Filippi Syndrome

Mendelian MONDO:0010092 Pathograph 9 Show in embeddings browser multiple congenital anomalies/dysmorphic syndrome-intellectual disability disorder of development or morphogenesis hereditary disease syndactyly

Filippi syndrome (craniodigital syndrome; OMIM 272440) is an ultra-rare autosomal recessive multiple-congenital-anomaly disorder caused by biallelic loss-of-function variants in CKAP2L, which encodes cytoskeleton-associated protein 2-like. The clinical core is craniodigital: cutaneous syndactyly of the fingers and toes, microcephaly, pre- and postnatal growth failure, a distinctive facies (broad nasal bridge, underdeveloped alae nasi, micrognathia), and variable intellectual disability. CKAP2L is the human ortholog of mouse Radmis (radial fiber and mitotic spindle), a microtubule-associated protein enriched in neural stem/progenitor cells that localizes to the mitotic spindle, spindle poles, centrosome, and the radial fibers of dividing radial glia. Patient cells lose CKAP2L from the spindle poles and show multipolar, disorganized spindles with chromosome missegregation, placing the disorder in the neural-progenitor centrosome-spindle family of microcephalies. A 2026 knockout-mouse and cell-biology study extended CKAP2L's role to negative regulation of primary cilium length and proposed reclassifying Filippi syndrome as a "centrosomopathy" with concurrent proliferation and ciliary defects; the same study found that Ckap2l-null mice do not reproduce the human developmental phenotype, which is curated here as an explicit human/model mismatch rather than smoothed over. Management is supportive and symptom-directed.

Ask OpenScientist

Ask a research question about Filippi Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Mappings
1
Inheritance
8
Pathophys.
19
Phenotypes
2
Hypotheses
4
Gaps
9
Pathograph
1
Genes
5
Medical Actions
9
References
🔗

Mappings

MONDO
MONDO:0010092 Filippi syndrome
skos:exactMatch MONDO
MONDO:0010092 is the exact disease concept (xrefs OMIM:272440, Orphanet:3255) and records CKAP2L (HGNC:26877) as the causal gene via RO:0004003, matching the gene curated in this entry.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
All molecularly confirmed families reported to date carry biallelic CKAP2L variants, most often homozygous frameshift alleles in consanguineous pedigrees, with two families reported as compound heterozygotes.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:25439729 SUPPORT Human Clinical
"Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi."
The gene-discovery paper states the recessive mode of inheritance and the core craniodigital phenotype.
PMID:34921061 SUPPORT Human Clinical
"All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine), and all but one have been homozygous for a pathogenic variant."
Documents that the recessive allelic spectrum is dominated by homozygous loss-of-function variants, with compound heterozygosity the exception.
◈

Mechanistic Hypotheses

2
Mitotic spindle / progenitor proliferation deficit model
mitotic_proliferation_deficit_model CANONICAL
Evidence balance 1 support
The established model: CKAP2L is a spindle-pole microtubule-associated protein required for bipolar spindle assembly and mitotic progression, and its biallelic loss produces multipolar spindles, chromosome missegregation, and cytokinesis failure. In the neural stem/progenitor compartment where the protein is enriched, this depletes the cortical progenitor pool and yields microcephaly; the same proliferation deficit is invoked, less directly, for the growth failure and craniodigital features.
Pathograph links
Biallelic CKAP2L Loss of Function -> Mitotic Spindle Disorganization and Cytokinesis Failure Loss of CKAP2L from the spindle poles removes a microtubule-associated regulator required for bipolar spindle assembly and mitotic progression.
Mitotic Spindle Disorganization and Cytokinesis Failure -> Neural Progenitor Division Failure Spindle disorganization is most consequential in the rapidly dividing neural stem/progenitor compartment where CKAP2L is enriched.
Mitotic Spindle Disorganization and Cytokinesis Failure -> Impaired Craniofacial and Digital Morphogenesis Proliferation failure in other embryonic progenitor fields is the proposed route to the craniofacial and autopod anomalies, though the tissue-level steps are not established.
Mitotic Spindle Disorganization and Cytokinesis Failure -> Pre- and Postnatal Growth Failure A generalized mitotic proliferation deficit is the proposed basis for symmetric intrauterine and postnatal growth restriction.
Neural Progenitor Division Failure -> Cortical Progenitor Pool Depletion Failed or misoriented progenitor divisions reduce the number of progenitors available to generate cortical neurons.
Cortical Progenitor Pool Depletion -> Reduced Cortical Neuron Output and Postnatal Microcephaly A smaller progenitor pool yields fewer cortical neurons and a smaller brain, expressed clinically as microcephaly.
Show evidence (1 reference)
PMID:25439729 SUPPORT Human Clinical
"Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome."
Establishes CKAP2L loss of function as the principal disease mechanism.
Centrosomopathy model (concurrent proliferation and ciliary defects)
centrosomopathy_ciliary_model EMERGING
Evidence balance 1 support
A 2026 proposal that Filippi syndrome should be reclassified as a centrosomopathy in which CKAP2L loss simultaneously impairs mitosis and de-represses primary cilium elongation, with ciliary signalling contributing to the non-neural (craniofacial, digital, and possibly renal) features. The ciliary-length data are from human and mouse cell lines only; no patient tissue or clinical correlate has yet been reported, and the strongest in vivo test to date (the Ckap2l knockout mouse) produced no developmental phenotype at all.
Pathograph links
Biallelic CKAP2L Loss of Function -> Primary Cilium Elongation Loss of CKAP2L from the ciliary basal body removes a negative regulator of primary cilium length.
Primary Cilium Elongation -> Impaired Craniofacial and Digital Morphogenesis Proposed contribution of disturbed ciliary signalling to the craniofacial and digit phenotype, by analogy with established ciliopathies. Not demonstrated in Filippi syndrome patients.
Show evidence (1 reference)
PMID:41370039 SUPPORT In Vitro
"these findings position CKAP2L as a multifunctional regulator of microtubule-based organelles and suggest that Filippi syndrome can be classified as a 'centrosomopathy' arising from concurrent defects in cell proliferation and ciliary function."
The source of the emerging reclassification, stated by its authors as a suggestion rather than a demonstrated disease mechanism.
?

