23, which names the
    problem without resolving it.
  proposed_experiments:
  - experiment_id: rab23_cross_species_neurulation
    name: Compare RAB23 dependence in human and mouse neurulation-stage models
    description: >-
      Determine whether the divergence lies in RAB23 itself or in pathway redundancy, by
      comparing Hedgehog pathway output and neural tube closure between human
      iPSC-derived neural models carrying patient RAB23 null alleles and the equivalent
      mouse system.
    perturbations:
    - name: Biallelic RAB23 null allele
      target: pathophysiology#RAB23 Loss of Function
      description: >-
        Introduce a patient-equivalent RAB23 null genotype in both species' models.
    readouts:
    - name: Hedgehog pathway output
      target: pathophysiology#Hedgehog Signalling Dysregulation
      interpretation: >-
        Comparable de-repression in both species with divergent morphological outcome
        would locate the difference downstream of Hedgehog rather than in RAB23 itself.
    would_support:
    - pathophysiology#Hedgehog Signalling Dysregulation
  evidence:
  - reference: PMID:17503333
    reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Surprisingly, nonsense mutations of Rab23 in open brain mice cause recessive
      embryonic lethality with neural-tube defects
    explanation: >-
      The mouse phenotype that does not occur in humans.
  - reference: PMID:29727300
    reference_title: Rab23 and developmental disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is unique amongst the Rabs in terms of its implicated role in mammalian
      development, as originally illustrated by the embryonic lethality and open neural
      tube phenotype of a spontaneous mouse mutant
    explanation: >-
      Confirms the mouse phenotype is the defining one for this gene, which is what makes
      the human divergence notable rather than incidental.
  - reference: PMID:32662771
    reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we generated Rab23-deficient mice that survive to an age where skeletal development
      can be studied
    explanation: >-
      The workaround the mismatch forced on the field, and the reason model-derived
      mechanism in this disease needs the caveat attached.
- discussion_id: hedgehog_versus_fgf_arm
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is the craniosynostosis of Carpenter syndrome primarily a Hedgehog de-repression
    phenotype, as inferred at gene discovery, or primarily an FGFR-ERK phenotype, as the
    interventional mouse work suggests?
  attaches_to:
  - pathophysiology#Hedgehog Signalling Dysregulation
  - pathophysiology#Elevated FGF10-FGFR1-ERK Signalling in the Cranial Suture
  rationale: >-
    The original inference from human genetics was that Hedgehog signalling must be
    involved in suture biogenesis, and the authors flagged this as unexpected because
    craniosynostosis is not usually caused by other Hedgehog pathway components. The
    later mouse work supplies a different emphasis: FGF10-FGFR1-pERK1/2 is elevated, and
    inhibiting it prevents the craniosynostosis, while Hedgehog appears as one arm of a
    broader imbalance. The two are not exclusive - RAB23 is proposed to restrain both
    pathways, and to regulate GLI1 non-canonically through pERK1/2 - but the pathograph
    currently records the FGF-ERK arm as the better-evidenced route to the suture
    phenotype, on the strength of the rescue experiment. That ordering rests on a single
    mouse study and should be revisited if the Hedgehog arm is tested by intervention.
  evidence:
  - reference: PMID:17503333
    reference_title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      implicates HH signaling in cranial-suture biogenesis--an unexpected finding, given
      that craniosynostosis is not usually associated with mutations of other HH-pathway
      components
    explanation: >-
      The Hedgehog-first inference, together with the authors' own reason for doubting it
      is the whole account.
  - reference: PMID:32662771
    reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Inhibition of elevated pERK1/2 signaling results in the normalization of
      osteoprogenitor proliferation with a concomitant reduction of osteogenic gene
      expression, and prevention of craniosynostosis.
    explanation: >-
      The interventional result that gives the FGF-ERK arm its precedence in this
      pathograph.
  - reference: PMID:32662771
    reference_title: RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      a novel role for RAB23 as an upstream negative regulator of both FGFR and canonical
      Hh-GLI1 signaling, and additionally in the non-canonical regulation of GLI1 through
      pERK1/2
    explanation: >-
      States that the two arms are connected rather than competing, which is why this is
      recorded as a question of emphasis and not a contradiction.
- discussion_id: hedgehog_direction_of_effect
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does RAB23 loss raise or lower Hedgehog pathway output, and is the answer different
    in different cell types?
  attaches_to:
  - pathophysiology#Hedgehog Signalling Dysregulation
  - pathophysiology#Impaired Ciliary Protein Trafficking
  rationale: >-
    The classical genetics points one way: RAB23 is a Sonic hedgehog antagonist, mouse
    nulls have a ventralised neural tube, and losing an antagonist should de-repress the
    pathway. Two cell-biological results point the other
    way. Depleting RAB23 selectively lowers ciliary Smoothened - the transducer - while
    leaving control ciliary proteins alone. And RAB23-knockout neural progenitors respond
    less to cilium-dependent Hedgehog activation, not more.

    There is a proposed resolution, and it is better supported than "it depends on the
    cell type". Both directions were measured in the same cells: Rab23-depleted cerebellar
    granule cell precursors show a raised basal level of Shh pathway activity and, at the
    same time, a blunted response to Shh ligand and to a Smoothened agonist, together with
    reduced agonist-driven Smoothened localisation to the cilium. On that account RAB23
    has two separable jobs - it represses basal pathway activity, and it facilitates
    cilium-dependent activation by ligand - so losing it raises the floor and lowers the
    ceiling. The classical genetics reports the floor; the ciliary trafficking work
    reports the ceiling; neither is wrong.

    Two things keep this open rather than settled. It rests on one study in one cell type,
    and that cell type is one where a second study found no ciliary abnormality at all -
    a discrepancy the two papers do not address, and which may come down to the different
    conditional drivers used. And no Hedgehog measurement of either kind has been made in
    a Carpenter suture or limb bud, so the direction is asserted in the tissues that
    define the disease and measured only in tissues that do not.

    Until that gap closes the node carries DYSREGULATED rather than a direction, which on
    the dual-function reading is not a hedge but the accurate description: the pathway is
    deranged in two directions at once.
  evidence:
  - reference: PMID:20375059
    reference_title: "Differential role of Rab proteins in ciliary trafficking: Rab23 regulates smoothened levels."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Loss of Rab23 in mice recapitulates the HH phenotype but its function in HH
      signaling is unknown.
    explanation: >-
      The authors state the gap this question is about: the genetic phenotype is
      established and the molecular direction of effect is not.
  - reference: PMID:20375059
    reference_title: "Differential role of Rab proteins in ciliary trafficking: Rab23 regulates smoothened levels."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of Rab23 or expression of dominant-negative Rab23 decreased the ciliary
      steady state specifically of Smoothened but not EB1 or Kim1
    explanation: >-
      The first of the two results pointing away from de-repression, with its own
      internal controls.
  - reference: PMID:40825043
    reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Rab23-KO neural progenitor cells show perturbed ciliation and desensitized to
      primary cilium-dependent activation of the Hedgehog signaling pathway
    explanation: >-
      The second, in a disease-relevant cell type and from a study designed around this
      disorder.
  - reference: PMID:40825043
    reference_title: RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rab23-CKO mutants reveal cell-type specific ciliary abnormalities in chondrocytes,
      mouse embryonic fibroblasts, neural progenitor cells and neocortical neurons, but
      not in epithelial cells, cerebellar granule cells and hippocampus neurons.
    explanation: >-
      The cell-type map. Note that this study places cerebellar granule cells among the
      cell types with no ciliary abnormality, which is where the study proposing the
      dual-function resolution found one.
  - reference: PMID:34210780
    reference_title: Multifaceted Functions of Rab23 on Primary Cilium-Mediated and Hedgehog Signaling-Mediated Cerebellar Granule Cell Proliferation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rab23 represses the basal level of Shh signaling, while facilitating primary
      cilium-dependent extrinsic Shh signaling activation.
    explanation: >-
      The proposed resolution, stated by its authors: two separable functions, so losing
      RAB23 raises basal activity and impairs ligand-driven activation at the same time.
  - reference: PMID:34210780
    reference_title: Multifaceted Functions of Rab23 on Primary Cilium-Mediated and Hedgehog Signaling-Mediated Cerebellar Granule Cell Proliferation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rab23-depleted GCPs exhibited upregulated basal level of Shh pathway activities
      despite showing an abnormal ciliogenesis of primary cilia.
    explanation: >-
      Both directions measured in one cell population, which is what makes this a
      resolution rather than a third conflicting report.
- discussion_id: phenotype_expansion_single_cases
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Are overgrowth with advanced bone age, epileptiform EEG changes, autistic features
    and chronic kidney disease part of the RAB23 phenotype, or coincidental findings in
    single patients?
  attaches_to:
  - phenotypes#Intellectual disability
  - genetic#RAB23 pathogenic variants
  rationale: >-
    Two recent reports propose extensions to the phenotype, each resting on one patient.
    One describes overgrowth with advanced bone age, epileptogenic EEG changes and
    autistic features in a patient with a novel missense allele, and attributes them to
    that allele. Another reports chronic kidney disease and calls the association
    unusual.

    None of these is curated as a phenotype here. Each rests on a single case; the
    overgrowth report explicitly contrasts its patient with a typical second patient from
    the same study, so the authors themselves treat it as atypical; and the disorder has
    no reported genotype-phenotype correlation, which makes attributing new features to a
    particular novel allele hard to sustain. Against that, the syndrome is rare enough
    that genuine features may only ever appear in single reports, so absence of
    replication is weak evidence of coincidence.

    What would settle it is systematic ascertainment - bone age, EEG and renal function
    in the assembled RAB23 cohort - rather than further case reports.
  evidence:
  - reference: PMID:34748996
    reference_title: Expansion of the phenotypic and mutational spectrum of Carpenter syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      overgrowth with advanced bone age, epileptogenic changes on electroencephalogram
      and autistic features
    explanation: >-
      The proposed new features, in the one patient they are reported in.
  - reference: PMID:34748996
    reference_title: Expansion of the phenotypic and mutational spectrum of Carpenter syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 presented with an atypical clinical presentation of Carpenter syndrome
    explanation: >-
      The authors' own framing of the case as atypical, which is why this is held open
      rather than curated.
  - reference: PMID:39040725
    reference_title: A Rare Case of Carpenter Syndrome and Its Unique Association With Chronic Kidney Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this case report highlights an unusual association of Carpenter syndrome with
      chronic kidney disease
    explanation: >-
      The renal claim, described by its own authors as unusual and as needing further
      exploration.
notes: >-
  Entity scope, and why this is a separate entry. Carpenter syndrome has two genetic
  forms, and this entry covers CRPT1 (RAB23), the common one. The repository already
  holds `MEGF8-Related_Carpenter_Syndrome` for CRPT2, whose own description states that
  MEGF8 acts through BMP-SMAD while RAB23 acts through FGF-ERK, "which is why CRPT1 and
  CRPT2 are curated separately". This entry fills the other half of that split and keeps
  the two pathographs mechanistically distinguishable rather than converging them on
  generic craniosynostosis nodes.

  Where the evidence comes from, and its limits. The gene-disease relationship and the
  phenotype frequencies are human. The suture mechanism - FGF10-FGFR1-pERK1/2, the
  osteoprogenitor proliferation, and the rescue - is entirely from one mouse study, and
  is graded MODEL_ORGANISM throughout. That matters more here than usual because of the
  viability mismatch recorded in the discussions: the mouse used had to be engineered to
  survive past the stage at which the classical null dies, so it is a modified system at
  exactly the point where mouse and human diverge.

  The ciliary arm rests on better-distributed evidence than the suture arm. It has two
  identified cargoes from independent cell-biological studies, and a study built around
  this disease that tests three vertebrate systems in parallel including patient-derived
  iPSCs. The human-cell result is the one worth knowing: within the same patients, neurons
  lose cilia while fibroblasts merely have shorter ones. Sampling the accessible cell type
  would have understated the defect.

  Phenotype frequencies. Counted frequencies (38/39 for cutaneous syndactyly) come from
  the 2024 CRPT2 series, which tabulates the cumulative CRPT1 literature as its
  comparator. Where only "almost universal" or "common" is available, the band follows
  that wording and each evidence explanation says so.

  Module conformance. Three nodes declare `conforms_to`. The Hedgehog node conforms to
  `ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction`, which independently
  carries the same GO:0007224 binding with the same DYSREGULATED modifier and for the same
  reason - the module describes the lesion as perturbing GLI activator/repressor balance
  rather than as a one-way change. The limb node conforms to
  `limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity
  Specification`, matching the sibling MEGF8 entry, which conforms its equivalent node to
  the same target.

  The ciliary node conforms to `ciliopathy_dysfunction#Basal Body and Transition Zone
  Dysfunction`, and that one needs a word because it is not an obvious fit. The module
  node's own list of gene classes - basal body, transition zone, BBSome, IFT components -
  does not include RAB23, which is a trafficking GTPase and not a structural component of
  any of them. What matches is the lesion the module node actually describes: a
  structurally present but functionally incompetent cilium that cannot correctly
  compartmentalize signalling machinery, bound to GO:0061512. That is precisely what the
  Smoothened and Kif17 results show for RAB23, so this is a substitution at the level of
  the component rather than a mismatch of mechanism.

  Pathograph connectivity, and what the edges into obesity, cardiac defects and umbilical
  hernia do and do not claim. Every phenotype is reachable from the RAB23 variant node,
  but three of those edges are weaker than the rest and are marked
  INDIRECT_UNKNOWN_INTERMEDIATES for a reason that goes beyond missing detail: no cited
  source traces any step between Hedgehog signalling and adiposity, cardiac morphology or
  umbilical closure in this disorder. What licenses the edges is that these are cardinal
  features of a syndrome whose cause is that pathway lesion - the same standard already
  applied to cryptorchidism. Read them as "belongs to this disease's malformation
  complex", not as "caused through this node by a known route".

  Obesity is the most pointed of the three. The gene-discovery paper offered RAB23 as "a
  new molecular target for studies of obesity", and on this literature that invitation has
  not been taken up: no metabolic or hypothalamic measurement in a RAB23 patient is
  reported anywhere in the sources cited here. The edge records the proposal, in the
  authors' own deliberately weak phrasing, and nothing more.

  Cardiac defects have one suggestive route rather than none: laterality defects are
  reported in RAB23 patients, and left-right patterning is Hedgehog- and Nodal-dependent.
  That is also the discriminator against MEGF8-related CRPT2, where laterality defects are
  frequent rather than rare.

  On whether obesity belongs on the ciliary node instead. The module this entry now
  conforms to has a node - `Hypothalamic Ciliary Signaling and Metabolic Dysfunction` -
  that is a properly specified route from a ciliary lesion to obesity, via leptin receptor
  trafficking in hypothalamic neurons. It is the mechanism Bardet-Biedl syndrome uses, and
  this entry does quote a study concluding that Carpenter syndrome is a ciliopathy. So the
  question is fair. The edge is nonetheless left on the Hedgehog node, because that is
  where the only citation puts it: the gene-discovery paper proposed the Hedgehog
  connection, and nothing in this literature reports a hypothalamic, leptin or metabolic
  measurement in a RAB23 patient. Moving the edge would swap a weakly cited attribution
  for an uncited but better-sounding one, which is the worse trade. If someone measures
  leptin signalling in these patients, the ciliary node is where the edge should go.

  Facies. Now curated as depressed nasal bridge, low-set ears and proptosis. An earlier
  version of this note declined to curate them, on the stated ground that "the only source
  in this entry that describes the face is a single case report". That was wrong, and
  wrong in a way worth recording: PMID:23599695 was already cached and already cited twice
  here, and its full text carries a disease-level statement of the facies plus two
  siblings examined individually. The survey behind the decision had missed a source the
  entry was already using, which is a worse failure than the omission it justified.

  Only proptosis has a nameable intermediate - shallow orbits following the altered
  calvarial growth - so it hangs off the osteogenic node. The nasal bridge and the ears
  sit with the rest of the malformation complex, on the pathway node with unknown
  intermediates.

  Terms where the specific one was wrong or absent. The corneal finding is bound to
  HP:0000481 Abnormal cornea morphology, not to HP:0007957 Corneal opacity: the source
  says "corneal anomaly" and nothing more, and the narrower term would assert an opacity
  nobody reported. That identifier came from the deep-research report's phenotype table,
  whose own Term Validation section had flagged the label as inconsistent - a third
  provider identifier defect after the wrong MONDO and HGNC IDs, and the quietest of the
  three, since this one is a real term for a real concept that is simply narrower than
  the claim.

  In the other direction, the craniofacial surgery treatment keeps the generic NCIT:C15329
  Surgical Procedure deliberately. NCIT has no term for suture release or fronto-orbital
  advancement, and NCIT:C15214 Craniotomy is a different operation. Recorded so the
  question is not re-raised.

  GeneReviews. There is no chapter for this disorder, so there is no `references:` block
  and nothing to tag. Searched `RAB23[TI] GeneReviews[TI]`, `Carpenter syndrome AND
  GeneReviews[book]` and `RAB23 AND GeneReviews[book]`, all zero. The craniosynostosis
  chapters that do exist are FGFR-related - Apert, Crouzon, Pfeiffer, Muenke and an FGFR
  Craniosynostosis Syndromes Overview - and none covers the RAB23 entity. Recorded so the
  search is not repeated.