Discussions and Knowledge Gaps

4
Why does a constitutive Ckap2l knockout mouse show no overt developmental abnormality — no microcephaly, no growth failure, no digit anomaly — when biallelic human CKAP2L loss of function causes a multiple-congenital-anomaly syndrome?
HUMAN MODEL MISMATCH OPEN mismatch_ckap2l_knockout_mouse_lacks_human_phenotype
Attached to
pathophysiology#Neural Progenitor Division Failure pathophysiology#Cortical Progenitor Pool Depletion pathophysiology#Reduced Cortical Neuron Output and Postnatal Microcephaly
This is the sharpest open problem in the disorder's mechanism. The canonical model attributes human microcephaly to CKAP2L-dependent neural progenitor division, and the mouse ortholog radmis was the source of that model — yet the 2026 constitutive knockout produced only reduced male fertility with abnormally elongated sperm flagella, not the human developmental phenotype. Candidate explanations that would change how the mechanism should be curated include: (1) mouse-specific paralog redundancy (e.g. CKAP2) that human progenitors lack; (2) a human-specific requirement in outer radial glia and the OSVZ, the compartment responsible for primate cortical expansion and absent from lissencephalic mouse cortex — the same argument already recorded for other progenitor microcephalies in this KB; or (3) that the human phenotype does not in fact arise from the progenitor-proliferation arm at all. Until this is resolved, the mouse data support the cellular spindle phenotype but do not license the inference from spindle defect to human microcephaly.
Proposed experiments
CKAP2L-null human cortical organoid phenotyping
human iPSC-derived organoid disease modeling Relation: this experiment is of type this experiment type This experiment is of type human iPSC-derived organoid disease modeling.
exp_ckap2l_human_cortical_organoid
Generate CKAP2L-null and patient-variant human iPSC-derived cortical organoids alongside isogenic controls and quantify apical and basal progenitor number, outer-radial-glia abundance, spindle orientation, and organoid size across corticogenesis.
Decision criterion
The progenitor arm is supported for human biology if CKAP2L-null organoids show reduced progenitor number and organoid size relative to isogenic controls; a null result would argue that the mouse-based progenitor model does not explain the human phenotype.
Ckap2l/Ckap2 paralog-redundancy test in mouse cortex
mouse compound-knockout genetic interaction study Relation: this experiment is of type this experiment type This experiment is of type mouse compound-knockout genetic interaction study.
exp_ckap2l_ckap2_paralog_redundancy
Compare Ckap2l single-knockout with Ckap2l;Ckap2 double-knockout mouse cortex for progenitor depletion, spindle phenotype, and brain size.
Decision criterion
Paralog redundancy explains the absent single-knockout phenotype if the double knockout, but not the single knockout, reproduces progenitor depletion and reduced brain size.
Spindle phenotype in primary human neural progenitors
primary human cell immunofluorescence assay Relation: this experiment is of type this experiment type This experiment is of type primary human cell immunofluorescence assay.
exp_ckap2l_primary_human_progenitor_spindle
Assay primary human fetal neural progenitors, or patient-derived cells differentiated to a progenitor state, for the multipolar-spindle and cytokinesis-failure phenotypes described in lymphoblastoid cells.
Decision criterion
The cellular defect is relevant to the disease-affected cell type if multipolar spindles and cytokinesis failure are reproduced in human neural progenitors, not only in lymphoblastoid lines.
Show evidence (1 reference)
PMID:41370039 SUPPORT Model Organism
"Ckap2l knockout mice show no overt developmental abnormalities, with the exception of reduced male fertility, evidenced by decreased sperm count, impaired motility, and abnormally elongated flagella."
Documents the failure of the constitutive mouse knockout to reproduce the human developmental phenotype — the mismatch itself.
By what tissue-level route does loss of a mitotic spindle protein produce cutaneous syndactyly of the fingers and toes — failure of interdigital programmed cell death, or a proliferation deficit in the autopod mesenchyme?
KNOWLEDGE GAP OPEN gap_syndactyly_mechanism_from_spindle_defect
Attached to
pathophysiology#Impaired Craniofacial and Digital Morphogenesis
Digit separation depends on interdigital apoptosis, not on progenitor proliferation, so the canonical proliferation-deficit model does not obviously explain the digital half of the craniodigital phenotype. No published experiment connects CKAP2L to interdigital cell death or to the SHH/GLI3/HOXD patterning gradients that drive the limb/digit serial-homology module. This is why this entry declares conformance to the neural-progenitor centrosome-spindle module for the microcephaly arm but deliberately declines to declare conformance to limb_digit_patterning_serial_homology for the syndactyly arm, despite the phenotype being serially homologous across hands and feet. Resolving the route would either license that second conformance or establish a distinct apoptosis-based mechanism.
Proposed experiments
Interdigital apoptosis versus proliferation in the autopod
conditional-knockout developmental histology study Relation: this experiment is of type this experiment type This experiment is of type conditional-knockout developmental histology study.
exp_ckap2l_interdigital_apoptosis
Examine autopod interdigital regions in a conditional limb-mesenchyme Ckap2l knockout (or an alternative model that expresses the digital phenotype) for reduced apoptosis versus reduced proliferation, using TUNEL/cleaved-caspase and mitotic-index staining at the embryonic stages of digit separation.
Decision criterion
Syndactyly is apoptosis-driven if interdigital TUNEL/cleaved-caspase signal is reduced with a preserved mitotic index, and proliferation-driven if the mitotic index falls with preserved interdigital cell death.
Hedgehog/GLI3-repressor output in CKAP2L-deficient limb mesenchyme
signalling-pathway readout assay Relation: this experiment is of type this experiment type This experiment is of type signalling-pathway readout assay.
exp_ckap2l_hedgehog_gli3_limb_output
Test whether CKAP2L loss perturbs Hedgehog pathway activity and the GLI3-repressor gradient in limb mesenchyme, by transcriptional readout of Hedgehog target genes and GLI3 processing assays.
Decision criterion
Conformance to the limb/digit patterning module would become appropriate if CKAP2L loss measurably shifts GLI3 processing or Hedgehog target-gene output in limb mesenchyme.
Should Filippi syndrome be reclassified as a centrosomopathy/ciliopathy, and is there a clinical correlate of the ciliary-length defect in patients?
EMERGING HYPOTHESIS OPEN gap_centrosomopathy_reclassification_clinical_correlate
Attached to
pathophysiology#Primary Cilium Elongation pathophysiology#Impaired Craniofacial and Digital Morphogenesis
The reclassification proposal rests on cell-line data showing elongated primary cilia after CKAP2L depletion. The clinical spectrum contains two features that are suggestive of a ciliopathy — renal cysts and renal hypoplasia, reported in three families in 2024 — but the two observations have never been connected in the same patients, and syndactyly plus microcephaly are not by themselves ciliopathy-specific. If the link holds, conformance to ciliopathy_dysfunction (and possibly renal_cystogenesis) would become appropriate; on current evidence it would be premature.
Proposed experiments
Cilium length and Hedgehog competence in patient fibroblasts
patient-derived primary fibroblast assay Relation: this experiment is of type this experiment type This experiment is of type patient-derived primary fibroblast assay.
exp_ckap2l_patient_fibroblast_cilium_length
Measure primary cilium length and Hedgehog-response competence in fibroblasts derived from individuals carrying biallelic CKAP2L variants, alongside isogenic or unaffected-relative controls.
Decision criterion
The centrosomopathy model gains patient-level support if biallelic-variant fibroblasts show significantly elongated cilia and blunted Hedgehog response relative to controls.
Systematic renal imaging in molecularly confirmed patients
cross-sectional clinical imaging study Relation: this experiment is of type this experiment type This experiment is of type cross-sectional clinical imaging study.
exp_ckap2l_systematic_renal_imaging
Image the kidneys of all reported and newly ascertained CKAP2L-confirmed patients to establish whether renal cysts and hypoplasia are recurrent rather than incidental.
Decision criterion
Renal involvement belongs in the core spectrum, and supports a ciliopathy reading, if cysts or hypoplasia are found in a substantial fraction of molecularly confirmed patients rather than only the three index families.
Show evidence (1 reference)
PMID:38738944 SUPPORT Human Clinical
"Given the limited number of reported Filippi syndrome patients to date and the ongoing discovery of new clinical aspects of the disease, exploring its potential connection with kidney and skin pigmentation abnormalities could be valuable for future research."
The authors themselves frame the renal association as provisional and in need of further study, which is why it supports only an emerging hypothesis.
Is there a genotype-phenotype correlation in CKAP2L-related Filippi syndrome — in particular, do hypomorphic (missense) alleles explain the reported patients with milder neurodevelopmental outcome?
KNOWLEDGE GAP OPEN gap_genotype_phenotype_correlation_ckap2l
Attached to
pathophysiology#Reduced Cortical Neuron Output and Postnatal Microcephaly
Cognitive outcome ranges from severe intellectual disability with epilepsy to preserved intellect in an adolescent male, yet almost all reported alleles are frameshift and presumed complete loss of function, leaving the variability unexplained by allele class alone. The single reported missense allele has not been functionally characterized. With only 43 published patients — a mixture of molecularly confirmed and clinically diagnosed cases — the cohort is too small and too heterogeneous to support a correlation analysis, which the systematic review states explicitly.
Proposed experiments
CKAP2L patient registry for genotype-phenotype analysis
multicentre patient registry study Relation: this experiment is of type this experiment type This experiment is of type multicentre patient registry study.
exp_ckap2l_patient_registry_genotype_phenotype
Establish an international CKAP2L patient registry with standardized neurodevelopmental, growth, and imaging assessment, restricted to molecularly confirmed cases, to power a genotype-phenotype analysis.
Decision criterion
A genotype-phenotype correlation exists if allele class or residual function stratifies neurodevelopmental outcome across the registry cohort.
Functional characterization of the p.Arg689His missense allele
variant functional rescue assay Relation: this experiment is of type this experiment type This experiment is of type variant functional rescue assay.
exp_ckap2l_arg689his_functional_characterization
Assay the p.Arg689His variant for CKAP2L spindle-pole localization, microtubule binding, and rescue of the multipolar-spindle phenotype in CKAP2L-null cells.
Decision criterion
The allele is hypomorphic rather than null if it retains partial spindle-pole localization and partially rescues the spindle phenotype.
Show evidence (1 reference)
PMID:42404495 SUPPORT Human Clinical
"Further studies will be needed to delineate genotype-phenotype correlation and standardize treatment guidelines."
The systematic review states the genotype-phenotype gap as an explicit conclusion.
⚙

Pathophysiology

8
Biallelic CKAP2L Loss of Function
Biallelic loss-of-function variants in CKAP2L — most commonly homozygous frameshift alleles, with rarer canonical splice-site, start-codon, and (in one family) missense alleles in trans — abolish or destabilize cytoskeleton-associated protein 2-like. CKAP2L is a bona fide microtubule-associated protein that localizes to microtubule-based organelles: the centrosome, the mitotic spindle and its poles, and the ciliary basal body. In lymphoblastoid cell lines from individuals homozygous for the founding c.571dupA allele, CKAP2L is no longer detectable at the spindle poles, establishing loss of function at the level of protein localization rather than a dominant-negative or gain-of-function mechanism.
Centrosomopathy model (concurrent proliferation and ciliary defects) Mitotic spindle / progenitor proliferation deficit model
CKAP2L hgnc:26877 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CKAP2L (hgnc:26877). hgnc:26877 is a gene from the HUGO Gene Nomenclature Committee.
microtubule binding GO:0008017 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased microtubule binding (GO:0008017). GO:0008017 is a molecular function from the Gene Ontology. ↓ DECREASED
spindle pole GO:0000922 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves spindle pole (GO:0000922). GO:0000922 is a cellular component from the Gene Ontology. centrosome GO:0005813 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves centrosome (GO:0005813). GO:0005813 is a cellular component from the Gene Ontology. ciliary basal body GO:0036064 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary basal body (GO:0036064). GO:0036064 is a cellular component from the Gene Ontology.
Downstream
Mitotic Spindle Disorganization and Cytokinesis Failure Loss of CKAP2L from the spindle poles removes a microtubule-associated regulator required for bipolar spindle assembly and mitotic progression. Mitotic spindle / progenitor proliferation deficit model
Primary Cilium Elongation Loss of CKAP2L from the ciliary basal body removes a negative regulator of primary cilium length. Centrosomopathy model (concurrent proliferation and ciliary defects)
Show evidence (4 references)
PMID:25439729 SUPPORT Human Clinical
"identified a homozygous frameshift mutation, c.571dupA"
Identifies the founding biallelic CKAP2L frameshift allele by homozygosity mapping and exome sequencing in a Sardinian family.
PMID:25439729 SUPPORT In Vitro
"In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles."
Demonstrates loss of CKAP2L from the spindle poles in patient-derived dividing cells, the direct molecular consequence of the frameshift allele.
PMID:41370039 SUPPORT In Vitro
"CKAP2L is a bona fide microtubule-associated protein that localizes to microtubule-based organelles, including the centrosome, mitotic spindle, and ciliary basal body."
Establishes the subcellular localization set that defines which microtubule-based organelles are at risk when CKAP2L is lost.
+ 1 more reference
Mitotic Spindle Disorganization and Cytokinesis Failure
Without CKAP2L at the spindle poles, dividing cells assemble disorganized, multipolar, and shortened mitotic spindles. The downstream mitotic consequences are twofold: chromosome missegregation (including chromosome bridges between separating daughter nuclei in the mouse knockdown model) and outright cytokinesis failure producing multinucleated cells. This is the conserved centrosome/spindle perturbation node of the neural-progenitor module, instantiated here by a spindle-pole-associated MAP rather than by a centriole-duplication or microtubule-severing lesion.
Mitotic spindle / progenitor proliferation deficit model
patient-derived lymphoblastoid cell (dividing) CL:0000542 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves patient-derived lymphoblastoid cell (dividing), annotated with lymphocyte (CL:0000542). CL:0000542 is a cell type from the Cell Ontology.
mitotic spindle organization GO:0007052 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mitotic spindle organization (GO:0007052). GO:0007052 is a biological process from the Gene Ontology. ⚠ ABNORMAL chromosome segregation GO:0007059 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromosome segregation (GO:0007059). GO:0007059 is a biological process from the Gene Ontology. ⚠ ABNORMAL cytokinesis GO:0000910 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cytokinesis (GO:0000910). GO:0000910 is a biological process from the Gene Ontology. ↓ DECREASED
mitotic spindle GO:0072686 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitotic spindle (GO:0072686). GO:0072686 is a cellular component from the Gene Ontology.
Downstream
Neural Progenitor Division Failure Spindle disorganization is most consequential in the rapidly dividing neural stem/progenitor compartment where CKAP2L is enriched. Mitotic spindle / progenitor proliferation deficit model
Impaired Craniofacial and Digital Morphogenesis Proliferation failure in other embryonic progenitor fields is the proposed route to the craniofacial and autopod anomalies, though the tissue-level steps are not established. Mitotic spindle / progenitor proliferation deficit model
Pre- and Postnatal Growth Failure A generalized mitotic proliferation deficit is the proposed basis for symmetric intrauterine and postnatal growth restriction. Mitotic spindle / progenitor proliferation deficit model
Show evidence (3 references)
PMID:25439729 SUPPORT In Vitro
"in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation"
Direct patient-cell evidence for multipolar spindles and chromosome missegregation as the cellular phenotype of CKAP2L loss.
PMID:41370039 SUPPORT In Vitro
"Depletion of CKAP2L leads to shortened mitotic spindles and cytokinesis failure, resulting in multinucleation."
Adds cytokinesis failure and multinucleation to the mitotic phenotype, independently of the chromosome-segregation defect.
PMID:24260314 SUPPORT Model Organism
"radmis loss-of-function by shRNAs induced the multipolar mitotic spindle structure, accompanied with the catastrophe of chromosome segregation including the long chromosome bridge between two separating daughter nuclei"
Mouse knockdown reproduces the same multipolar-spindle and chromosome-segregation phenotype seen in human patient cells.
Neural Progenitor Division Failure
CKAP2L/radmis is enriched in neural stem/progenitor cells and, in the embryonic and perinatal brain, decorates both the bipolar mitotic spindle and the radial (basal) fiber of dividing radial glia — the two structures that set division geometry and daughter-cell fate during corticogenesis. Perturbing radmis dosage in vivo shifts progenitors out of cycle: forced expression reduced progenitor proliferation, increased cell-cycle exit, depleted the Tbr2-positive basal progenitor population, and shrank the embryonic subventricular zone. Loss of function disorganizes the same spindle. Both directions converge on failure of the normal proliferative/neurogenic division balance.
Mitotic spindle / progenitor proliferation deficit model
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology. radial glial cell CL:0000681 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves radial glial cell (CL:0000681). CL:0000681 is a cell type from the Cell Ontology.
neural precursor cell proliferation GO:0061351 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural precursor cell proliferation (GO:0061351). GO:0061351 is a biological process from the Gene Ontology. ↓ DECREASED mitotic spindle assembly GO:0090307 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mitotic spindle assembly (GO:0090307). GO:0090307 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Cortical Progenitor Pool Depletion Failed or misoriented progenitor divisions reduce the number of progenitors available to generate cortical neurons. Mitotic spindle / progenitor proliferation deficit model
Show evidence (3 references)
PMID:24260314 SUPPORT Model Organism
"In embryonic and perinatal brains, radmis localized to bipolar mitotic spindles and radial fibers (basal processes) of dividing NSPCs."
Places the protein at the spindle and radial fiber of dividing cortical progenitors, the structures that determine division geometry and fate.
PMID:24260314 SUPPORT Model Organism
"revealed that radmis directed a reduction in NSPC proliferation and a concomitant increase in cell cycle exit, causing a reduction in the Tbr2-positive basal progenitor population and shrinkage of the embryonic subventricular zone"
Partial rather than full support: this is an in utero electroporation gain-of-function experiment, so it shows that radmis dosage controls progenitor proliferation and cell-cycle exit, but does not by itself model the human loss-of-function allele.
PMID:25439729 SUPPORT Model Organism
"The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors."
The gene-discovery paper explicitly grounds the human disease mechanism in the neural-progenitor cell-division role of the mouse ortholog.
Cortical Progenitor Pool Depletion
Sustained failure of progenitor division during corticogenesis distorts the apical and basal progenitor pools. In the mouse model the measured readouts were loss of Tbr2-positive basal progenitors and shrinkage of the embryonic subventricular zone; the equivalent human tissue measurement has not been made, so this node is inferred for human disease from the cellular and mouse data plus the resulting head-circumference phenotype.
Mitotic spindle / progenitor proliferation deficit model
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
neural precursor cell proliferation GO:0061351 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural precursor cell proliferation (GO:0061351). GO:0061351 is a biological process from the Gene Ontology. ↓ DECREASED cell division GO:0051301 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell division (GO:0051301). GO:0051301 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Cortical Neuron Output and Postnatal Microcephaly A smaller progenitor pool yields fewer cortical neurons and a smaller brain, expressed clinically as microcephaly. Mitotic spindle / progenitor proliferation deficit model
Show evidence (1 reference)
PMID:24260314 SUPPORT Model Organism
"These findings uncover the indispensable role of radmis in mitotic spindle formation and cell-cycle progression of NSPCs."
Supports an indispensable requirement for the protein in progenitor cell-cycle progression, the process whose failure depletes the pool.
Reduced Cortical Neuron Output and Postnatal Microcephaly
The clinical endpoint of the progenitor arm is microcephaly with variable neurodevelopmental impairment — developmental delay, intellectual disability, speech impairment, and in some individuals epilepsy. Severity is notably variable across reported patients, extending to at least one adolescent with preserved intellect, so cognitive impairment should not be treated as obligate.
cortical neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cortical neuron, annotated with neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Show evidence (2 references)
PMID:25439729 SUPPORT Human Clinical
"Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities."
Documents the variable neurodevelopmental and extra-neural features accompanying microcephaly.
PMID:18553552 SUPPORT Human Clinical
"We report on a child with Filippi syndrome who shows syndactyly of fingers and toes, severe pre- and post-natal growth retardation, postnatal microcephaly, epilepsy, and severe mental retardation with speech impairment."
Clinical characterization establishing the postnatal (rather than congenital) evolution of the microcephaly alongside epilepsy and severe cognitive/speech impairment.
Primary Cilium Elongation
A second, more recently described arm: CKAP2L also localizes to the ciliary basal body and acts as a conserved negative regulator of primary cilium length, so its loss markedly lengthens cilia in both human and mouse cells. On this basis Filippi syndrome has been proposed to be a "centrosomopathy" in which proliferation and ciliary signalling defects act together. The arm is curated as an EMERGING hypothesis, not as established disease mechanism: no patient tissue has been shown to carry elongated cilia, and no ciliopathy-specific clinical feature has been causally tied to it.
Centrosomopathy model (concurrent proliferation and ciliary defects)
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
cilium assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology. ↕ DYSREGULATED
ciliary basal body GO:0036064 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary basal body (GO:0036064). GO:0036064 is a cellular component from the Gene Ontology.
Downstream
Impaired Craniofacial and Digital Morphogenesis Proposed contribution of disturbed ciliary signalling to the craniofacial and digit phenotype, by analogy with established ciliopathies. Not demonstrated in Filippi syndrome patients. Centrosomopathy model (concurrent proliferation and ciliary defects)
Show evidence (2 references)
PMID:41370039 SUPPORT In Vitro
"we uncover a conserved function for CKAP2L as a negative regulator of primary cilium length; its loss markedly increases ciliary length in both human and mouse cells."
Establishes the ciliary-length phenotype of CKAP2L loss in human and mouse cells, the empirical basis of the centrosomopathy proposal.
PMID:41370039 SUPPORT In Vitro
"these findings position CKAP2L as a multifunctional regulator of microtubule-based organelles and suggest that Filippi syndrome can be classified as a 'centrosomopathy' arising from concurrent defects in cell proliferation and ciliary function."
The centrosomopathy reclassification is offered by the authors as a suggestion drawn from cell-line data, not demonstrated in patient tissue, so it is recorded as partial support for an emerging model.
Impaired Craniofacial and Digital Morphogenesis
The craniodigital arm of the disorder: cutaneous syndactyly of the fingers and toes, together with the distinctive facies (broad, high nasal bridge, thin/underdeveloped alae nasi, micrognathia, high frontal hairline). This node is deliberately curated as an under-explained convergence point. The syndactyly is serially homologous — hands and feet are both affected — which is the pattern the limb/digit serial-homology module was built for, but no experiment links CKAP2L to the SHH/GLI3/HOXD patterning gradients that drive that module, so no conformance is asserted. Whether the digits fail to separate because interdigital cell death is reduced or because autopod progenitor proliferation is impaired is unresolved (see the knowledge-gap discussion).
limb development GO:0060173 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal limb development (GO:0060173). GO:0060173 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:42404495 SUPPORT Human Clinical
"The most frequent findings were characteristic craniofacial dysmorphism, digital syndactyly, microcephaly, short stature or growth retardation, and neurodevelopmental impairment."
Systematic review across 43 patients establishing craniofacial dysmorphism and digital syndactyly as the most frequent findings.
PMID:25439729 SUPPORT Human Clinical
"Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi."
Names the specific facial features (broad nasal bridge, underdeveloped alae nasi) that define the craniofacial component.
Pre- and Postnatal Growth Failure
Symmetric growth restriction beginning in utero and continuing postnatally is one of the most consistent features of the syndrome and is the systemic expression of a generalized proliferation deficit. Growth failure is reported as severe in several individuals and is present in essentially all molecularly confirmed cases.
Show evidence (1 reference)
PMID:33913579 SUPPORT Human Clinical
"characterized by pre- and postnatal growth retardation, microcephaly, distinctive facial appearance, developmental delay/intellectual disability, and variable syndactylies of the fingers and toes"
States pre- and postnatal growth retardation as a defining component of the clinical definition.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Filippi Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

19
Genitourinary 2
Cryptorchidism OCCASIONAL HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25439729 SUPPORT Human Clinical
"Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities."
Reports undescended testicles in a subset of affected males.
Renal Cysts VERY_RARE HP:0000107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal cyst (HP:0000107). HP:0000107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38738944 SUPPORT Human Clinical
"including renal hypoplasia/aplasia, renal cysts, renal cortical thinning, hypomelanotic, and hypermelanotic macules"
Documents renal cysts among the newly described urinary-system features.
Head and Neck 4
Microcephaly VERY_FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42404495 SUPPORT Human Clinical
"The most frequent findings were characteristic craniofacial dysmorphism, digital syndactyly, microcephaly, short stature or growth retardation, and neurodevelopmental impairment."
Microcephaly is listed among the most frequent findings in the 43-patient systematic review, supporting the VERY_FREQUENT band.
Distinctive Craniofacial Dysmorphism VERY_FREQUENT Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42404495 SUPPORT Human Clinical
"The most frequent findings were characteristic craniofacial dysmorphism, digital syndactyly, microcephaly, short stature or growth retardation, and neurodevelopmental impairment."
Craniofacial dysmorphism heads the list of most frequent findings in the 43-patient systematic review, supporting the VERY_FREQUENT band.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34921061 SUPPORT Human Clinical
"Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability."
Documents micrognathia in molecularly confirmed patients.
Dental Anomalies Abnormality of the dentition HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42404495 SUPPORT Human Clinical
"Additional manifestations included dental anomalies, skeletal abnormalities, neurologic involvement, cardiovascular defects, and genitourinary abnormalities."
Lists dental anomalies among the additional manifestations across the reported cohort.
Limbs 3
Cutaneous Syndactyly of Fingers VERY_FREQUENT Cutaneous finger syndactyly HP:0010554 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutaneous finger syndactyly (HP:0010554). HP:0010554 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42404495 SUPPORT Human Clinical
"The most frequent findings were characteristic craniofacial dysmorphism, digital syndactyly, microcephaly, short stature or growth retardation, and neurodevelopmental impairment."
The systematic review of 43 patients lists digital syndactyly among the most frequent findings, supporting the VERY_FREQUENT band.
Toe Syndactyly HP:0001770 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Toe syndactyly (HP:0001770). HP:0001770 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18553552 SUPPORT Human Clinical
"a child with Filippi syndrome who shows syndactyly of fingers and toes"
Documents involvement of both fingers and toes in the same individual.
Talipes Equinovarus VERY_RARE HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33913579 SUPPORT Human Clinical
"a further female patient of Filippi syndrome who additionally had a unilateral congenital talipes equinovarus (CTEV), a feature not previously recorded, is described"
Single-patient report explicitly framed as a previously unrecorded feature, supporting the VERY_RARE band.
Nervous System 4
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33913579 SUPPORT Human Clinical
"developmental delay/intellectual disability, and variable syndactylies of the fingers and toes"
Includes developmental delay in the clinical definition of the syndrome.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25439729 SUPPORT Human Clinical
"Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities."
Partial support: the gene-discovery paper qualifies intellectual disability as present in only some affected individuals, which is why no frequency band is asserted here.
PMID:35224850 SUPPORT Human Clinical
"Expansion of the neurodevelopmental phenotypic spectrum of CKAP2L-related Filippi syndrome to include an adolescent male with normal intellect."
Establishes that intellectual disability is not obligate. The source is a correspondence piece indexed in PubMed without an abstract, so the article title is the only verifiable quotable text; it states the finding directly. Recorded as PARTIAL because no further clinical detail is available from the cached record.
Delayed Speech and Language Development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18553552 SUPPORT Human Clinical
"severe mental retardation with speech impairment"
Documents speech impairment in a clinically characterized patient (dated terminology in the source).
Seizures OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25439729 SUPPORT Human Clinical
"Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities."
"Some affected individuals" maps to the OCCASIONAL band for seizures.
Growth 2
Intrauterine Growth Restriction Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25439729 SUPPORT Human Clinical
"characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features"
Explicitly includes prenatal growth failure in the disease definition.
Short Stature VERY_FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42404495 SUPPORT Human Clinical
"The most frequent findings were characteristic craniofacial dysmorphism, digital syndactyly, microcephaly, short stature or growth retardation, and neurodevelopmental impairment."
Short stature or growth retardation is listed among the most frequent findings across the 43 reported patients.
Other 4
Wide Nasal Bridge HP:0000431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide nasal bridge (HP:0000431). HP:0000431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25439729 SUPPORT Human Clinical
"distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi"
Names the broad nasal bridge as a defining facial feature.
Underdeveloped Alae Nasi Underdeveloped nasal alae HP:0000430 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Underdeveloped nasal alae (HP:0000430). HP:0000430 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25439729 SUPPORT Human Clinical
"distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi"
Names underdeveloped alae nasi as a defining facial feature.
Renal Hypoplasia VERY_RARE HP:0000089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal hypoplasia (HP:0000089). HP:0000089 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38738944 SUPPORT Human Clinical
"These patients exhibited novel clinical features that have not previously been associated with Filippi syndrome, including renal hypoplasia/aplasia, renal cysts, renal cortical thinning, hypomelanotic, and hypermelanotic macules."
The only report of renal involvement, in three families; the "not previously associated" framing supports a VERY_RARE band pending replication.
Hypopigmented and Hyperpigmented Macules VERY_RARE Hypopigmented skin patches HP:0001053 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypopigmented skin patches (HP:0001053). HP:0001053 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38738944 SUPPORT Human Clinical
"including renal hypoplasia/aplasia, renal cysts, renal cortical thinning, hypomelanotic, and hypermelanotic macules"
Documents both hypo- and hyperpigmented macules; the HPO term captures the hypopigmented component only.
🧬