  Not asserted. No mechanism is claimed for the adipose phenotype at any level. No
  clinical trials, datasets or disease-modifying treatment are recorded, because none is
  reported in this literature.
  The pERK1/2 inhibition result is deliberately curated as a model rescue rather than as
  a treatment: it is a prophylactic mouse experiment with no human counterpart.
datasets: []

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Entity scope, and why this is a separate entry. Carpenter syndrome has two genetic forms, and this entry covers CRPT1 (RAB23), the common one. The repository already holds `MEGF8-Related_Carpenter_Syndrome` for CRPT2, whose own description states that MEGF8 acts through BMP-SMAD while RAB23 acts through FGF-ERK, "which is why CRPT1 and CRPT2 are curated separately". This entry fills the other half of that split and keeps the two pathographs mechanistically distinguishable rather than converging them on generic craniosynostosis nodes. Where the evidence comes from, and its limits. The gene-disease relationship and the phenotype frequencies are human. The suture mechanism - FGF10-FGFR1-pERK1/2, the osteoprogenitor proliferation, and the rescue - is entirely from one mouse study, and is graded MODEL_ORGANISM throughout. That matters more here than usual because of the viability mismatch recorded in the discussions: the mouse used had to be engineered to survive past the stage at which the classical null dies, so it is a modified system at exactly the point where mouse and human diverge. The ciliary arm rests on better-distributed evidence than the suture arm. It has two identified cargoes from independent cell-biological studies, and a study built around this disease that tests three vertebrate systems in parallel including patient-derived iPSCs. The human-cell result is the one worth knowing: within the same patients, neurons lose cilia while fibroblasts merely have shorter ones. Sampling the accessible cell type would have understated the defect. Phenotype frequencies. Counted frequencies (38/39 for cutaneous syndactyly) come from the 2024 CRPT2 series, which tabulates the cumulative CRPT1 literature as its comparator. Where only "almost universal" or "common" is available, the band follows that wording and each evidence explanation says so. Module conformance. Three nodes declare `conforms_to`. The Hedgehog node conforms to `ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction`, which independently carries the same GO:0007224 binding with the same DYSREGULATED modifier and for the same reason - the module describes the lesion as perturbing GLI activator/repressor balance rather than as a one-way change. The limb node conforms to `limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity Specification`, matching the sibling MEGF8 entry, which conforms its equivalent node to the same target. The ciliary node conforms to `ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction`, and that one needs a word because it is not an obvious fit. The module node's own list of gene classes - basal body, transition zone, BBSome, IFT components - does not include RAB23, which is a trafficking GTPase and not a structural component of any of them. What matches is the lesion the module node actually describes: a structurally present but functionally incompetent cilium that cannot correctly compartmentalize signalling machinery, bound to GO:0061512. That is precisely what the Smoothened and Kif17 results show for RAB23, so this is a substitution at the level of the component rather than a mismatch of mechanism. Pathograph connectivity, and what the edges into obesity, cardiac defects and umbilical hernia do and do not claim. Every phenotype is reachable from the RAB23 variant node, but three of those edges are weaker than the rest and are marked INDIRECT_UNKNOWN_INTERMEDIATES for a reason that goes beyond missing detail: no cited source traces any step between Hedgehog signalling and adiposity, cardiac morphology or umbilical closure in this disorder. What licenses the edges is that these are cardinal features of a syndrome whose cause is that pathway lesion - the same standard already applied to cryptorchidism. Read them as "belongs to this disease's malformation complex", not as "caused through this node by a known route". Obesity is the most pointed of the three. The gene-discovery paper offered RAB23 as "a new molecular target for studies of obesity", and on this literature that invitation has not been taken up: no metabolic or hypothalamic measurement in a RAB23 patient is reported anywhere in the sources cited here. The edge records the proposal, in the authors' own deliberately weak phrasing, and nothing more. Cardiac defects have one suggestive route rather than none: laterality defects are reported in RAB23 patients, and left-right patterning is Hedgehog- and Nodal-dependent. That is also the discriminator against MEGF8-related CRPT2, where laterality defects are frequent rather than rare. On whether obesity belongs on the ciliary node instead. The module this entry now conforms to has a node - `Hypothalamic Ciliary Signaling and Metabolic Dysfunction` - that is a properly specified route from a ciliary lesion to obesity, via leptin receptor trafficking in hypothalamic neurons. It is the mechanism Bardet-Biedl syndrome uses, and this entry does quote a study concluding that Carpenter syndrome is a ciliopathy. So the question is fair. The edge is nonetheless left on the Hedgehog node, because that is where the only citation puts it: the gene-discovery paper proposed the Hedgehog connection, and nothing in this literature reports a hypothalamic, leptin or metabolic measurement in a RAB23 patient. Moving the edge would swap a weakly cited attribution for an uncited but better-sounding one, which is the worse trade. If someone measures leptin signalling in these patients, the ciliary node is where the edge should go. Facies. Now curated as depressed nasal bridge, low-set ears and proptosis. An earlier version of this note declined to curate them, on the stated ground that "the only source in this entry that describes the face is a single case report". That was wrong, and wrong in a way worth recording: PMID:23599695 was already cached and already cited twice here, and its full text carries a disease-level statement of the facies plus two siblings examined individually. The survey behind the decision had missed a source the entry was already using, which is a worse failure than the omission it justified. Only proptosis has a nameable intermediate - shallow orbits following the altered calvarial growth - so it hangs off the osteogenic node. The nasal bridge and the ears sit with the rest of the malformation complex, on the pathway node with unknown intermediates. Terms where the specific one was wrong or absent. The corneal finding is bound to HP:0000481 Abnormal cornea morphology, not to HP:0007957 Corneal opacity: the source says "corneal anomaly" and nothing more, and the narrower term would assert an opacity nobody reported. That identifier came from the deep-research report's phenotype table, whose own Term Validation section had flagged the label as inconsistent - a third provider identifier defect after the wrong MONDO and HGNC IDs, and the quietest of the three, since this one is a real term for a real concept that is simply narrower than the claim. In the other direction, the craniofacial surgery treatment keeps the generic NCIT:C15329 Surgical Procedure deliberately. NCIT has no term for suture release or fronto-orbital advancement, and NCIT:C15214 Craniotomy is a different operation. Recorded so the question is not re-raised. GeneReviews. There is no chapter for this disorder, so there is no `references:` block and nothing to tag. Searched `RAB23[TI] GeneReviews[TI]`, `Carpenter syndrome AND GeneReviews[book]` and `RAB23 AND GeneReviews[book]`, all zero. The craniosynostosis chapters that do exist are FGFR-related - Apert, Crouzon, Pfeiffer, Muenke and an FGFR Craniosynostosis Syndromes Overview - and none covers the RAB23 entity. Recorded so the search is not repeated. Not asserted. No mechanism is claimed for the adipose phenotype at any level. No clinical trials, datasets or disease-modifying treatment are recorded, because none is reported in this literature. The pERK1/2 inhibition result is deliberately curated as a model rescue rather than as a treatment: it is a prophylactic mouse experiment with no human counterpart.

Review round 2: corneal term rebound, facies curated after a false rationale, VP shunt added · 2026-09-01T19:12:25Z · View source

Addressed the round-2 review on PR #10415. All four round-1 findings were confirmed closed by the reviewer; three new findings were raised and all three were correct. Finding 1 (corneal term too specific). My error, and the description made it worse by asserting the wrong thing about the ontology: it called HP:0007957 Corneal opacity 'the general corneal-opacity term'. It is not general - HP:0000481 Abnormal cornea morphology is its parent. The source says 'corneal anomaly (2/4)' and nothing more, so the narrower term asserted an opacity nobody reported. Rebound to HP:0000481, phenotype renamed to Corneal anomaly, downstream edge target updated, description corrected. The identifier came from the deep-research report's phenotype table, whose own Term Validation section had flagged the label as inconsistent - a third provider identifier defect after the invented MONDO and HGNC IDs, and the quietest kind, since this one is a real term for a real concept that is merely narrower than the claim. Finding 2 (facies rationale factually wrong). The reviewer was right and this was the substantive finding. The notes block declined to curate the characteristic facies on the ground that 'the only source in this entry that describes the face is a single case report giving hypertelorism, exorbitism'. PMID:23599695 was already cached and already cited twice in this entry, and its full text carries a disease-level statement ('Facial abnormalities include flat nasal bridge, broad cheeks and malformed and unevenly set ears') plus two siblings examined individually, each with depressed nasal bridge and low-set ears. The survey behind the scoping decision had missed a source the entry was already using. Curated Depressed nasal bridge (HP:0005280), Low-set ears (HP:0000369) and Proptosis (HP:0000520), all wired into the pathograph; the note now records what the evidence actually is and that the earlier rationale was wrong. Finding 3 (generic cardiac surgery term). Rebound from NCIT:C15329 Surgical Procedure to NCIT:C157806 Cardiac Surgery, which is reachable from NCIT:C25218 and is what the rest of the KB uses. Also recorded in notes that the craniofacial surgery treatment keeps the generic term deliberately, since NCIT has no suture-release or fronto-orbital-advancement term and Craniotomy is a different operation. One correction to the review, made by reading the same source: the reviewer stated that VP shunt and orchidopexy are 'verified absent from all 21 cached refs' and that declining to curate them was correct. The VP shunt is not absent. PMID:23599695 says one of the two siblings 'had dilatation of the lateral ventricles which required a ventriculo-peritoneal shunt'. Added Ventriculoperitoneal shunt (NCIT:C168483) as a treatment targeting Hydrocephalus, and cited the same paper on the Hydrocephalus phenotype as a second independent family. The sibling pair is itself informative - same allele, one child shunted and one not - and is curated as such. Orchidopexy does remain unquotable in the cached set. Proptosis is the one craniofacial feature with a nameable intermediate (shallow orbits following altered calvarial growth), so it hangs off the osteogenic node with INDIRECT_KNOWN_INTERMEDIATES rather than off the pathway node with the rest of the facies. Validation: 133/133 snippets verified (up from 122), 17 phenotypes with 0 orphans (up from 14), 21 cited PMIDs, all offline gates clean.

Create: RAB23-related Carpenter syndrome (CRPT1) · 2026-09-01T17:29:29Z · View source

New disease entry for RAB23-related Carpenter syndrome (CRPT1, MONDO:0008710), curated from the primary literature with one openscientist deep-research report used for leads. Mechanism as curated: biallelic RAB23 loss of function reaches the phenotype by two routes that the entry keeps separate - impaired ciliary protein trafficking, and elevated FGF10-FGFR1-ERK signalling in the cranial suture. Three distinct molecular routes to the loss of function are curated (nonsense-mediated decay of truncating transcripts; loss of the C-terminal prenylatable cysteine in a late frameshift; switch-II distortion in the Y79del in-frame allele), together with the absence of any reported genotype-phenotype correlation that licenses treating them as one functional lesion. Two findings are curated against the simple account. First, the ciliary defect is cell-type conditional: a conditional knockout mouse, patient-derived iPSCs and zebrafish morphants show cilia disturbed in chondrocytes, fibroblasts, neural progenitors and neocortical neurons but not in epithelial cells, cerebellar granule cells or hippocampal neurons, and within the same patients neurons lose cilia while fibroblasts merely have shorter ones. Second, the direction of the Hedgehog effect is not a single sign: RAB23 depletion lowers ciliary Smoothened and RAB23-null neural progenitors are desensitized to Hedgehog, both of which are reduced output rather than de-repression. The reconciliation curated here is the dual-function account, in which RAB23 both represses basal pathway activity and facilitates cilium-dependent activation by ligand - both measured in one cell population, so losing RAB23 raises the floor and lowers the ceiling. The pathway modifier is DYSREGULATED on that reading rather than as a hedge, the contrary results are curated as REFUTE items on the node, and an open-question discussion records what keeps it unsettled: the dual-function result is one study in cerebellar granule cells, a cell type a second study reports as having no ciliary abnormality, and no Hedgehog measurement of either kind exists in a Carpenter suture or limb bud. Sections: 6 pathophysiology nodes, 10 phenotypes (all reachable from the variant node), 6 variants, prevalence including the one-in-a-million birth estimate, one experimental model (patient iPSC neural lineage), four animal models, craniofacial surgical management with operative-planning hazards, clinical and prenatal diagnosis entries, and four discussions including a HUMAN_MODEL_MISMATCH for the mouse/human viability difference. Deliberately not curated: overgrowth with advanced bone age, epileptiform EEG, autistic features and chronic kidney disease, each proposed on a single case; held as an open knowledge gap instead. Provider defect found and corrected: the report carried MONDO:0008544 for this disease, which is tetramelic monodactyly. This is the third invented MONDO ID in three reports launched with an empty mondo_id variable (issue #9888); it is the most dangerous of the three because a limb-malformation term looks plausible beside a polysyndactyly syndrome. The report also gave HGNC:9776 for RAB23; the entry uses hgnc:14263. Validation: 109/109 snippets verified against cached references, schema and term validation pass, all offline gates clean, 21 cited PMIDs (of 22 cached; the one left unused is a Trypanosoma flagellar Rab23 paper), no orphan phenotypes.

OpenScientist ▸

RAB23-related Carpenter Syndrome (CRPT1): Comprehensive Disease Characterization Report

openscientist-autonomous 23 citations 2026-09-01T16:42:44.973147

RAB23-related Carpenter Syndrome (CRPT1): Comprehensive Disease Characterization Report

Summary

RAB23-related Carpenter syndrome (Carpenter syndrome type 1, CRPT1; historically acrocephalopolysyndactyly type II; OMIM #201000; ORPHA:65759; MONDO:0008544) is an ultra-rare autosomal-recessive multiple-congenital-malformation disorder with an estimated prevalence of roughly 1 in 1,000,000 births. It is caused by biallelic loss-of-function variants in RAB23 (gene OMIM *606144; HGNC:9776; NCBI Gene 51715; UniProt Q9ULC3; chromosome 6p11.2), which encodes a small RAB-family GTPase that functions as a negative regulator of Hedgehog (HH) signaling and a regulator of ciliary membrane trafficking. When RAB23 function is lost, ciliary Smoothened turnover is impaired and downstream GLI-mediated transcription and FGF10–ERK signaling are de-repressed, and primary-cilium formation is perturbed in a cell-type–dependent manner. The convergent developmental consequence is the near-universal clinical dyad of multisuture craniosynostosis and preaxial polysyndactyly, accompanied by frequent obesity, congenital heart disease, cryptorchidism/hypogenitalism, umbilical hernia, and variable (~75%) intellectual impairment.

The molecular pathology is a classic recessive loss-of-function paradigm: most pathogenic alleles are truncating and subject to nonsense-mediated decay (NMD), and even in-frame or missense lesions (e.g., Y79del, disrupting the switch-II region; or C-terminal frameshifts that abolish the prenylatable cysteine) converge on loss of RAB23 activity. A recurrent L145X founder mutation in patients of northern European descent illustrates the population genetics of the disorder. A clinically overlapping but genetically distinct subtype, CRPT2 (OMIM #614976), is caused by biallelic MEGF8 variants and is distinguished by frequent left–right patterning defects and predominantly single-midline-suture synostosis.

Management is entirely symptomatic and reconstructive. Early cranial-vault expansion / fronto-orbital advancement (ideally within 6–12 months of life, and urgently in the setting of raised intracranial pressure) is the cornerstone, complemented by cardiac surgery, hand/foot reconstruction, orchidopexy, and multidisciplinary developmental support. No disease-modifying pharmacotherapy or gene therapy exists. Prognosis is variable and multisystem; intellectual outcome correlates with the presence of cerebral malformations and untreated raised intracranial pressure rather than being invariable, and affected individuals can survive to adulthood and pregnancy.

Key Findings

Finding 1 — RAB23 biallelic loss-of-function is the cause of CRPT1

Carpenter syndrome type 1 is caused by biallelic loss-of-function mutations in RAB23. The gene was identified by homozygosity mapping across 15 independent families, which linked disease to chromosome 6p12.1–q12 and identified five distinct RAB23 mutations (four truncating and one missense). RAB23 encodes a member of the RAB guanosine-triphosphatase (GTPase) family of vesicle-transport proteins and functions as a negative regulator of Hedgehog signaling. The loss-of-function mechanism is reinforced at the transcript level: truncating mutations produce mRNAs that are degraded by nonsense-mediated decay (NMD), an important contributor to pathogenesis. [human clinical / in vitro]

"we found linkage to chromosome 6p12.1-q12 and, in 15 independent families, identified five different mutations (four truncating and one missense) in RAB23, which encodes a member of the RAB guanosine triphosphatase (GTPase) family of vesicle transport proteins and acts as a negative regulator of hedgehog (HH) signaling" — PMID: 17503333
"We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations." — PMID: 21412941

Ontology anchors: gene RAB23 (HGNC:9776); GO:0007224 (smoothened signaling pathway); GO:0045879 (negative regulation of smoothened signaling pathway).

Finding 2 — Core phenotype: multisuture craniosynostosis + polysyndactyly, with frequent obesity, cardiac defects, and cryptorchidism

Multisuture craniosynostosis and polysyndactyly are present in essentially all molecularly confirmed patients described to date, and abnormal external genitalia (cryptorchidism) are universal in affected boys. The cardinal clinical picture — historically termed acrocephalopolysyndactyly — comprises craniosynostosis, short fingers, soft-tissue syndactyly, preaxial polydactyly, congenital heart disease, hypogenitalism, obesity, and umbilical hernia. As many as three-fourths of patients have some degree of intellectual impairment. No genotype–phenotype correlations are apparent. [human clinical]

"Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys." — PMID: 21412941
"Acrocephalopolysyndactyly or Carpenter syndrome consists of craniosynostosis, short fingers, soft tissue syndactyly, preaxial polydactyly, congenital heart disease, hypogenitalism, obesity, and umbilical hernia. As many as three-fourths of the patients have some degree of intellectual impairment." — PMID: 8352858

Suggested HPO terms: HP:0001363 (Craniosynostosis); HP:0004440 (Coronal craniosynostosis); HP:0100259 (Polysyndactyly); HP:0100258 (Preaxial polydactyly); HP:0001159 (Syndactyly); HP:0001513 (Obesity); HP:0001627 (Abnormal heart morphology); HP:0000028 (Cryptorchidism); HP:0001537 (Umbilical hernia); HP:0001249 (Intellectual disability).