Genetic Associations

1
CKAP2L (Causative (biallelic loss of function))
Gene: CKAP2L hgnc:26877 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CKAP2L (hgnc:26877). hgnc:26877 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (4 references)
PMID:25439729 SUPPORT Human Clinical
"Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome."
Establishes CKAP2L loss-of-function variants as the principal cause of the syndrome.
PMID:25439729 SUPPORT Human Clinical
"Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects."
Replication cohort: biallelic CKAP2L variants in 4 of 8 additional clinically diagnosed individuals — supporting causation while also showing that clinically diagnosed Filippi syndrome is genetically heterogeneous.
PMID:34921061 SUPPORT Human Clinical
"Whole-exome sequencing of the family identified a missense variant, c.2066G > A;p.(Arg689His), in trans with a frameshift variant, c.1169_1173del;p.(Ile390LysfsTer4), in CKAP2L"
Extends the allelic spectrum beyond pure loss-of-function alleles with the first reported missense variant, found in trans with a frameshift.
+ 1 more reference
💊

Medical Actions

5
Supportive and Symptom-Directed Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying therapy exists. Reported management across the published cohort is supportive and symptom-directed, coordinated across genetics, neurology, orthopaedics/plastic surgery, ophthalmology, dentistry, and nephrology as dictated by the individual's features.
Show evidence (1 reference)
PMID:42404495 SUPPORT Human Clinical
"Reported management was mainly supportive and symptom-directed, including surgical correction of syndactyly and rehabilitative therapies."
The systematic review's management summary across all reported patients.
Surgical Correction of Syndactyly
Action: orthopedic surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthopedic surgical procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Operative separation of the fused digits is the main structural intervention reported, undertaken to improve hand function and, secondarily, foot mechanics.
Show evidence (1 reference)
PMID:42404495 SUPPORT Human Clinical
"including surgical correction of syndactyly and rehabilitative therapies"
Identifies syndactyly release as the principal reported surgical intervention.
Developmental and Rehabilitative Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physical, occupational, and speech/language therapy for the developmental delay, motor impairment, and speech impairment that accompany the microcephaly.
Show evidence (1 reference)
PMID:42404495 SUPPORT Human Clinical
"including surgical correction of syndactyly and rehabilitative therapies"
Rehabilitative therapies are named as a component of reported management.
Anti-Seizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Standard anti-seizure pharmacotherapy for the subset of individuals with epilepsy. No agent is mechanism-matched to the CKAP2L spindle defect.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Autosomal recessive counseling with a 25% sibling recurrence risk, carrier testing for at-risk relatives, and discussion of the high rate of consanguinity in reported families. Counseling should also convey that clinically diagnosed Filippi syndrome is genetically heterogeneous — only about half of clinically diagnosed individuals in the replication cohort carried biallelic CKAP2L variants — so a negative CKAP2L result does not exclude the clinical diagnosis.
Show evidence (1 reference)
PMID:25439729 SUPPORT Human Clinical
"Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects."
Supports the counseling point that only a fraction of clinically diagnosed individuals carry biallelic CKAP2L variants.
📊

Prevalence

1
Worldwide (published case reports and series)
Cases In Literature Ultra Rare
A PRISMA systematic review searching PubMed, Embase, and Web of Science from inception to June 2025 recovered only 43 reported patients across 22 studies, and that count includes clinically diagnosed and Filippi-like overlapping phenotypes as well as molecularly confirmed CKAP2L cases. No population-based prevalence estimate exists.
Show evidence (1 reference)
PMID:42404495 SUPPORT Human Clinical
"Twenty-two studies comprising 43 reported patients were included."
Gives the total published case count underpinning the ultra-rare classification.
{ }