Finding 3 — Recurrent L145X founder mutation; MEGF8 defines the distinct CRPT2 subtype

Among reported patients, 10 individuals were homozygous for the same nonsense mutation, L145X, on a common haplotype, indicating a founder effect in patients of northern European descent. Separately, a clinically overlapping but genetically distinct disorder — CRPT2 — is caused by biallelic MEGF8 variants and is frequently associated with abnormal left-right patterning (situs inversus, dextrocardia, transposition of the great arteries). Laterality defects occur in nearly half of MEGF8 cases but are rare in RAB23 cases, providing a clinically useful discriminator. [human clinical]

"In 10 patients, the disease was caused by homozygosity for the same nonsense mutation, L145X, that resides on a common haplotype, indicative of a founder effect in patients of northern European descent." — PMID: 17503333
"we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning" — PMID: 23063620

Additional recurrent/founder-type alleles reported include c.82C>T p.(Arg28*) (first molecularly confirmed continental-African case, Tanzania; PMID: 33368989) and c.86dupA in a Comorian family (PMID: 20358613).

Finding 4 — RAB23 coordinates suture osteogenesis by repressing FGF-ERK and GLI1; loss causes a context-dependent ciliopathy

In mouse calvarial models, RAB23 is active in osteoblasts at the osteogenic front and regulates both Hedgehog and FGF pathways, repressing FGF10–pERK1/2 and GLI1 during early osteogenesis. Across three independent vertebrate systems — Rab23 conditional-knockout mice, Carpenter-syndrome patient-derived iPSCs, and zebrafish morphants — RAB23 loss recapitulates CS/ciliopathy features and consistently perturbs primary-cilium formation, but in a cell-type–dependent (context-dependent) manner (affecting chondrocytes, mouse embryonic fibroblasts, neural progenitors, and neocortical neurons differently). [model organism / iPSC]

"RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1" — PMID: 32662771
"all three different vertebrate mutant models consistently show a perturbation of primary cilia formation, intriguingly, in a context-dependent manner" — PMID: 40825043

Suggested GO terms: GO:0060348 (bone development); GO:0001503 (ossification); GO:0060271 (cilium assembly); GO:0070848 (response to growth factor).

Finding 5 — RAB23 controls ciliary Smoothened turnover and Kif17 trafficking

Mechanistically, depletion of Rab23 or expression of dominant-negative Rab23 decreases the ciliary steady-state level specifically of Smoothened (but not of control ciliary proteins EB1 or Kim1), implicating RAB23 in protein turnover within the cilium. RAB23 also exists in a complex with the kinesin-2 motor Kif17 and importin β2, and ciliary localization of Kif17 is disrupted in Rab23-depleted cells. RAB23 is enriched at the primary cilium. Together these establish the physical basis by which RAB23 loss dysregulates the ciliary Hedgehog signal-transduction apparatus. [in vitro]

"Depletion of Rab23 or expression of dominant-negative Rab23 decreased the ciliary steady state specifically of Smoothened but not EB1 or Kim1, suggesting a role of Rab23 in protein turnover in the cilium." — PMID: 20375059
"ciliary localization of the kinesin-2 motor protein Kif17 was disrupted in Rab23-depleted cells" — PMID: 26136363

Suggested GO terms: GO:0005929 (cilium); GO:0060170 (ciliary membrane); GO:0042073 (intraciliary transport).

Finding 6 — Structural basis of loss of function: switch-II disruption and loss of prenylation

High-resolution crystal structures of human RAB23 (wild-type and the Y79del clinical mutant, bound to GDP and to the non-hydrolyzable GTP analog GMPPNP) demonstrate that the Y79 deletion causes structural distortions in the switch-II region relative to wild type, potentially disrupting binding to interacting partners and thereby producing loss of function. Clinical point mutations M12K, C85R, and Y79del all fall within the GTPase domain. A second, orthogonal loss-of-function mechanism arises from truncating frameshift variants (e.g., p.Val161Leufs) that remove the C-terminal prenylatable cysteine, so that the truncated protein fails to undergo the lipid modification required to associate with target membranes. [computational/structural / in vitro]

"the Y79 deletion mutant exhibited structural distortions in the switch II region relative to that of the WT. The structural changes potentially disrupted the binding of Rab23 Y79del to its interacting partners, thus leading to a loss-of-function and the development of Carpenter syndrome" — PMID: 39615683
"Due to the loss of the C-terminally prenylatable cysteine residue, the truncated protein will probably fail to associate with the target cellular membranes due to the absence of the necessary lipid modification." — PMID: 23599695

Suggested GO terms: GO:0003924 (GTPase activity); GO:0005525 (GTP binding); GO:0018344 (protein geranylgeranylation).

Finding 7 — Ultra-rare autosomal recessive disorder; model organisms

Carpenter syndrome has an estimated prevalence of ~1 in a million births. Disease models that recapitulate CS features include Rab23 conditional-knockout mice, CS patient-derived iPSCs, and zebrafish morphants. The spontaneous mouse mutant "open brain" (opb) carries a homozygous Rab23 mutation and shows embryonic lethality with open neural-tube defects — a notable species difference, since human RAB23-null homozygosity is not lethal, indicating a divergent early-developmental requirement. RAB23 also regulates Nodal expression in the left lateral plate mesoderm and Kupffer's vesicle, contributing to left–right patterning. [human clinical / model organism]

"This syndrome's rarity, with an estimated prevalence of one in a million births" — PMID: 39040725
"the embryonic lethality and open neural tube phenotype of a spontaneous mouse mutant that carries homozygous mutation of open brain, a gene encoding Rab23" — PMID: 29727300
"including Rab23 conditional knockout (CKO) mouse mutants, CS patient-derived induced pluripotent stem cells (iPSCs), and zebrafish morphants" — PMID: 40825043

Finding 8 — Management is multidisciplinary and reconstructive

Management is centered on early surgical release of the fused sutures with fronto-orbital advancement, clearly indicated particularly in cases of elevated intracranial pressure. Early correction of craniofacial deformity is usually safe within 6 to 12 months of life; operative planning uses 3D CT because venous drainage abnormalities and ectatic emissary veins can cause significant intraoperative bleeding. Advanced techniques include cranial-vault remodeling and monobloc distraction osteogenesis. Cardiac defects (e.g., Tetralogy of Fallot) require surgical correction, and treated patients can survive to adulthood and successful pregnancy. No CS-specific pharmacotherapy or gene therapy exists; care is supportive and reconstructive. [human clinical]

"early release of craniosynostoses with fronto-orbital advancement is clearly indicated in the CS literature, particularly in cases of elevated intracranial pressure" — PMID: 25162549
"Early correction of craniofacial deformity in Carpenter's syndrome is usually safe within 6 to 12 months. Venous drainage abnormalities and ectatic emissary veins can lead to significant bleeding" — PMID: 34244844

Suggested NCIT terms: cranial-vault remodeling / fronto-orbital advancement; distraction osteogenesis (NCIT:C92968); cardiac surgical correction; orchidopexy; rehabilitation therapy.

Finding 9 — Lifelong multisystem morbidity; intellectual outcome is variable, not invariable

Although up to three-fourths of patients show some degree of intellectual impairment, mental retardation is not an invariable feature; the most severe developmental delay is associated with cerebral malformations demonstrable on MRI/CT, so neuroradiologic examination can help predict intellectual outcome. Characteristic craniofacial features include marked absence/underdevelopment of the anterior cranial fossa with bulging of the middle cranial fossa, and there is no correlation between the degree of craniofacial dysmorphology and brain dysmorphology. Congenital and progressive residual cardiac defects contribute to morbidity, and an atypical case associated chronic kidney disease with CS. The phenotypic spectrum has been expanded to include overgrowth with advanced bone age, epileptogenic EEG changes, and autistic features. [human clinical]

"Because mental retardation is not an invariable feature of this syndrome or other craniosynostosis syndromes, neuroradiologic examination may help in predicting the intellectual outcome in these patients." — PMID: 8352858
"overgrowth with advanced bone age, epileptogenic changes on electroencephalogram and autistic features" — PMID: 34748996

Finding 10 — Identifiers and nosology

RAB23-related Carpenter syndrome = CRPT1 / acrocephalopolysyndactyly type II, OMIM #201000, caused by RAB23 (gene OMIM 606144; HGNC:9776; NCBI Gene 51715; UniProt Q9ULC3; chromosome 6p11.2). A second locus, MEGF8 (CRPT2, OMIM #614976), causes a subtype with substantial clinical overlap but frequent laterality defects and typically single-midline-suture synostosis, whereas RAB23-CRPT1 shows multi-suture craniosynostosis. Orphanet ORPHA:65759; MONDO:0008544. [human clinical]*

"Craniosynostosis in CRPT2 commonly involves a single midline suture in comparison to the multi-suture craniosynostosis characteristic of CRPT1." — PMID: 38760421
"mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning" — PMID: 23063620

Mechanistic Model / Interpretation

The unifying interpretation is that RAB23 is a ciliary "brake" on morphogen signaling. Under normal conditions, RAB23 at the primary cilium promotes turnover of Smoothened and correct trafficking of ciliary motors (Kif17), thereby keeping Hedgehog/GLI output — and, in cranial osteoblasts, FGF10–ERK output — appropriately low. Removing this brake (through NMD-mediated protein loss, switch-II GTPase-cycle disruption, or loss of prenylation-dependent membrane targeting) de-represses these pathways. Because different tissues rely on cilium-dependent signaling to different degrees, RAB23 loss manifests as a context-dependent ciliopathy: strongest and most consistent in the developing skull (multisuture synostosis) and limb (polysyndactyly), with variable CNS, cardiac, and metabolic consequences.

Ordered causal chain (initiating lesion → clinical manifestation):

Biallelic RAB23 loss-of-function variant (truncating → NMD; or switch-II/prenylation-disrupting) results in absent/non-functional RAB23 GTPase protein. (Demonstrated.)
Loss of RAB23 at the primary cilium leads to failure of normal ciliary protein turnover — specifically dysregulated ciliary Smoothened and disrupted Kif17 motor trafficking. (Demonstrated in vitro.)
Dysregulated ciliary Smoothened results in de-repression of Hedgehog (GLI-mediated) signaling; in parallel, RAB23 loss de-represses FGF10–pERK1/2 signaling at the cranial osteogenic front. (Demonstrated in calvarial models.)
Branch A (skull): De-repressed HH/GLI1 + FGF-ERK in cranial osteoblasts leads to premature/accelerated osteogenic differentiation and multisuture craniosynostosis. (Demonstrated.)
Branch B (limb): Altered HH gradient in the limb bud results in preaxial polydactyly/polysyndactyly. (Inferred from HH-pathway biology and model phenotypes.)
Branch C (CNS/cardiac/other): Context-dependent perturbation of primary-cilium formation and Nodal regulation leads to cerebral malformations, variable intellectual impairment, cardiac defects, and (rarely) laterality anomalies. (Partly demonstrated, partly inferred.)

 RAB23 biallelic LOF (NMD / switch-II / no prenylation)
 │
 ▼
   Loss of ciliary RAB23 function
(dysregulated Smoothened turnover, ↓Kif17 trafficking)
 │
┌────────┴─────────┐
▼                  ▼
 De-repressed HH/GLI1   De-repressed FGF10–pERK1/2
│                  │
└────────┬─────────┘
 ▼
   Aberrant osteogenic & patterning programs
│           │            │
▼           ▼            ▼
  Multisuture   Preaxial     Cilium-dependent
 craniosynostosis polysyndactyly CNS/cardiac defects

This model explains the near-universal core dyad, the variable expressivity, the correlation of cognitive outcome with cerebral malformation, and the absence of genotype–phenotype correlation (all pathogenic alleles converge on the same loss-of-function endpoint). It also clarifies why the closely related CRPT2 (MEGF8) shares the craniosynostosis/limb phenotype yet reaches it through a distinct, largely Hedgehog-independent BMPR1A–BMP-SMAD route and adds laterality defects (PMID: 42399640).

Section-by-Section Report

1. Disease Information

Overview. RAB23-related Carpenter syndrome is a rare autosomal-recessive syndromic craniosynostosis (an "acrocephalopolysyndactyly") defined by the co-occurrence of multisuture craniosynostosis and polysyndactyly with a constellation of additional malformations (obesity, congenital heart disease, hypogenitalism, umbilical hernia, and frequently intellectual impairment).

Key identifiers.

Resource	Identifier
OMIM (disease, CRPT1)	#201000
OMIM (gene)	*606144 (RAB23)
Orphanet	ORPHA:65759
MONDO	MONDO:0008544
HGNC	HGNC:9776 (RAB23)
NCBI Gene	51715
Ensembl	ENSG00000112210
UniProt	Q9ULC3
Cytoband	6p11.2
ICD-10	Q87.0 / Q75.x
SNOMED CT	21086008 (Acrocephalopolysyndactyly)
MeSH	Acrocephalopolysyndactyly

Synonyms: Carpenter syndrome; Carpenter syndrome type 1 (CRPT1); acrocephalopolysyndactyly type II (ACPS II); ACPS2.

Data source type: Information is derived from aggregated disease-level resources (OMIM, Orphanet) and from individual patient reports/case series in the primary literature; the disorder is too rare for EHR-scale cohorts.

2. Etiology

Causal factor: purely genetic — biallelic loss-of-function variants in RAB23 (Finding 1). There is no known environmental, infectious, or toxic contribution to CRPT1.

Genetic risk factors: The disease requires two pathogenic RAB23 alleles; heterozygous carriers are unaffected. A founder L145X allele elevates carrier frequency in populations of northern European descent (Finding 3); other recurrent alleles (p.Arg28*, c.86dupA) occur in specific pedigrees/populations. Consanguinity substantially raises risk owing to autosomal-recessive inheritance (multiple reported families are consanguineous). Genetic heterogeneity exists at the disease level: MEGF8 causes CRPT2.

Environmental / lifestyle / protective factors / gene–environment interactions: None established. No environmental risk factors, protective genetic or environmental factors, or gene–environment interactions have been demonstrated for this Mendelian disorder. (Not applicable / not available.)

3. Phenotypes

Onset is congenital; features are structural. Frequencies are qualitative given small cohorts.

Phenotype	Type	Frequency	HPO term
Multisuture craniosynostosis (often bicoronal + sagittal + metopic; cloverleaf/turricephaly)	Physical/skeletal	Near-universal (~100%)	HP:0001363 / HP:0002676
Polysyndactyly (preaxial polydactyly, cutaneous syndactyly, brachydactyly)	Physical/skeletal	Near-universal (~100%)	HP:0100259 / HP:0100258 / HP:0001159
Cryptorchidism / abnormal genitalia (males)	Physical	Universal in boys	HP:0000028
Obesity	Physical/metabolic	Frequent	HP:0001513
Congenital heart disease (ASD, VSD, PDA, ToF, TGA)	Clinical sign	Frequent (~30–50%)	HP:0001627
Intellectual disability / developmental delay	Behavioral/cognitive	~75% (variable)	HP:0001249
Umbilical hernia	Physical	Frequent	HP:0001537
Characteristic facies (flat nasal bridge, hypertelorism, low-set ears)	Physical	Frequent	HP:0000316 / HP:0005280
Genu valgum / short stature / skeletal dysplasia	Physical/skeletal	Variable	HP:0002857 / HP:0004322
Hydrocephalus / cerebral malformations	Clinical sign	Occasional	HP:0000238 / HP:0002011
Corneal/ophthalmic anomalies	Clinical sign	Occasional	HP:0007957
Atypical: overgrowth/advanced bone age, seizures, autistic features	Various	Rare	HP:0001548 / HP:0001250 / HP:0000729

Onset: congenital (some prenatally detectable). Severity/progression: structural anomalies are static in origin but craniosynostosis can drive progressive raised intracranial pressure; cardiac lesions may progress. Variable expressivity, including intrafamilial (PMID: 20358613). Quality of life: substantial and lifelong (reconstructive-surgery burden, motor/orthopedic complications, cardiac limitation, cognitive outcome); no CS-specific validated QoL instrument data exist.

4. Genetic / Molecular Information

Causal gene: RAB23 (6p11.2), ~237-aa small GTPase, 6 coding exons. Variant spectrum: predominantly truncating (nonsense, frameshift, splice-site) with occasional missense/in-frame deletions; ≥12 distinct mutations across dozens of families. Classification: biallelic pathogenic/likely-pathogenic per ACMG/AMP (PVS1 for null alleles; segregation; functional evidence). Functional consequence: loss of function via (i) NMD of truncating transcripts, (ii) switch-II structural disruption (Y79del), and (iii) loss of C-terminal prenylation/membrane targeting (Findings 1, 6). Allele frequency: pathogenic alleles are extremely rare in gnomAD. Origin: germline. Modifier genes / epigenetics / large chromosomal abnormalities: none established for CRPT1 (karyotype typically normal).

Representative variants: L145X (founder, N. European); p.Arg28* (Tanzania); c.86dupA (Comoros); c.481G>C p.Val161Leufs*16 (exon-6 skipping, prenylation loss); M12K, C85R, Y79del (GTPase-domain).

5. Environmental Information

Not applicable. CRPT1 is a monogenic disorder with no established environmental, lifestyle, or infectious contributors. (Obesity, once present, is a genetically driven feature that may be modifiable by diet/lifestyle as supportive care, but is not an environmental cause.)

6. Mechanism / Pathophysiology

See the "Mechanistic Model / Interpretation" section above for the full ordered causal chain and diagram.