Source YAML

click to show 
name: Filippi Syndrome
disease_term:
  preferred_term: Filippi syndrome
  term:
    id: MONDO:0010092
    label: Filippi syndrome
creation_date: "2026-07-12T07:27:01Z"
category: Mendelian
description: >-
  Filippi syndrome (craniodigital syndrome; OMIM 272440) is an ultra-rare
  autosomal recessive multiple-congenital-anomaly disorder caused by biallelic
  loss-of-function variants in CKAP2L, which encodes cytoskeleton-associated
  protein 2-like. The clinical core is craniodigital: cutaneous syndactyly of
  the fingers and toes, microcephaly, pre- and postnatal growth failure, a
  distinctive facies (broad nasal bridge, underdeveloped alae nasi,
  micrognathia), and variable intellectual disability. CKAP2L is the human
  ortholog of mouse Radmis (radial fiber and mitotic spindle), a
  microtubule-associated protein enriched in neural stem/progenitor cells that
  localizes to the mitotic spindle, spindle poles, centrosome, and the radial
  fibers of dividing radial glia. Patient cells lose CKAP2L from the spindle
  poles and show multipolar, disorganized spindles with chromosome
  missegregation, placing the disorder in the neural-progenitor
  centrosome-spindle family of microcephalies. A 2026 knockout-mouse and
  cell-biology study extended CKAP2L's role to negative regulation of primary
  cilium length and proposed reclassifying Filippi syndrome as a
  "centrosomopathy" with concurrent proliferation and ciliary defects; the same
  study found that Ckap2l-null mice do not reproduce the human developmental
  phenotype, which is curated here as an explicit human/model mismatch rather
  than smoothed over. Management is supportive and symptom-directed.
synonyms:
- type 1 syndactyly-microcephaly-intellectual disability syndrome
- craniodigital syndrome
- Scott craniodigital syndrome
- FLPIS
parents:
- multiple congenital anomalies/dysmorphic syndrome-intellectual disability
- disorder of development or morphogenesis
- hereditary disease
- syndactyly
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010092
      label: Filippi syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0010092 is the exact disease concept (xrefs OMIM:272440,
      Orphanet:3255) and records CKAP2L (HGNC:26877) as the causal gene via
      RO:0004003, matching the gene curated in this entry.
references:
- reference: PMID:25439729
  title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
- reference: PMID:42404495
  title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
- reference: PMID:41370039
  title: Filippi syndrome-associated CKAP2L modulates microtubule dynamics essential for mitosis and ciliary length regulation.
- reference: PMID:24260314
  title: Radmis, a novel mitotic spindle protein that functions in cell division of neural progenitors.
- reference: PMID:34921061
  title: Novel variants identified in CKAP2L in two siblings with Filippi syndrome.
- reference: PMID:33913579
  title: Identification of a novel pathogenic variant in CKAP2L and literature review in a child with Filippi syndrome and congenital talipes equinovarus.
- reference: PMID:38738944
  title: "Filippi syndrome: Three new families suggest that urinary system abnormalities may belong to clinical spectrum of the disease."
- reference: PMID:18553552
  title: "Filippi syndrome: further clinical characterization."
- reference: PMID:35224850
  title: Expansion of the neurodevelopmental phenotypic spectrum of CKAP2L-related Filippi syndrome to include an adolescent male with normal intellect.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    All molecularly confirmed families reported to date carry biallelic CKAP2L
    variants, most often homozygous frameshift alleles in consanguineous
    pedigrees, with two families reported as compound heterozygotes.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Filippi syndrome is a rare, presumably autosomal-recessive disorder
      characterized by microcephaly, pre- and postnatal growth failure,
      syndactyly, and distinctive facial features, including a broad nasal
      bridge and underdeveloped alae nasi.
    explanation: >-
      The gene-discovery paper states the recessive mode of inheritance and the
      core craniodigital phenotype.
  - reference: PMID:34921061
    reference_title: Novel variants identified in CKAP2L in two siblings with Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of the previously reported probands have presumed loss-of-function
      variants (frameshift, canonical splice site, starting methionine), and all
      but one have been homozygous for a pathogenic variant.
    explanation: >-
      Documents that the recessive allelic spectrum is dominated by homozygous
      loss-of-function variants, with compound heterozygosity the exception.
prevalence:
- population: Worldwide (published case reports and series)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A PRISMA systematic review searching PubMed, Embase, and Web of Science
    from inception to June 2025 recovered only 43 reported patients across 22
    studies, and that count includes clinically diagnosed and Filippi-like
    overlapping phenotypes as well as molecularly confirmed CKAP2L cases. No
    population-based prevalence estimate exists.
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-two studies comprising 43 reported patients were included."
    explanation: >-
      Gives the total published case count underpinning the ultra-rare
      classification.
pathophysiology:
- name: Biallelic CKAP2L Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic loss-of-function variants in CKAP2L — most commonly homozygous
    frameshift alleles, with rarer canonical splice-site, start-codon, and (in
    one family) missense alleles in trans — abolish or destabilize
    cytoskeleton-associated protein 2-like. CKAP2L is a bona fide
    microtubule-associated protein that localizes to microtubule-based
    organelles: the centrosome, the mitotic spindle and its poles, and the
    ciliary basal body. In lymphoblastoid cell lines from individuals
    homozygous for the founding c.571dupA allele, CKAP2L is no longer detectable
    at the spindle poles, establishing loss of function at the level of protein
    localization rather than a dominant-negative or gain-of-function mechanism.
  genes:
  - preferred_term: CKAP2L
    term:
      id: hgnc:26877
      label: CKAP2L
  molecular_functions:
  - preferred_term: microtubule binding
    term:
      id: GO:0008017
      label: microtubule binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: spindle pole
    term:
      id: GO:0000922
      label: spindle pole
  - preferred_term: centrosome
    term:
      id: GO:0005813
      label: centrosome
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified a homozygous frameshift mutation, c.571dupA
    explanation: >-
      Identifies the founding biallelic CKAP2L frameshift allele by homozygosity
      mapping and exome sequencing in a Sardinian family.
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs
      established from the individuals homozygous for the c.571dupA mutation did
      not show CKAP2L at the spindle poles.
    explanation: >-
      Demonstrates loss of CKAP2L from the spindle poles in patient-derived
      dividing cells, the direct molecular consequence of the frameshift allele.
  - reference: PMID:41370039
    reference_title: Filippi syndrome-associated CKAP2L modulates microtubule dynamics essential for mitosis and ciliary length regulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CKAP2L is a bona fide microtubule-associated protein that localizes to
      microtubule-based organelles, including the centrosome, mitotic spindle,
      and ciliary basal body.
    explanation: >-
      Establishes the subcellular localization set that defines which
      microtubule-based organelles are at risk when CKAP2L is lost.
  - reference: PMID:24260314
    reference_title: Radmis, a novel mitotic spindle protein that functions in cell division of neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      a novel microtubule-associated protein (MAP) enriched in NSPCs
    explanation: >-
      The mouse ortholog radmis/ckap2l was first identified as a
      microtubule-associated protein enriched in neural stem/progenitor cells,
      explaining the tissue bias of the human phenotype.
  downstream:
  - target: Mitotic Spindle Disorganization and Cytokinesis Failure
    description: >-
      Loss of CKAP2L from the spindle poles removes a microtubule-associated
      regulator required for bipolar spindle assembly and mitotic progression.
    hypothesis_groups:
    - mitotic_proliferation_deficit_model
  - target: Primary Cilium Elongation
    description: >-
      Loss of CKAP2L from the ciliary basal body removes a negative regulator of
      primary cilium length.
    hypothesis_groups:
    - centrosomopathy_ciliary_model
- name: Mitotic Spindle Disorganization and Cytokinesis Failure
  biological_scale: CELLULAR
  conforms_to: "neural_progenitor_centrosome_spindle_dysfunction#Centrosome and Mitotic Spindle Perturbation"
  description: >-
    Without CKAP2L at the spindle poles, dividing cells assemble disorganized,
    multipolar, and shortened mitotic spindles. The downstream mitotic
    consequences are twofold: chromosome missegregation (including chromosome
    bridges between separating daughter nuclei in the mouse knockdown model)
    and outright cytokinesis failure producing multinucleated cells. This is the
    conserved centrosome/spindle perturbation node of the neural-progenitor
    module, instantiated here by a spindle-pole-associated MAP rather than by a
    centriole-duplication or microtubule-severing lesion.
  cell_types:
  - preferred_term: patient-derived lymphoblastoid cell (dividing)
    term:
      id: CL:0000542
      label: lymphocyte
  biological_processes:
  - preferred_term: mitotic spindle organization
    term:
      id: GO:0007052
      label: mitotic spindle organization
    modifier: ABNORMAL
  - preferred_term: chromosome segregation
    term:
      id: GO:0007059
      label: chromosome segregation
    modifier: ABNORMAL
  - preferred_term: cytokinesis
    term:
      id: GO:0000910
      label: cytokinesis
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitotic spindle
    term:
      id: GO:0072686
      label: mitotic spindle
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      in cells from the affected individuals, we observed an increase in the
      number of disorganized spindle microtubules owing to multipolar
      configurations and defects in chromosome segregation
    explanation: >-
      Direct patient-cell evidence for multipolar spindles and chromosome
      missegregation as the cellular phenotype of CKAP2L loss.
  - reference: PMID:41370039
    reference_title: Filippi syndrome-associated CKAP2L modulates microtubule dynamics essential for mitosis and ciliary length regulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of CKAP2L leads to shortened mitotic spindles and cytokinesis
      failure, resulting in multinucleation.
    explanation: >-
      Adds cytokinesis failure and multinucleation to the mitotic phenotype,
      independently of the chromosome-segregation defect.
  - reference: PMID:24260314
    reference_title: Radmis, a novel mitotic spindle protein that functions in cell division of neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      radmis loss-of-function by shRNAs induced the multipolar mitotic spindle
      structure, accompanied with the catastrophe of chromosome segregation
      including the long chromosome bridge between two separating daughter
      nuclei
    explanation: >-
      Mouse knockdown reproduces the same multipolar-spindle and
      chromosome-segregation phenotype seen in human patient cells.
  downstream:
  - target: Neural Progenitor Division Failure
    description: >-
      Spindle disorganization is most consequential in the rapidly dividing
      neural stem/progenitor compartment where CKAP2L is enriched.
    hypothesis_groups:
    - mitotic_proliferation_deficit_model
  - target: Impaired Craniofacial and Digital Morphogenesis
    description: >-
      Proliferation failure in other embryonic progenitor fields is the proposed
      route to the craniofacial and autopod anomalies, though the tissue-level
      steps are not established.
    hypothesis_groups:
    - mitotic_proliferation_deficit_model
  - target: Pre- and Postnatal Growth Failure
    description: >-
      A generalized mitotic proliferation deficit is the proposed basis for
      symmetric intrauterine and postnatal growth restriction.
    hypothesis_groups:
    - mitotic_proliferation_deficit_model
- name: Neural Progenitor Division Failure
  biological_scale: CELLULAR
  conforms_to: "neural_progenitor_centrosome_spindle_dysfunction#Abnormal Progenitor Division and Fate Choice"
  description: >-
    CKAP2L/radmis is enriched in neural stem/progenitor cells and, in the
    embryonic and perinatal brain, decorates both the bipolar mitotic spindle
    and the radial (basal) fiber of dividing radial glia — the two structures
    that set division geometry and daughter-cell fate during corticogenesis.
    Perturbing radmis dosage in vivo shifts progenitors out of cycle: forced
    expression reduced progenitor proliferation, increased cell-cycle exit,
    depleted the Tbr2-positive basal progenitor population, and shrank the
    embryonic subventricular zone. Loss of function disorganizes the same
    spindle. Both directions converge on failure of the normal
    proliferative/neurogenic division balance.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
    modifier: DECREASED
  - preferred_term: mitotic spindle assembly
    term:
      id: GO:0090307
      label: mitotic spindle assembly
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24260314
    reference_title: Radmis, a novel mitotic spindle protein that functions in cell division of neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In embryonic and perinatal brains, radmis localized to bipolar mitotic
      spindles and radial fibers (basal processes) of dividing NSPCs.
    explanation: >-
      Places the protein at the spindle and radial fiber of dividing cortical
      progenitors, the structures that determine division geometry and fate.
  - reference: PMID:24260314
    reference_title: Radmis, a novel mitotic spindle protein that functions in cell division of neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      revealed that radmis directed a reduction in NSPC proliferation and a
      concomitant increase in cell cycle exit, causing a reduction in the
      Tbr2-positive basal progenitor population and shrinkage of the embryonic
      subventricular zone
    explanation: >-
      Partial rather than full support: this is an in utero electroporation
      gain-of-function experiment, so it shows that radmis dosage controls
      progenitor proliferation and cell-cycle exit, but does not by itself model
      the human loss-of-function allele.
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The function of this protein was unknown until it was rediscovered in mice
      as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal
      role in cell division of neural progenitors.
    explanation: >-
      The gene-discovery paper explicitly grounds the human disease mechanism in
      the neural-progenitor cell-division role of the mouse ortholog.
  downstream:
  - target: Cortical Progenitor Pool Depletion
    description: >-
      Failed or misoriented progenitor divisions reduce the number of
      progenitors available to generate cortical neurons.
    hypothesis_groups:
    - mitotic_proliferation_deficit_model
- name: Cortical Progenitor Pool Depletion
  biological_scale: TISSUE
  conforms_to: "neural_progenitor_centrosome_spindle_dysfunction#Progenitor Pool Distortion"
  description: >-
    Sustained failure of progenitor division during corticogenesis distorts the
    apical and basal progenitor pools. In the mouse model the measured readouts
    were loss of Tbr2-positive basal progenitors and shrinkage of the embryonic
    subventricular zone; the equivalent human tissue measurement has not been
    made, so this node is inferred for human disease from the cellular and mouse
    data plus the resulting head-circumference phenotype.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
    modifier: DECREASED
  - preferred_term: cell division
    term:
      id: GO:0051301
      label: cell division
    modifier: DECREASED
  evidence:
  - reference: PMID:24260314
    reference_title: Radmis, a novel mitotic spindle protein that functions in cell division of neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings uncover the indispensable role of radmis in mitotic spindle
      formation and cell-cycle progression of NSPCs.
    explanation: >-
      Supports an indispensable requirement for the protein in progenitor
      cell-cycle progression, the process whose failure depletes the pool.
  downstream:
  - target: Reduced Cortical Neuron Output and Postnatal Microcephaly
    description: >-
      A smaller progenitor pool yields fewer cortical neurons and a smaller
      brain, expressed clinically as microcephaly.
    hypothesis_groups:
    - mitotic_proliferation_deficit_model
- name: Reduced Cortical Neuron Output and Postnatal Microcephaly
  biological_scale: ORGANISM
  conforms_to: "neural_progenitor_centrosome_spindle_dysfunction#Abnormal Cortical Neuron Output and Gyration"
  description: >-
    The clinical endpoint of the progenitor arm is microcephaly with variable
    neurodevelopmental impairment — developmental delay, intellectual
    disability, speech impairment, and in some individuals epilepsy. Severity is
    notably variable across reported patients, extending to at least one
    adolescent with preserved intellect, so cognitive impairment should not be
    treated as obligate.
  cell_types:
  - preferred_term: cortical neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some affected individuals have intellectual disability, seizures,
      undescended testicles in males, and teeth and hair abnormalities.
    explanation: >-
      Documents the variable neurodevelopmental and extra-neural features
      accompanying microcephaly.
  - reference: PMID:18553552
    reference_title: "Filippi syndrome: further clinical characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a child with Filippi syndrome who shows syndactyly of fingers
      and toes, severe pre- and post-natal growth retardation, postnatal
      microcephaly, epilepsy, and severe mental retardation with speech
      impairment.
    explanation: >-
      Clinical characterization establishing the postnatal (rather than
      congenital) evolution of the microcephaly alongside epilepsy and severe
      cognitive/speech impairment.
- name: Primary Cilium Elongation
  biological_scale: CELLULAR
  description: >-
    A second, more recently described arm: CKAP2L also localizes to the ciliary
    basal body and acts as a conserved negative regulator of primary cilium
    length, so its loss markedly lengthens cilia in both human and mouse cells.
    On this basis Filippi syndrome has been proposed to be a "centrosomopathy"
    in which proliferation and ciliary signalling defects act together. The arm
    is curated as an EMERGING hypothesis, not as established disease mechanism:
    no patient tissue has been shown to carry elongated cilia, and no
    ciliopathy-specific clinical feature has been causally tied to it.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DYSREGULATED
  cellular_components:
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  evidence:
  - reference: PMID:41370039
    reference_title: Filippi syndrome-associated CKAP2L modulates microtubule dynamics essential for mitosis and ciliary length regulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we uncover a conserved function for CKAP2L as a negative regulator of
      primary cilium length; its loss markedly increases ciliary length in both
      human and mouse cells.
    explanation: >-
      Establishes the ciliary-length phenotype of CKAP2L loss in human and mouse
      cells, the empirical basis of the centrosomopathy proposal.
  - reference: PMID:41370039
    reference_title: Filippi syndrome-associated CKAP2L modulates microtubule dynamics essential for mitosis and ciliary length regulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      these findings position CKAP2L as a multifunctional regulator of
      microtubule-based organelles and suggest that Filippi syndrome can be
      classified as a 'centrosomopathy' arising from concurrent defects in cell
      proliferation and ciliary function.
    explanation: >-
      The centrosomopathy reclassification is offered by the authors as a
      suggestion drawn from cell-line data, not demonstrated in patient tissue,
      so it is recorded as partial support for an emerging model.
  downstream:
  - target: Impaired Craniofacial and Digital Morphogenesis
    description: >-
      Proposed contribution of disturbed ciliary signalling to the craniofacial
      and digit phenotype, by analogy with established ciliopathies. Not
      demonstrated in Filippi syndrome patients.
    hypothesis_groups:
    - centrosomopathy_ciliary_model
- name: Impaired Craniofacial and Digital Morphogenesis
  biological_scale: TISSUE
  description: >-
    The craniodigital arm of the disorder: cutaneous syndactyly of the fingers
    and toes, together with the distinctive facies (broad, high nasal bridge,
    thin/underdeveloped alae nasi, micrognathia, high frontal hairline). This
    node is deliberately curated as an under-explained convergence point. The
    syndactyly is serially homologous — hands and feet are both affected — which
    is the pattern the limb/digit serial-homology module was built for, but no
    experiment links CKAP2L to the SHH/GLI3/HOXD patterning gradients that drive
    that module, so no conformance is asserted. Whether the digits fail to
    separate because interdigital cell death is reduced or because autopod
    progenitor proliferation is impaired is unresolved (see the knowledge-gap
    discussion).
  biological_processes:
  - preferred_term: limb development
    term:
      id: GO:0060173
      label: limb development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequent findings were characteristic craniofacial dysmorphism,
      digital syndactyly, microcephaly, short stature or growth retardation, and
      neurodevelopmental impairment.
    explanation: >-
      Systematic review across 43 patients establishing craniofacial dysmorphism
      and digital syndactyly as the most frequent findings.
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Filippi syndrome is a rare, presumably autosomal-recessive disorder
      characterized by microcephaly, pre- and postnatal growth failure,
      syndactyly, and distinctive facial features, including a broad nasal
      bridge and underdeveloped alae nasi.
    explanation: >-
      Names the specific facial features (broad nasal bridge, underdeveloped
      alae nasi) that define the craniofacial component.
- name: Pre- and Postnatal Growth Failure
  biological_scale: ORGANISM
  description: >-
    Symmetric growth restriction beginning in utero and continuing postnatally
    is one of the most consistent features of the syndrome and is the systemic
    expression of a generalized proliferation deficit. Growth failure is
    reported as severe in several individuals and is present in essentially all
    molecularly confirmed cases.
  evidence:
  - reference: PMID:33913579
    reference_title: Identification of a novel pathogenic variant in CKAP2L and literature review in a child with Filippi syndrome and congenital talipes equinovarus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by pre- and postnatal growth retardation, microcephaly,
      distinctive facial appearance, developmental delay/intellectual
      disability, and variable syndactylies of the fingers and toes
    explanation: >-
      States pre- and postnatal growth retardation as a defining component of
      the clinical definition.
mechanistic_hypotheses:
- hypothesis_group_id: mitotic_proliferation_deficit_model
  hypothesis_label: Mitotic spindle / progenitor proliferation deficit model
  status: CANONICAL
  description: >-
    The established model: CKAP2L is a spindle-pole microtubule-associated
    protein required for bipolar spindle assembly and mitotic progression, and
    its biallelic loss produces multipolar spindles, chromosome missegregation,
    and cytokinesis failure. In the neural stem/progenitor compartment where the
    protein is enriched, this depletes the cortical progenitor pool and yields
    microcephaly; the same proliferation deficit is invoked, less directly, for
    the growth failure and craniodigital features.
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings show that loss-of-function mutations in CKAP2L are a major
      cause of Filippi syndrome.
    explanation: >-
      Establishes CKAP2L loss of function as the principal disease mechanism.
- hypothesis_group_id: centrosomopathy_ciliary_model
  hypothesis_label: Centrosomopathy model (concurrent proliferation and ciliary defects)
  status: EMERGING
  description: >-
    A 2026 proposal that Filippi syndrome should be reclassified as a
    centrosomopathy in which CKAP2L loss simultaneously impairs mitosis and
    de-represses primary cilium elongation, with ciliary signalling contributing
    to the non-neural (craniofacial, digital, and possibly renal) features. The
    ciliary-length data are from human and mouse cell lines only; no patient
    tissue or clinical correlate has yet been reported, and the strongest
    in vivo test to date (the Ckap2l knockout mouse) produced no developmental
    phenotype at all.
  evidence:
  - reference: PMID:41370039
    reference_title: Filippi syndrome-associated CKAP2L modulates microtubule dynamics essential for mitosis and ciliary length regulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      these findings position CKAP2L as a multifunctional regulator of
      microtubule-based organelles and suggest that Filippi syndrome can be
      classified as a 'centrosomopathy' arising from concurrent defects in cell
      proliferation and ciliary function.
    explanation: >-
      The source of the emerging reclassification, stated by its authors as a
      suggestion rather than a demonstrated disease mechanism.
phenotypes:
- category: Skeletal
  name: Cutaneous Syndactyly of Fingers
  description: >-
    Cutaneous (soft-tissue) syndactyly of the fingers is the digital half of the
    craniodigital core and is among the most frequent findings across reported
    patients.
  phenotype_term:
    preferred_term: Cutaneous finger syndactyly
    term:
      id: HP:0010554
      label: Cutaneous finger syndactyly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequent findings were characteristic craniofacial dysmorphism,
      digital syndactyly, microcephaly, short stature or growth retardation, and
      neurodevelopmental impairment.
    explanation: >-
      The systematic review of 43 patients lists digital syndactyly among the
      most frequent findings, supporting the VERY_FREQUENT band.
- category: Skeletal
  name: Toe Syndactyly
  description: >-
    Syndactyly involves the toes as well as the fingers, making the autopod
    phenotype serially homologous across fore- and hindlimb.
  phenotype_term:
    preferred_term: Toe syndactyly
    term:
      id: HP:0001770
      label: Toe syndactyly
  evidence:
  - reference: PMID:18553552
    reference_title: "Filippi syndrome: further clinical characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a child with Filippi syndrome who shows syndactyly of fingers and toes
    explanation: >-
      Documents involvement of both fingers and toes in the same individual.
- category: Neurologic
  name: Microcephaly
  description: >-
    Microcephaly is the defining head-size phenotype and is described as
    postnatal in clinically characterized patients.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequent findings were characteristic craniofacial dysmorphism,
      digital syndactyly, microcephaly, short stature or growth retardation, and
      neurodevelopmental impairment.
    explanation: >-
      Microcephaly is listed among the most frequent findings in the 43-patient
      systematic review, supporting the VERY_FREQUENT band.
- category: Growth
  name: Intrauterine Growth Restriction
  description: >-
    Growth failure begins prenatally, distinguishing the disorder from
    conditions with purely postnatal growth deceleration.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by microcephaly, pre- and postnatal growth failure,
      syndactyly, and distinctive facial features
    explanation: >-
      Explicitly includes prenatal growth failure in the disease definition.
- category: Growth
  name: Short Stature
  description: >-
    Postnatal growth failure manifests as short stature and is among the most
    frequent findings in the systematic review.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequent findings were characteristic craniofacial dysmorphism,
      digital syndactyly, microcephaly, short stature or growth retardation, and
      neurodevelopmental impairment.
    explanation: >-
      Short stature or growth retardation is listed among the most frequent
      findings across the 43 reported patients.
- category: Craniofacial
  name: Distinctive Craniofacial Dysmorphism
  description: >-
    A recognizable facial gestalt — high, broad nasal bridge, thin
    underdeveloped alae nasi, micrognathia, and a high frontal hairline — is the
    craniofacial half of the craniodigital core and is the single most frequent
    finding across reported patients.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequent findings were characteristic craniofacial dysmorphism,
      digital syndactyly, microcephaly, short stature or growth retardation, and
      neurodevelopmental impairment.
    explanation: >-
      Craniofacial dysmorphism heads the list of most frequent findings in the
      43-patient systematic review, supporting the VERY_FREQUENT band.
- category: Craniofacial
  name: Wide Nasal Bridge
  description: >-
    A high, broad nasal bridge is part of the characteristic facies used to
    recognize the syndrome clinically.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      distinctive facial features, including a broad nasal bridge and
      underdeveloped alae nasi
    explanation: >-
      Names the broad nasal bridge as a defining facial feature.
- category: Craniofacial
  name: Underdeveloped Alae Nasi
  description: >-
    Thin, underdeveloped alae nasi accompany the broad nasal bridge in the
    characteristic facies.
  phenotype_term:
    preferred_term: Underdeveloped nasal alae
    term:
      id: HP:0000430
      label: Underdeveloped nasal alae
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      distinctive facial features, including a broad nasal bridge and
      underdeveloped alae nasi
    explanation: >-
      Names underdeveloped alae nasi as a defining facial feature.
- category: Craniofacial
  name: Micrognathia
  description: >-
    Micrognathia is part of the characteristic facies and was present in the
    sibling pair reported with compound heterozygous CKAP2L variants.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:34921061
    reference_title: Novel variants identified in CKAP2L in two siblings with Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two brothers who presented with microcephaly,
      micrognathia, syndactyly, dysmorphic features, and intellectual
      disability.
    explanation: >-
      Documents micrognathia in molecularly confirmed patients.
- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Neurodevelopmental impairment, including motor and speech delay, is among
    the most frequent findings.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33913579
    reference_title: Identification of a novel pathogenic variant in CKAP2L and literature review in a child with Filippi syndrome and congenital talipes equinovarus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay/intellectual disability, and variable syndactylies of
      the fingers and toes
    explanation: >-
      Includes developmental delay in the clinical definition of the syndrome.
- category: Neurologic
  name: Intellectual Disability
  description: >-
    Intellectual disability is frequent but not obligate — the reported spectrum
    extends to an adolescent male with normal intellect, so cognitive outcome
    should not be presumed from the molecular diagnosis alone.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some affected individuals have intellectual disability, seizures,
      undescended testicles in males, and teeth and hair abnormalities.
    explanation: >-
      Partial support: the gene-discovery paper qualifies intellectual
      disability as present in only some affected individuals, which is why no
      frequency band is asserted here.
  - reference: PMID:35224850
    reference_title: Expansion of the neurodevelopmental phenotypic spectrum of CKAP2L-related Filippi syndrome to include an adolescent male with normal intellect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Expansion of the neurodevelopmental phenotypic spectrum of CKAP2L-related
      Filippi syndrome to include an adolescent male with normal intellect.
    explanation: >-
      Establishes that intellectual disability is not obligate. The source is a
      correspondence piece indexed in PubMed without an abstract, so the article
      title is the only verifiable quotable text; it states the finding
      directly. Recorded as PARTIAL because no further clinical detail is
      available from the cached record.
- category: Neurologic
  name: Delayed Speech and Language Development
  description: >-
    Speech impairment is described in clinically characterized patients
    alongside cognitive impairment.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:18553552
    reference_title: "Filippi syndrome: further clinical characterization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe mental retardation with speech impairment
    explanation: >-
      Documents speech impairment in a clinically characterized patient (dated
      terminology in the source).
- category: Neurologic
  name: Seizures
  description: >-
    Epilepsy occurs in a subset of affected individuals.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some affected individuals have intellectual disability, seizures,
      undescended testicles in males, and teeth and hair abnormalities.
    explanation: >-
      "Some affected individuals" maps to the OCCASIONAL band for seizures.
- category: Genitourinary
  name: Cryptorchidism
  description: >-
    Undescended testicles are reported in affected males.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some affected individuals have intellectual disability, seizures,
      undescended testicles in males, and teeth and hair abnormalities.
    explanation: >-
      Reports undescended testicles in a subset of affected males.
- category: Dental
  name: Dental Anomalies
  description: >-
    Teeth abnormalities are a recognized accompanying feature and were confirmed
    as a recurrent finding in the systematic review.
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional manifestations included dental anomalies, skeletal
      abnormalities, neurologic involvement, cardiovascular defects, and
      genitourinary abnormalities.
    explanation: >-
      Lists dental anomalies among the additional manifestations across the
      reported cohort.
- category: Renal
  name: Renal Hypoplasia
  description: >-
    Renal hypoplasia/aplasia and cortical thinning were reported in three new
    families in 2024 and proposed as an addition to the clinical spectrum.
  phenotype_term:
    preferred_term: Renal hypoplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
  frequency: VERY_RARE
  evidence:
  - reference: PMID:38738944
    reference_title: "Filippi syndrome: Three new families suggest that urinary system abnormalities may belong to clinical spectrum of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients exhibited novel clinical features that have not previously
      been associated with Filippi syndrome, including renal hypoplasia/aplasia,
      renal cysts, renal cortical thinning, hypomelanotic, and hypermelanotic
      macules.
    explanation: >-
      The only report of renal involvement, in three families; the "not
      previously associated" framing supports a VERY_RARE band pending
      replication.
- category: Renal
  name: Renal Cysts
  description: >-
    Renal cysts were reported in the same 2024 series. Their mechanistic
    interest is disproportionate to their frequency: cystic kidney disease is a
    canonical ciliopathy readout and would be the most direct clinical support
    for the emerging centrosomopathy model.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  frequency: VERY_RARE
  evidence:
  - reference: PMID:38738944
    reference_title: "Filippi syndrome: Three new families suggest that urinary system abnormalities may belong to clinical spectrum of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including renal hypoplasia/aplasia, renal cysts, renal cortical thinning,
      hypomelanotic, and hypermelanotic macules
    explanation: >-
      Documents renal cysts among the newly described urinary-system features.
- category: Dermatologic
  name: Hypopigmented and Hyperpigmented Macules
  description: >-
    Hypomelanotic and hypermelanotic macules were described in the same 2024
    three-family series as a newly recognized pigmentary feature.
  phenotype_term:
    preferred_term: Hypopigmented skin patches
    term:
      id: HP:0001053
      label: Hypopigmented skin patches
  frequency: VERY_RARE
  evidence:
  - reference: PMID:38738944
    reference_title: "Filippi syndrome: Three new families suggest that urinary system abnormalities may belong to clinical spectrum of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including renal hypoplasia/aplasia, renal cysts, renal cortical thinning,
      hypomelanotic, and hypermelanotic macules
    explanation: >-
      Documents both hypo- and hyperpigmented macules; the HPO term captures the
      hypopigmented component only.
- category: Skeletal
  name: Talipes Equinovarus
  description: >-
    Unilateral congenital talipes equinovarus was reported once as a feature not
    previously recorded in the syndrome.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  frequency: VERY_RARE
  evidence:
  - reference: PMID:33913579
    reference_title: Identification of a novel pathogenic variant in CKAP2L and literature review in a child with Filippi syndrome and congenital talipes equinovarus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a further female patient of Filippi syndrome who additionally had a
      unilateral congenital talipes equinovarus (CTEV), a feature not previously
      recorded, is described
    explanation: >-
      Single-patient report explicitly framed as a previously unrecorded
      feature, supporting the VERY_RARE band.
genetic:
- name: CKAP2L
  association: Causative (biallelic loss of function)
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CKAP2L
    term:
      id: hgnc:26877
      label: CKAP2L
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    Reported alleles are predominantly frameshift (c.571dupA/p.Ile191Asnfs*6,
    c.552_555delCAAA/p.Asn184Lysfs*8, c.554_555del, c.981_982del,
    c.1463_1467del, c.1169_1173del/p.Ile390LysfsTer4), with canonical splice-site
    and start-codon alleles also described. The single reported missense allele
    (c.2066G>A/p.Arg689His) was found in trans with a frameshift allele. MONDO
    records CKAP2L (HGNC:26877) as the causal gene for MONDO:0010092 via
    RO:0004003, matching this curation.
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings show that loss-of-function mutations in CKAP2L are a major
      cause of Filippi syndrome.
    explanation: >-
      Establishes CKAP2L loss-of-function variants as the principal cause of the
      syndrome.
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger sequencing of CKAP2L in a further eight unrelated individuals with
      clinical features consistent with Filippi syndrome revealed biallelic
      mutations in four subjects.
    explanation: >-
      Replication cohort: biallelic CKAP2L variants in 4 of 8 additional
      clinically diagnosed individuals — supporting causation while also showing
      that clinically diagnosed Filippi syndrome is genetically heterogeneous.
  - reference: PMID:34921061
    reference_title: Novel variants identified in CKAP2L in two siblings with Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing of the family identified a missense variant,
      c.2066G > A;p.(Arg689His), in trans with a frameshift variant,
      c.1169_1173del;p.(Ile390LysfsTer4), in CKAP2L
    explanation: >-
      Extends the allelic spectrum beyond pure loss-of-function alleles with the
      first reported missense variant, found in trans with a frameshift.
  - reference: PMID:38738944
    reference_title: "Filippi syndrome: Three new families suggest that urinary system abnormalities may belong to clinical spectrum of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three patients had homozygous frameshift variants of the CKAP2L gene,
      specifically NM_152515.3: c.554_555del, c.981_982del, and c.1463_1467del,
      with the second being a novel variant.
    explanation: >-
      Three additional molecularly confirmed families with homozygous frameshift
      alleles.
treatments:
- name: Supportive and Symptom-Directed Care
  description: >-
    No disease-modifying therapy exists. Reported management across the
    published cohort is supportive and symptom-directed, coordinated across
    genetics, neurology, orthopaedics/plastic surgery, ophthalmology, dentistry,
    and nephrology as dictated by the individual's features.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reported management was mainly supportive and symptom-directed, including
      surgical correction of syndactyly and rehabilitative therapies.
    explanation: >-
      The systematic review's management summary across all reported patients.
- name: Surgical Correction of Syndactyly
  description: >-
    Operative separation of the fused digits is the main structural intervention
    reported, undertaken to improve hand function and, secondarily, foot
    mechanics.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including surgical correction of syndactyly and rehabilitative therapies
    explanation: >-
      Identifies syndactyly release as the principal reported surgical
      intervention.
- name: Developmental and Rehabilitative Therapy
  description: >-
    Physical, occupational, and speech/language therapy for the developmental
    delay, motor impairment, and speech impairment that accompany the
    microcephaly.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including surgical correction of syndactyly and rehabilitative therapies
    explanation: >-
      Rehabilitative therapies are named as a component of reported management.
- name: Anti-Seizure Medication
  description: >-
    Standard anti-seizure pharmacotherapy for the subset of individuals with
    epilepsy. No agent is mechanism-matched to the CKAP2L spindle defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Genetic Counseling
  description: >-
    Autosomal recessive counseling with a 25% sibling recurrence risk, carrier
    testing for at-risk relatives, and discussion of the high rate of
    consanguinity in reported families. Counseling should also convey that
    clinically diagnosed Filippi syndrome is genetically heterogeneous — only
    about half of clinically diagnosed individuals in the replication cohort
    carried biallelic CKAP2L variants — so a negative CKAP2L result does not
    exclude the clinical diagnosis.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25439729
    reference_title: Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger sequencing of CKAP2L in a further eight unrelated individuals with
      clinical features consistent with Filippi syndrome revealed biallelic
      mutations in four subjects.
    explanation: >-
      Supports the counseling point that only a fraction of clinically
      diagnosed individuals carry biallelic CKAP2L variants.
discussions:
- discussion_id: mismatch_ckap2l_knockout_mouse_lacks_human_phenotype
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does a constitutive Ckap2l knockout mouse show no overt developmental
    abnormality — no microcephaly, no growth failure, no digit anomaly — when
    biallelic human CKAP2L loss of function causes a multiple-congenital-anomaly
    syndrome?
  attaches_to:
  - "pathophysiology#Neural Progenitor Division Failure"
  - "pathophysiology#Cortical Progenitor Pool Depletion"
  - "pathophysiology#Reduced Cortical Neuron Output and Postnatal Microcephaly"
  rationale: >-
    This is the sharpest open problem in the disorder's mechanism. The canonical
    model attributes human microcephaly to CKAP2L-dependent neural progenitor
    division, and the mouse ortholog radmis was the source of that model — yet
    the 2026 constitutive knockout produced only reduced male fertility with
    abnormally elongated sperm flagella, not the human developmental phenotype.
    Candidate explanations that would change how the mechanism should be curated
    include: (1) mouse-specific paralog redundancy (e.g. CKAP2) that human
    progenitors lack; (2) a human-specific requirement in outer radial glia and
    the OSVZ, the compartment responsible for primate cortical expansion and
    absent from lissencephalic mouse cortex — the same argument already recorded
    for other progenitor microcephalies in this KB; or (3) that the human
    phenotype does not in fact arise from the progenitor-proliferation arm at
    all. Until this is resolved, the mouse data support the cellular spindle
    phenotype but do not license the inference from spindle defect to human
    microcephaly.
  proposed_experiments:
  - experiment_id: exp_ckap2l_human_cortical_organoid
    name: CKAP2L-null human cortical organoid phenotyping
    description: >-
      Generate CKAP2L-null and patient-variant human iPSC-derived cortical
      organoids alongside isogenic controls and quantify apical and basal
      progenitor number, outer-radial-glia abundance, spindle orientation, and
      organoid size across corticogenesis.
    experiment_type:
      preferred_term: human iPSC-derived organoid disease modeling
    decision_criterion: >-
      The progenitor arm is supported for human biology if CKAP2L-null organoids
      show reduced progenitor number and organoid size relative to isogenic
      controls; a null result would argue that the mouse-based progenitor model
      does not explain the human phenotype.
  - experiment_id: exp_ckap2l_ckap2_paralog_redundancy
    name: Ckap2l/Ckap2 paralog-redundancy test in mouse cortex
    description: >-
      Compare Ckap2l single-knockout with Ckap2l;Ckap2 double-knockout mouse
      cortex for progenitor depletion, spindle phenotype, and brain size.
    experiment_type:
      preferred_term: mouse compound-knockout genetic interaction study
    decision_criterion: >-
      Paralog redundancy explains the absent single-knockout phenotype if the
      double knockout, but not the single knockout, reproduces progenitor
      depletion and reduced brain size.
  - experiment_id: exp_ckap2l_primary_human_progenitor_spindle
    name: Spindle phenotype in primary human neural progenitors
    description: >-
      Assay primary human fetal neural progenitors, or patient-derived cells
      differentiated to a progenitor state, for the multipolar-spindle and
      cytokinesis-failure phenotypes described in lymphoblastoid cells.
    experiment_type:
      preferred_term: primary human cell immunofluorescence assay
    decision_criterion: >-
      The cellular defect is relevant to the disease-affected cell type if
      multipolar spindles and cytokinesis failure are reproduced in human neural
      progenitors, not only in lymphoblastoid lines.
  evidence:
  - reference: PMID:41370039
    reference_title: Filippi syndrome-associated CKAP2L modulates microtubule dynamics essential for mitosis and ciliary length regulation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Ckap2l knockout mice show no overt developmental abnormalities, with the
      exception of reduced male fertility, evidenced by decreased sperm count,
      impaired motility, and abnormally elongated flagella.
    explanation: >-
      Documents the failure of the constitutive mouse knockout to reproduce the
      human developmental phenotype — the mismatch itself.
- discussion_id: gap_syndactyly_mechanism_from_spindle_defect
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what tissue-level route does loss of a mitotic spindle protein produce
    cutaneous syndactyly of the fingers and toes — failure of interdigital
    programmed cell death, or a proliferation deficit in the autopod
    mesenchyme?
  attaches_to:
  - "pathophysiology#Impaired Craniofacial and Digital Morphogenesis"
  rationale: >-
    Digit separation depends on interdigital apoptosis, not on progenitor
    proliferation, so the canonical proliferation-deficit model does not
    obviously explain the digital half of the craniodigital phenotype. No
    published experiment connects CKAP2L to interdigital cell death or to the
    SHH/GLI3/HOXD patterning gradients that drive the limb/digit serial-homology
    module. This is why this entry declares conformance to the neural-progenitor
    centrosome-spindle module for the microcephaly arm but deliberately declines
    to declare conformance to limb_digit_patterning_serial_homology for the
    syndactyly arm, despite the phenotype being serially homologous across hands
    and feet. Resolving the route would either license that second conformance
    or establish a distinct apoptosis-based mechanism.
  proposed_experiments:
  - experiment_id: exp_ckap2l_interdigital_apoptosis
    name: Interdigital apoptosis versus proliferation in the autopod
    description: >-
      Examine autopod interdigital regions in a conditional limb-mesenchyme
      Ckap2l knockout (or an alternative model that expresses the digital
      phenotype) for reduced apoptosis versus reduced proliferation, using
      TUNEL/cleaved-caspase and mitotic-index staining at the embryonic stages
      of digit separation.
    experiment_type:
      preferred_term: conditional-knockout developmental histology study
    decision_criterion: >-
      Syndactyly is apoptosis-driven if interdigital TUNEL/cleaved-caspase
      signal is reduced with a preserved mitotic index, and
      proliferation-driven if the mitotic index falls with preserved
      interdigital cell death.
  - experiment_id: exp_ckap2l_hedgehog_gli3_limb_output
    name: Hedgehog/GLI3-repressor output in CKAP2L-deficient limb mesenchyme
    description: >-
      Test whether CKAP2L loss perturbs Hedgehog pathway activity and the
      GLI3-repressor gradient in limb mesenchyme, by transcriptional readout of
      Hedgehog target genes and GLI3 processing assays.
    experiment_type:
      preferred_term: signalling-pathway readout assay
    decision_criterion: >-
      Conformance to the limb/digit patterning module would become appropriate
      if CKAP2L loss measurably shifts GLI3 processing or Hedgehog target-gene
      output in limb mesenchyme.
- discussion_id: gap_centrosomopathy_reclassification_clinical_correlate
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: >-
    Should Filippi syndrome be reclassified as a centrosomopathy/ciliopathy, and
    is there a clinical correlate of the ciliary-length defect in patients?
  attaches_to:
  - "pathophysiology#Primary Cilium Elongation"
  - "pathophysiology#Impaired Craniofacial and Digital Morphogenesis"
  rationale: >-
    The reclassification proposal rests on cell-line data showing elongated
    primary cilia after CKAP2L depletion. The clinical spectrum contains two
    features that are suggestive of a ciliopathy — renal cysts and renal
    hypoplasia, reported in three families in 2024 — but the two observations
    have never been connected in the same patients, and syndactyly plus
    microcephaly are not by themselves ciliopathy-specific. If the link holds,
    conformance to ciliopathy_dysfunction (and possibly renal_cystogenesis)
    would become appropriate; on current evidence it would be premature.
  proposed_experiments:
  - experiment_id: exp_ckap2l_patient_fibroblast_cilium_length
    name: Cilium length and Hedgehog competence in patient fibroblasts
    description: >-
      Measure primary cilium length and Hedgehog-response competence in
      fibroblasts derived from individuals carrying biallelic CKAP2L variants,
      alongside isogenic or unaffected-relative controls.
    experiment_type:
      preferred_term: patient-derived primary fibroblast assay
    decision_criterion: >-
      The centrosomopathy model gains patient-level support if biallelic-variant
      fibroblasts show significantly elongated cilia and blunted Hedgehog
      response relative to controls.
  - experiment_id: exp_ckap2l_systematic_renal_imaging
    name: Systematic renal imaging in molecularly confirmed patients
    description: >-
      Image the kidneys of all reported and newly ascertained CKAP2L-confirmed
      patients to establish whether renal cysts and hypoplasia are recurrent
      rather than incidental.
    experiment_type:
      preferred_term: cross-sectional clinical imaging study
    decision_criterion: >-
      Renal involvement belongs in the core spectrum, and supports a ciliopathy
      reading, if cysts or hypoplasia are found in a substantial fraction of
      molecularly confirmed patients rather than only the three index families.
  evidence:
  - reference: PMID:38738944
    reference_title: "Filippi syndrome: Three new families suggest that urinary system abnormalities may belong to clinical spectrum of the disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the limited number of reported Filippi syndrome patients to date and
      the ongoing discovery of new clinical aspects of the disease, exploring
      its potential connection with kidney and skin pigmentation abnormalities
      could be valuable for future research.
    explanation: >-
      The authors themselves frame the renal association as provisional and in
      need of further study, which is why it supports only an emerging
      hypothesis.
- discussion_id: gap_genotype_phenotype_correlation_ckap2l
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is there a genotype-phenotype correlation in CKAP2L-related Filippi
    syndrome — in particular, do hypomorphic (missense) alleles explain the
    reported patients with milder neurodevelopmental outcome?
  attaches_to:
  - "pathophysiology#Reduced Cortical Neuron Output and Postnatal Microcephaly"
  rationale: >-
    Cognitive outcome ranges from severe intellectual disability with epilepsy
    to preserved intellect in an adolescent male, yet almost all reported
    alleles are frameshift and presumed complete loss of function, leaving the
    variability unexplained by allele class alone. The single reported missense
    allele has not been functionally characterized. With only 43 published
    patients — a mixture of molecularly confirmed and clinically diagnosed
    cases — the cohort is too small and too heterogeneous to support a
    correlation analysis, which the systematic review states explicitly.
  proposed_experiments:
  - experiment_id: exp_ckap2l_patient_registry_genotype_phenotype
    name: CKAP2L patient registry for genotype-phenotype analysis
    description: >-
      Establish an international CKAP2L patient registry with standardized
      neurodevelopmental, growth, and imaging assessment, restricted to
      molecularly confirmed cases, to power a genotype-phenotype analysis.
    experiment_type:
      preferred_term: multicentre patient registry study
    decision_criterion: >-
      A genotype-phenotype correlation exists if allele class or residual
      function stratifies neurodevelopmental outcome across the registry cohort.
  - experiment_id: exp_ckap2l_arg689his_functional_characterization
    name: Functional characterization of the p.Arg689His missense allele
    description: >-
      Assay the p.Arg689His variant for CKAP2L spindle-pole localization,
      microtubule binding, and rescue of the multipolar-spindle phenotype in
      CKAP2L-null cells.
    experiment_type:
      preferred_term: variant functional rescue assay
    decision_criterion: >-
      The allele is hypomorphic rather than null if it retains partial
      spindle-pole localization and partially rescues the spindle phenotype.
  evidence:
  - reference: PMID:42404495
    reference_title: "Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further studies will be needed to delineate genotype-phenotype correlation
      and standardize treatment guidelines.
    explanation: >-
      The systematic review states the genotype-phenotype gap as an explicit
      conclusion.
notes: >-
  Diagnostic boundary. The literature distinguishes molecularly confirmed
  CKAP2L-related Filippi syndrome from "Filippi-like" overlapping craniodigital
  phenotypes, and the 2026 systematic review deliberately included both, which
  inflates the apparent phenotypic spectrum. Only about half of the individuals
  with a clinical Filippi diagnosis in the original replication cohort carried
  biallelic CKAP2L variants (4 of 8), so figures drawn from mixed cohorts should
  not be read as CKAP2L genotype-specific. This entry is scoped to
  CKAP2L-related disease (MONDO:0010092); phenotype frequencies taken from the
  systematic review are cohort-level, and the mechanism is anchored exclusively
  on molecularly confirmed evidence.


  Module conformance. The microcephaly arm conforms across four nodes of
  neural_progenitor_centrosome_spindle_dysfunction (perturbation → abnormal
  progenitor division → pool distortion → cortical output). Conformance to
  limb_digit_patterning_serial_homology is deliberately NOT declared even though
  the syndactyly is serially homologous across hands and feet, because no
  evidence links CKAP2L to the patterning-gradient trigger that module requires;
  see the syndactyly knowledge-gap discussion. Conformance to
  ciliopathy_dysfunction is likewise withheld pending a patient-level correlate
  of the cell-line ciliary phenotype.


  Historical note. The condition is also indexed as syndactyly type I with
  microcephaly and intellectual disability, and as Scott craniodigital syndrome;
  older reports predate the 2014 gene discovery and are clinical diagnoses only.
  Pre-2014 literature (including PMID:18553552) tested and excluded GJA1 before
  CKAP2L was known.
📚

References & Deep Research

References

9
PMID:25439729
Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
No top-level findings curated for this source.
PMID:42404495
Clinical and Genetic Spectrum of Filippi Syndrome: A Systematic Review of Published Case Reports and Case Series.
No top-level findings curated for this source.
PMID:41370039
Filippi syndrome-associated CKAP2L modulates microtubule dynamics essential for mitosis and ciliary length regulation.
No top-level findings curated for this source.
PMID:24260314
Radmis, a novel mitotic spindle protein that functions in cell division of neural progenitors.
No top-level findings curated for this source.
PMID:34921061
Novel variants identified in CKAP2L in two siblings with Filippi syndrome.
No top-level findings curated for this source.
PMID:33913579
Identification of a novel pathogenic variant in CKAP2L and literature review in a child with Filippi syndrome and congenital talipes equinovarus.
No top-level findings curated for this source.
PMID:38738944
Filippi syndrome: Three new families suggest that urinary system abnormalities may belong to clinical spectrum of the disease.
No top-level findings curated for this source.
PMID:18553552
Filippi syndrome: further clinical characterization.
No top-level findings curated for this source.
PMID:35224850
Expansion of the neurodevelopmental phenotypic spectrum of CKAP2L-related Filippi syndrome to include an adolescent male with normal intellect.
No top-level findings curated for this source.