Molecular pathways: Sonic Hedgehog/GLI (primary; de-repressed), FGF10–ERK1/2 (MAPK), Nodal/left–right patterning. (CRPT2/MEGF8: BMP–SMAD.) KEGG: Hedgehog (hsa04340); MAPK (hsa04010); Reactome: Signaling by Hedgehog.
Cellular processes: ciliogenesis and intraciliary transport; osteoblast differentiation/ossification; cell proliferation (e.g., cerebellar granule-cell precursors — Hedgehog de-repression links to medulloblastoma biology, PMID: 34210780).
Protein dysfunction: loss of GTPase cycling (switch-II) and loss of membrane targeting (prenylation).
Subcellular compartments: primary cilium/ciliary membrane, basal body, Golgi-derived vesicles, plasma membrane.
Immune/metabolic: no primary immune involvement; obesity implicates Hedgehog's role in adipogenesis/energy balance.
GO terms: GO:0007224; GO:0045879; GO:0060271; GO:0042073; GO:0003924; GO:0018342; GO:0001503; GO:0007368. CL terms: osteoblast CL:0000062; chondrocyte CL:0000138; neural progenitor CL:0011020; fibroblast CL:0000057; adipocyte CL:0000136.
Molecular profiling (omics): No large transcriptomic/proteomic/metabolomic patient datasets exist for this ultra-rare disease; mechanistic data derive from targeted mouse/zebrafish/iPSC assays.

7. Anatomical Structures Affected

Organ/system level: skeletal (cranial sutures/skull UBERON:0004339; digits UBERON:0002544; long bones); cardiovascular (heart UBERON:0000948); nervous system/brain (UBERON:0000955 — anterior cranial fossa hypoplasia, bulging middle fossa, hydrocephalus); reproductive (testis UBERON:0000473 — cryptorchidism); abdominal wall (umbilical hernia); renal (rare CKD, PMID: 39040725); visual (cornea/eye UBERON:0000970); endocrine/metabolic (adiposity).
Tissue level: bone (UBERON:0001474), cartilage (UBERON:0002418), nervous tissue, cardiac muscle.
Cell level: osteoblasts, chondrocytes, cardiomyocytes, neural progenitors/neurons, adipocytes.
Subcellular level: primary cilium (GO:0005929), ciliary membrane (GO:0060170), basal body (GO:0036064), plasma membrane.
Lateralization: craniofacial/acral involvement is bilateral (often asymmetric); situs/laterality defects are asymmetric and rare in CRPT1.

8. Temporal Development

Onset: congenital; malformations form during embryogenesis and are evident at birth (some prenatally detectable — abnormal skull shape, bowed femora, cardiac defect; PMID: 25168863).
Onset pattern: structural/insidious (developmental), not acute.
Progression: underlying malformations are static in origin, but secondary processes are progressive (raised ICP from skull growth against fused sutures; progression of residual cardiac lesions, PMID: 23706836; worsening obesity/orthopedic problems). Chronic, lifelong; no spontaneous remission.
Critical period: first 6–12 months of life for cranial-vault surgery to protect brain growth and vision.

9. Inheritance and Population

Epidemiology: ultra-rare; prevalence ~1 in 1,000,000 births (~0.1 per 100,000); incidence not precisely quantified; <~100 molecularly confirmed cases.
Inheritance: autosomal recessive (OMIM #201000).
Penetrance: effectively complete for the core dyad in biallelic-null genotypes.
Expressivity: variable, including intrafamilial; no genotype–phenotype correlation.
Genetic anticipation / germline mosaicism: not features of this disorder; recurrence risk follows standard AR 25%.
Founder effects: L145X (northern European); other recurrent alleles in specific populations (Comoros, Tanzania, Arabian Peninsula).
Consanguinity: strong contributor.
Carrier frequency: low overall; elevated in consanguineous/founder populations.
Demographics: reported worldwide; no strong sex bias in occurrence (male-specific genital findings emphasized); diagnosed in infancy/childhood.

10. Diagnostics

Clinical/imaging: recognition of the craniosynostosis + polysyndactyly gestalt; 3D CT of the skull (suture fusion, cranial-fossa morphology, venous/emissary-vein assessment for operative planning); brain MRI (cerebral malformations — prognostic); echocardiography; skeletal survey. Prenatal ultrasound/fetal CT may show abnormal skull shape, bowed femora, cardiac defect.
Laboratory/biomarkers: no specific biochemical biomarker or enzyme assay; diagnosis is molecular.
Genetic testing (definitive): single-gene RAB23 sequencing (6 coding exons); craniosynostosis gene panels including RAB23 and MEGF8; WES for atypical presentations/second locus; WGS for deep-intronic/structural variants; chromosomal microarray/karyotype mainly to exclude mimics; RNA/splicing analysis to prove pathogenicity of splice variants.
Diagnostic criteria: no formal consensus criteria; characteristic phenotype + biallelic RAB23 variants.
Differential diagnosis: Apert, Pfeiffer, Crouzon, Saethre–Chotzen, Muenke (FGFR/TWIST-related, usually dominant); Greig cephalopolysyndactyly (GLI3); Bardet–Biedl and other ciliopathies; other ACPS variants; and MEGF8-related CRPT2 (laterality/situs defects, usually single-midline-suture synostosis).
Screening: no population newborn screening; cascade/carrier testing and prenatal/preimplantation genetic testing once familial variants are known.

11. Outcome / Prognosis

Survival/mortality: no formal survival statistics; life expectancy is often near-normal with successful surgical management, and patients can reach adulthood and pregnancy. Early mortality risk relates chiefly to severe congenital heart disease, airway compromise, and raised-ICP complications.
Morbidity/function: significant lifelong morbidity — variable cognitive impairment (up to ~75%), visual/airway issues, repeated craniofacial/orthopedic/cardiac surgeries, mobility limitation from hand/foot anomalies.
Complications: raised intracranial pressure, hydrocephalus, operative bleeding from ectatic emissary veins, progressive cardiac disease, obesity-related sequelae, rare CKD.
Prognostic factors: presence/absence of cerebral malformation on imaging (predicts cognitive outcome), severity/timeliness of craniosynostosis correction, cardiac disease severity. No molecular prognostic biomarker; no genotype–phenotype correlation.
QoL measures: no disease-specific validated instruments reported.

12. Treatment

No disease-modifying, pharmacologic, gene, cell, or RNA therapy exists. Management is symptomatic, reconstructive, and multidisciplinary.

Surgical/interventional (mainstay): cranial vault expansion / fronto-orbital advancement (first 6–12 months, esp. with raised ICP); monobloc/midface distraction osteogenesis (NCIT:C92968); hand/foot reconstruction; cardiac surgery; orchidopexy; umbilical hernia repair; orthopedic correction of genu valgum/scoliosis; VP shunt for hydrocephalus.
Supportive/rehabilitative: ophthalmology, airway/sleep management, audiology, developmental/physical/occupational/speech therapy, special education, dietary/lifestyle management of obesity.
Pharmacotherapy/pharmacogenomics: none specific/applicable.
Experimental/targeted: none in clinical use. Mechanistically, SMO inhibitors rescue Hh-dependent limb defects and BMP type-I receptor inhibition rescues MEGF8-driven craniosynostosis in models (PMID: 42399640) — proof-of-concept only. No registered interventional trials specific to RAB23 Carpenter syndrome.
Treatment strategy: individualized, staged surgical algorithm prioritizing ICP relief and airway/cardiac stabilization, then facial/skeletal reconstruction and developmental support.

13. Prevention

Primary prevention: not possible; risk reduction centers on genetic counseling for at-risk (especially consanguineous) couples and carrier relatives.
Secondary prevention: prenatal diagnosis when a familial variant is known (or ultrasound suspicion); early postnatal craniofacial/cardiac evaluation and timely surgery.
Tertiary prevention: surveillance/management of raised ICP, cardiac, visual, airway, orthopedic, and metabolic complications.
Genetic screening: cascade carrier testing, PGT-M, and prenatal testing once variants are identified.
Immunization / public-health / environmental interventions: not applicable.

14. Other Species / Natural Disease

Taxonomy of models: Mus musculus (NCBI:txid10090), Danio rerio (NCBI:txid7955).
Orthologous genes: mouse Rab23 (NCBI Gene 19334; classic "open brain," opb allele); zebrafish rab23. RAB23 is conserved across metazoans and even present in flagellated protists such as Trypanosoma brucei (correlating with cilia/flagella; PMID: 21676215).
Natural disease in animals: no well-characterized spontaneous naturally occurring companion-animal/wildlife "Carpenter syndrome" is documented; the mouse opb mutant is a spontaneous laboratory mutation. Veterinary relevance is primarily as research models.
Comparative biology: disease mechanisms (Hedgehog antagonism, ciliary trafficking, left–right patterning) are highly conserved; a key species difference is that homozygous Rab23 null is embryonic-lethal (open neural tube) in mice but viable in humans.
Transmission: not applicable (non-communicable genetic disease; no zoonotic potential).

15. Model Organisms

Model	Type	Key features / recapitulation	Reference
"Open brain" (opb) mouse	Spontaneous mammalian mutant	Open neural-tube defect, embryonic lethal (more severe than human); established Rab23 as Shh antagonist	PMID: 29727300
Rab23 conditional-KO mouse	Genetic (conditional)	Best mammalian model; skeletal/chondrocyte/neural CS features; context-dependent cilia defects	PMID: 40825043
Calvarial/osteoblast explant	Ex vivo	RAB23 represses FGF10-pERK1/2 & GLI1 in osteogenesis	PMID: 32662771
CS patient-derived iPSCs	In vitro human	Perturbed cilium formation, context-dependent	PMID: 40825043
Zebrafish morphants	Vertebrate	Ciliopathy/patterning defects; Nodal/laterality	PMID: 40825043
MDCK/knockdown cells; recombinant RAB23	In vitro / structural	Ciliary Smoothened/Kif17 trafficking; crystal structures (WT, Y79del)	PMID: 20375059, PMID: 26136363, PMID: 39615683

Phenotype recapitulation & limitations: models reproduce craniofacial/skeletal defects, ciliary dysfunction, and Hedgehog/Nodal dysregulation, but no single model captures the full human multisystem spectrum; the mouse null's lethality and species-specific developmental requirements limit direct translation. Resources: MGI (mouse), ZFIN (zebrafish), IMPC/KOMP, Cellosaurus (iPSC lines), PDB (RAB23 structures).

Evidence Base

PMID	Contribution	Role
17503333	Gene discovery; RAB23 as HH negative regulator; L145X founder	Foundational — supports F1, F3
21412941	NMD of truncating alleles; universal core features	Supports F1, F2
8352858	Clinical spectrum; cerebral malformation predicts cognition	Supports F2, F9
23063620	MEGF8/CRPT2 with laterality defects	Supports F3, F10
32662771	RAB23 represses FGF10-pERK1/2 and GLI1 in osteogenesis	Supports F4
40825043	Context-dependent ciliopathy across 3 models	Supports F4, F7
20375059	RAB23 regulates ciliary Smoothened turnover	Supports F5
26136363	RAB23–Kif17 ciliary trafficking	Supports F5
39615683	Crystal structure; Y79del disrupts switch-II	Supports F6
23599695	Loss of prenylatable cysteine → membrane-targeting failure	Supports F6
39040725	Prevalence ~1/1,000,000; CKD association	Supports F7, F9
29727300	Open brain mouse; species difference	Supports F7
25162549	FOA indicated, esp. raised ICP	Supports F8
34244844	Surgical timing 6–12 mo; bleeding risk	Supports F8
34748996	Expanded phenotype/mutations	Supports F9
38760421	CRPT1 multi-suture vs CRPT2 single-midline	Supports F10
42399640	MEGF8 BMP-SMAD mechanism (contrast to RAB23-FGF-ERK)	Mechanistic contrast
25168863	Prenatal findings; novel splice variant	Supports Diagnostics
20358613	Comorian family; intrafamilial variability	Supports Inheritance
33368989	First continental-African case (R28X)	Supports Population
23706836	Adult survival/pregnancy; cardiac progression	Supports Prognosis

Consistency: No contradictory findings were encountered. All ten confirmed findings are mutually reinforcing, spanning human genetics, structural biology, cell biology, and clinical management. The one apparent tension — mouse null lethality vs. viable human null — is explicitly reconciled as a species-specific developmental requirement.

Limitations and Knowledge Gaps

Rarity limits epidemiology and outcomes data: no robust prevalence/incidence by region, no survival curves, and no validated CS-specific quality-of-life data.
Genotype–phenotype: no correlations identified; the basis of variable expressivity (including within families) is unexplained — possible modifier genes/epigenetics remain uncharacterized.
Mechanistic gaps: the precise molecular partners disrupted by the switch-II lesion, and the tissue-specific determinants of the "context-dependent" cilium phenotype, are not fully defined. The link from ciliary Smoothened dysregulation to the specific (preaxial) limb pattern is inferred.
No therapeutics pipeline: absence of pharmacologic pathway-modulation (e.g., SMO inhibitor) data for CRPT1, in contrast to emerging pathway-specific rescue concepts in CRPT2 models.
Population coverage: most molecular data derive from European and a handful of African/Middle-Eastern pedigrees; the global variant landscape is incompletely sampled.

Proposed Follow-up Experiments / Actions

Assemble an international CRPT1 registry to quantify phenotype frequencies, natural history, raised-ICP incidence, and neurodevelopmental outcomes with denominators.
Systematic RAB23 variant curation (ClinVar/gnomAD reconciliation) with functional assays (GTPase cycling, ciliary Smoothened turnover, membrane association) to standardize ACMG classification and probe genotype–phenotype signals.
Test pathway-targeted rescue in Rab23-CKO mice and patient iPSC-derived cranial mesenchyme: SMO/GLI antagonists and FGF-ERK inhibitors, benchmarking against BMP-receptor-inhibition rescue reported for MEGF8/CRPT2.
Single-cell and spatial transcriptomics of cranial sutures in Rab23 models to map cell-type-specific de-repression of HH and FGF programs and identify the "context" determining the cilium phenotype.
Prospective neuroimaging-outcome study to validate MRI/CT cerebral-malformation findings as a quantitative prognostic biomarker for intellectual outcome.
Search for modifier loci/epigenetic marks underlying intrafamilial variability using trio/family designs.

Report compiled from 10 confirmed findings across 33 reviewed papers over 5 investigation iterations. Evidence types: human clinical (case series/reports), model organism (mouse, zebrafish), in vitro (iPSC, cell lines), and computational/structural (crystallography). Frequencies are approximate given the ultra-rare nature of the disorder; no large-scale omics, QoL, or survival datasets currently exist for CRPT1.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	23
Resolved	23
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	23
On topic	17
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	53
Resolved	51
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	27
Terms named correctly	15
Terms named as a different term	9
Terms whose name is worth a second look	3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0008544 (3 mentions) - the report calls it "MONDO"; MONDO calls it tetramelic monodactyly
HP:0001513 (2 mentions) - the report calls it "Obesity", "Frequent"; HP calls it Obesity
HP:0001627 (2 mentions) - the report calls it "Abnormal heart morphology", "Frequent (~30–50%)"; HP calls it Abnormal heart morphology
HP:0000028 (2 mentions) - the report calls it "Cryptorchidism", "Universal in boys"; HP calls it Cryptorchidism
HP:0001537 (2 mentions) - the report calls it "Umbilical hernia", "Frequent"; HP calls it Umbilical hernia
HP:0001249 (2 mentions) - the report calls it "Intellectual disability", "~75% (variable)"; HP calls it Intellectual disability
HP:0007957 (1 mention) - the report calls it "Occasional"; HP calls it Corneal opacity
UBERON:0000955 (1 mention) - the report calls it "anterior cranial fossa hypoplasia, bulging middle fossa, hydrocephalus"; UBERON calls it brain
UBERON:0001474 (1 mention) - the report calls it "Tissue level: bone"; UBERON calls it bone element**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0100259 (2 mentions) - the report calls it "Polysyndactyly"; HP calls it Postaxial polydactyly
GO:0005929 (2 mentions) - the report calls it "cilium", "Subcellular level: primary cilium"; GO calls it cilium**, and lists "primary cilium" among its other names
UBERON:0000473 (1 mention) - the report calls it "cryptorchidism"; UBERON calls it testis, and lists "orchis" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0001513 - called "Obesity", "Frequent"
HP:0001627 - called "Abnormal heart morphology", "Frequent (~30–50%)"
HP:0000028 - called "Cryptorchidism", "Universal in boys"
HP:0001537 - called "Umbilical hernia", "Frequent"
HP:0001249 - called "Intellectual disability", "~75% (variable)"
GO:0005929 - called "cilium", "Subcellular level:** primary cilium"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

Deep Research

RAB23-related Carpenter Syndrome (CRPT1): Comprehensive Disease Characterization Report

Summary

Key Findings

Finding 1 — RAB23 biallelic loss-of-function is the cause of CRPT1

Finding 2 — Core phenotype: multisuture craniosynostosis + polysyndactyly, with frequent obesity, cardiac defects, and cryptorchidism

Finding 3 — Recurrent L145X founder mutation; MEGF8 defines the distinct CRPT2 subtype

Finding 4 — RAB23 coordinates suture osteogenesis by repressing FGF-ERK and GLI1; loss causes a context-dependent ciliopathy

Finding 5 — RAB23 controls ciliary Smoothened turnover and Kif17 trafficking

Finding 6 — Structural basis of loss of function: switch-II disruption and loss of prenylation

Finding 7 — Ultra-rare autosomal recessive disorder; model organisms

Finding 8 — Management is multidisciplinary and reconstructive

Finding 9 — Lifelong multisystem morbidity; intellectual outcome is variable, not invariable

Finding 10 — Identifiers and nosology

Mechanistic Model / Interpretation

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver