TUBGCP2-related Lissencephaly Spectrum Disorder

Mendelian MONDO:0032893 Pathograph 30 Show in embeddings browser congenital nervous system disorder hereditary neurological disease

TUBGCP2-related lissencephaly spectrum disorder is an autosomal recessive neurodevelopmental disease caused by biallelic TUBGCP2 variants. The 2025 eight-person literature review found pachygyria, microcephaly, and developmental delay in all eight individuals, seizures and dysmorphic facial features in seven, and a variable set of callosal, cerebellar, brainstem, and white-matter abnormalities. Later reports added a pachygyria-polymicrogyria complex with a thick corpus callosum and cystic leukomalacia to the radiological spectrum. Mechanistic evidence is narrower than the clinical association. For the p.Glu311Lys allele, structural analysis predicts disruption of the GCP2-GCP3 electrostatic interface, while patient fibroblasts show faint delocalization of gamma-tubulin, HAUS6, and NEDD1 but normal GCP2 abundance. Neither microtubule nucleation nor neuronal migration has been measured in patient neural cells. Depletion models in zebrafish and Drosophila reproduce reduced brain size; zebrafish pH3 staining establishes an altered developing-brain mitotic state but cannot distinguish mitotic arrest from over-proliferation.

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1
Inheritance
7
Pathophys.
19
Phenotypes
4
Gaps
30
Pathograph
1
Genes
3
Medical Actions
3
Models
7
References
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic TUBGCP2 variants have been reported in homozygous and compound configurations, including two paternal missense variants opposite a maternal multi-exon deletion. Recurrence counseling depends on confirming the familial variants and parental phase rather than assuming a single configuration for every family.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:31630790 SUPPORT Human Clinical
"Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder"
The delineating study's own statement of the mode of inheritance and the disease class.
PMID:31630790 SUPPORT Human Clinical
"By querying clinical exome sequencing cases and through GeneMatcher-facilitated collaborations, we found three additional families with bi-allelic variation and similarly affected phenotypes"
Documents both homozygous and compound heterozygous configurations across independent families.
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Discussions and Knowledge Gaps

4
Do TUBGCP2 disease alleles act by loss of function, or by interfering with gamma-TuRC assembly while the subunit remains present?
KNOWLEDGE GAP OPEN gap_tubgcp2_functional_impact_class
Attached to
pathophysiology#Biallelic TUBGCP2 Variation
The mixed allele series includes missense, splice-altering, frameshift, and multi-exon deletion variants, but no common assay establishes their effects. For p.Glu311Lys, GCP2 abundance is preserved while gamma-tubulin, HAUS6, and NEDD1 localization changes. That allele-specific result does not classify the truncating, splice, or deletion alleles and does not demonstrate a dominant-negative mechanism. Functional impact therefore remains UNKNOWN.
Proposed experiments
Allele-series rescue in TUBGCP2-null cells
exp_tubgcp2_allele_series_rescue
Re-express each reported allele in a TUBGCP2 knockout background and score gamma-TuRC assembly, nucleation rate, and HAUS6/NEDD1 localization. A matched allele series would distinguish preserved, partial, and absent function without inferring an effect from variant class alone.
Do patient neural progenitors show altered gamma-TuRC localization, microtubule nucleation, mitotic dynamics, or neuronal migration?
KNOWLEDGE GAP OPEN gap_tubgcp2_human_neural_validation
Attached to
pathophysiology#Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation pathophysiology#Altered Developing-Brain Mitotic State pathophysiology#Neuronal Migration Failure
Current functional evidence comes from p.Glu311Lys skin fibroblasts and low-fidelity depletion/null animal models. The human cortical imaging suggests a migration disorder, but no patient-derived neural system measures migration, mitosis, or nucleation. This missing bridge prevents a causal assignment from the fibroblast localization phenotype to cortical malformation.
Proposed experiments
Isogenic patient iPSC neural-progenitor and migration assays
exp_tubgcp2_patient_neural_models
Generate patient and corrected iPSC-derived neural progenitors and cortical organoids; quantify gamma-TuRC localization, microtubule nucleation, live-cell mitotic timing, progenitor survival, and radial migration.
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"Currently, functional and proteomic studies on TUBGCP2 gene variants in human neurons are lacking."
The review explicitly identifies the human-neural evidence gap.
Why does TUBGCP2 disease produce a thin corpus callosum in most patients but a thick one in at least one, and does the direction track the allele?
KNOWLEDGE GAP OPEN gap_tubgcp2_corpus_callosum_direction
Attached to
phenotypes#Thin Corpus Callosum phenotypes#Thick Corpus Callosum
Thin corpus callosum occurred in 6/8 people in the 2025 review, while a later patient with homozygous c.2647dupC/p.Gln883Profs*62 had a thick corpus callosum. With one thick-callosum report, it is unknown whether direction tracks genotype, age, a modifier, or measurement differences.
Proposed experiments
Genotype-stratified callosal morphometry across reported cases
exp_tubgcp2_callosal_morphometry
Pool published TUBGCP2 MRIs, measure callosal cross-sectional area against age norms, and test whether truncating alleles separate from missense alleles on that measure.
Show evidence (1 reference)
PMID:40448381 SUPPORT Human Clinical
"Brain MRI revealed cortical malformations consistent with the pachygyria-polymicrogyria complex, as well as a thickened corpus callosum."
Direct evidence for the later opposite-direction callosal finding.
Does L-serine alter a disease-relevant phenotype in TUBGCP2 neural models?
OPEN QUESTION OPEN gap_tubgcp2_l_serine_translation
Attached to
pathophysiology#Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation
A patient-fibroblast experiment found an 8% proliferation increase in both patient and control cells and a larger numerical reduction in cytotoxicity in patient cells, but neither result reached statistical significance. There is no animal or human treatment evidence, so L-serine remains a model-only observation rather than a treatment.
Show evidence (1 reference)
PMID:33458610 SUPPORT In Vitro
"L-serine treatment in cultured skin fibroblasts revealed an 8% increased proliferation in both TUBGCP2-patient and control, while a 26% reduction of cytotoxicity was detected in patient-derived cells compared to 14% in controls. These changes did not reach statistical significance."
The exact nonsignificant in-vitro result that motivates, but does not answer, the question.
⚙

Pathophysiology

7
Biallelic TUBGCP2 Variation
The disease is associated with biallelic germline TUBGCP2 variants. Reported configurations include homozygous missense and frameshift variants, compound-heterozygous missense and splice-altering variants, and two paternal missense variants opposite a maternal deletion of exons 2-14. The functional class is left UNKNOWN because no study has compared the full allele series in a common functional assay.
TUBGCP2 hgnc:18599 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TUBGCP2 (hgnc:18599). hgnc:18599 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: missense, splice-altering, frameshift, multi-exon deletion variant_origin: GERMLINE functional_impact_category: UNKNOWN
Disease-wide context spanning homozygous, compound-heterozygous, and hemizygous-by-deletion configurations; zygosity is intentionally omitted because the schema has no generic biallelic value. Truncating and deletion alleles are not assigned loss of function without a direct assay, and no dominant-negative mechanism has been demonstrated.
Downstream
Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation The p.Glu311Lys allele has computational and patient-fibroblast evidence; whether the same proximal effect applies to every reported allele is not established.
Dysmorphic Facial Features The developmental route from TUBGCP2 variation to facial dysmorphism is unknown.
Show evidence (1 reference)
PMID:31630790 SUPPORT Human Clinical
"By querying clinical exome sequencing cases and through GeneMatcher-facilitated collaborations, we found three additional families with bi-allelic variation and similarly affected phenotypes"
Establishes the replicated biallelic gene-disease association without assigning a uniform molecular effect to the different alleles.
Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation
Evidence for this proximal cellular state is allele-specific. Structural analysis predicts that p.Glu311Lys disrupts electrostatic interaction at the GCP2-GCP3 interface. Primary fibroblasts carrying that allele have normal GCP2 abundance but faint delocalization of gamma-tubulin, HAUS6, and NEDD1, plus broader cytoskeletal proteomic changes. The study did not measure microtubule-nucleation rate, and fibroblasts are not a neural model.
microtubule cytoskeleton organization GO:0000226 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated microtubule cytoskeleton organization (GO:0000226). GO:0000226 is a biological process from the Gene Ontology. ↕ DYSREGULATED
gamma-tubulin ring complex GO:0000931 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves dysregulated gamma-tubulin ring complex (GO:0000931). GO:0000931 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 dysregulated centrosome (GO:0005813). GO:0005813 is a cellular component from the Gene Ontology.
Experimental models
p.Glu311Lys Patient Fibroblasts PRIMARY CELL CULTURE Measures gamma-tubulin, HAUS6, and NEDD1 localization and GCP2 abundance for p.Glu311Lys in primary patient cells.
Downstream
Altered Developing-Brain Mitotic State A mitotic-state abnormality is seen in a depletion model, but its route from the human variant-dependent fibroblast state is not established.
Neuronal Migration Failure Migration is inferred from human cortical imaging; it has not been assayed in patient neural cells or either animal model.
Associated Non-Cortical Structural Brain Abnormalities The developmental route to the non-cortical MRI findings is unresolved.
Show evidence (4 references)
PMID:33458610 SUPPORT Computational
"This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3."
Computational support limited to the p.Glu311Lys interface prediction; it is not a cellular measurement and is not generalized to other alleles.
PMID:33458610 SUPPORT In Vitro
"In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels."
Directly measures altered gamma-tubulin localization and preserved GCP2 abundance in p.Glu311Lys patient fibroblasts.
PMID:33458610 SUPPORT In Vitro
"However, in mitosis, patient fibroblasts presented a faint delocalization of two components associated with the γ-TuRC complex, HAUS6 and NEDD1 (Figure 3A, lower panel, and 3C)."
Exact patient-fibroblast evidence for altered localization of two gamma-TuRC-associated proteins; it does not establish reduced nucleation.
+ 1 more reference
Altered Developing-Brain Mitotic State
Zebrafish tubgcp2 morphants have increased phospho-histone H3-positive cells in the developing brain. This is direction-neutral mechanistic evidence: the experiment establishes altered mitotic cell abundance but explicitly cannot distinguish mitotic arrest from over-proliferation. No comparable measurement has been made in patient neural cells.
Animal models
tubgcp2 Morpholino Zebrafish Danio rerio partially recapitulates Measures altered abundance of mitotic cells in the developing morphant brain.
Downstream
Reduced Brain Growth and Microcephaly The model links altered mitotic-cell abundance with reduced brain size, but the intervening cell-fate and population dynamics remain unresolved.
Show evidence (1 reference)
PMID:36078134 SUPPORT Model Organism
"Compared to the control group (Figure 3a), we find significant and similar accumulation of mitotic brain cells in the morphant small-brain groups for both splicing and translation disruption (Figure 3b–d). However, these data do not distinguish over-proliferation from mitotic arrest."
Supports a direction-neutral mitotic/proliferative disturbance in a low-fidelity depletion model, not decreased proliferation or migration.
Reduced Brain Growth and Microcephaly
Microcephaly was present in all eight individuals summarized in the 2025 review. Independent zebrafish and fly depletion/null models show reduced brain size, but those low-fidelity models do not establish the human cellular route or reproduce the cortical-folding phenotype.
Animal models
tubgcp2 Morpholino Zebrafish Danio rerio partially recapitulates Reproduces reduced larval head width and demonstrates partial wild-type-mRNA rescue.
Grip84-cg7716 Double-Knockout Fly Drosophila melanogaster partially recapitulates Reproduces reduced brain surface area in a two-homolog null background.
Downstream
Microcephaly The tissue-level reduced-brain-growth state is expressed clinically as microcephaly.
Global Developmental Delay The neurodevelopmental intermediates producing global delay are unresolved.
Seizures The epileptogenic circuit intermediates are unresolved.
Developmental Regression The mechanism of regression in the severely affected patient is unresolved.
Generalized Hypotonia The neural and motor-system intermediates producing hypotonia are unresolved.
Spasticity The corticospinal intermediates producing spasticity are unresolved.
Show evidence (2 references)
PMID:40017707 SUPPORT Human Clinical
"All eight patients (three females and five males, ages ranging from 1 to 10 years) presented with LIS and microcephaly."
Direct human support for universal microcephaly in the eight-person review set.
PMID:36078134 SUPPORT Model Organism
"In larvae injected with splice- or translation-blocking MOs, an experimental average of 88% develop the microcephaly phenotype (defined as a reduction of head width by more than two standard deviations compared to controls) (Figure 2a)."
Supports reduced brain size in a zebrafish depletion model, with no claim that it reproduces the human cortical or allelic mechanism.
Neuronal Migration Failure
The founding study interpreted pachygyria and subcortical band heterotopia as presumably caused by disrupted neuronal migration. Migration has not been directly measured in patient-derived neural cells, zebrafish, or fly, so this node remains a partially supported imaging-based hypothesis.
neuron migration GO:0001764 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated neuron migration (GO:0001764). GO:0001764 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Lissencephaly Spectrum Cortical Malformation A migration defect is a plausible route to the cortical phenotype, but direct cellular validation and relevant intermediates are lacking.
Show evidence (1 reference)
PMID:31630790 SUPPORT Human Clinical
"Brain imaging from all five affected individuals revealed varying degrees of cortical malformations including pachygyria and subcortical band heterotopia, presumably caused by disruption of neuronal migration."
The authors explicitly hedge the imaging-to-mechanism inference; migration itself was not assayed.
Lissencephaly Spectrum Cortical Malformation
The cortical phenotype spans pachygyria, agyria, subcortical band heterotopia, and a reported pachygyria-polymicrogyria complex. Pachygyria was present in all eight people summarized in the 2025 review. Cystic leukomalacia is kept separate as a non-cortical radiological extension.
Downstream
Pachygyria Pachygyria is the constant cortical imaging manifestation in the review set.
Subcortical Band Heterotopia Subcortical band heterotopia is a less frequent cortical manifestation.
Polymicrogyria Polymicrogyria was reported as part of a pachygyria-polymicrogyria complex.
Show evidence (2 references)
PMID:40017707 SUPPORT Human Clinical
"the TUBGCP2 variants were found to cause lissencephaly spectrum diseases, with the main clinical manifestations being microcephaly, lissencephaly (including agyria, pachygyria, or subcortical band heterotopia)"
Defines the human cortical-malformation spectrum.
PMID:40448381 SUPPORT Human Clinical
"Brain MRI revealed cortical malformations consistent with the pachygyria-polymicrogyria complex, as well as a thickened corpus callosum."
Extends the directly observed cortical phenotype to a pachygyria-polymicrogyria complex.
Associated Non-Cortical Structural Brain Abnormalities
Callosal, cerebellar, brainstem, white-matter, cystic, and visual-system abnormalities expand the structural spectrum beyond the cortex. Their developmental links to TUBGCP2 and to each other are not established.
Downstream
Thin Corpus Callosum
Cerebellar Volume Loss
Subependymal Cysts
Brainstem Hypoplasia
Cerebral White Matter Abnormality
Thick Corpus Callosum
Optic Atrophy
Cerebral Visual Impairment
Show evidence (2 references)
PMID:40017707 SUPPORT Human Clinical
"All eight patients had abnormal brain MRI findings, including pachygyria in eight (100%); thin corpus callosum in six (75%); cerebellar volume loss in three (37.5%); SBH, subependymal cyst, thin brainstem, and cystic foci in white matter in two each (25%); delayed myelination in one (12.5%); and..."
Quantifies the non-cortical MRI findings in the eight-person review set.
PMID:42472988 SUPPORT Human Clinical
"we identified a rare case of TUBGCP2-related tubulinopathy presenting with cystic leukomalacia, expanding the known radiological spectrum."
Supports cystic leukomalacia as a later non-cortical radiological extension, not as evidence for the cortical-malformation mechanism.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for TUBGCP2-related Lissencephaly Spectrum Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

19
Eye 1
Optic Atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"Moreover, a few patients present with visual system abnormalities, including optic atrophy and cortical blindness."
Supports optic atrophy without a count-based frequency.
Head and Neck 2
Microcephaly OBLIGATE 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:40017707 SUPPORT Human Clinical
"All eight patients (three females and five males, ages ranging from 1 to 10 years) presented with LIS and microcephaly."
8/8 in the 2025 review set is direct support for the OBLIGATE band.
Dysmorphic Facial Features 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:40017707 SUPPORT Human Clinical
"seven patients (87.5%) had dysmorphic facial features, including recruitment in the ear of five (71.4%); narrow forehead, thick eyebrows, and smooth philtrum in four each (57.1%)"
7/8 = 87.5% broad dysmorphism in the 2025 review set, which is VERY_FREQUENT; narrow forehead occurred in only four of those seven.
Musculoskeletal 2
Generalized Hypotonia HP:0001290 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized hypotonia (HP:0001290). HP:0001290 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33458610 SUPPORT Human Clinical
"She presented with severe developmental delay, hypotonia, and intractable epilepsy at age 6 months and lost all motor and cognitive abilities gradually by 4 years of age."
Exact patient-level evidence for hypotonia; it also documents regression, which is curated separately.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33458610 SUPPORT Human Clinical
"Neurological examination revealed microcephaly, atrophy, and contractures of the extremities with brisk deep tendon reflexes and spasticity."
Exact patient-examination evidence for spasticity.
Nervous System 8
Polymicrogyria HP:0002126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polymicrogyria (HP:0002126). HP:0002126 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40448381 SUPPORT Human Clinical
"Brain MRI revealed cortical malformations consistent with the pachygyria-polymicrogyria complex, as well as a thickened corpus callosum."
Direct case-report support for polymicrogyria in the cortical spectrum.
Global Developmental Delay OBLIGATE 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:40017707 SUPPORT Human Clinical
"All eight patients exhibited DD, with six (75%) having speech and motor delay"
8/8 in the 2025 review set is OBLIGATE; the same sentence supplies the developmental-domain breakdown.
Seizures VERY_FREQUENT 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:40017707 SUPPORT Human Clinical
"Seizures occurred in seven of the eight (87.5%) patients, with the age at seizure onset ranging from 5 months to 4 years and a median age of 21.5 months."
7/8 = 87.5% in the 2025 review set, which is VERY_FREQUENT, and the same sentence supplies the onset window.
Thin Corpus Callosum FREQUENT Hypoplasia of the corpus callosum HP:0002079 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the corpus callosum (HP:0002079). HP:0002079 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"All eight patients had abnormal brain MRI findings, including pachygyria in eight (100%); thin corpus callosum in six (75%)"
6/8 = 75% in the 2025 review set, which is FREQUENT.
Cerebellar Volume Loss FREQUENT Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"cerebellar volume loss in three (37.5%)"
3/8 = 37.5% in the 2025 review set, which is FREQUENT (30-79%).
Cerebral White Matter Abnormality OCCASIONAL Abnormal cerebral white matter morphology HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"SBH, subependymal cyst, thin brainstem, and cystic foci in white matter in two each (25%)"
2/8 = 25% in the 2025 review set, which is OCCASIONAL.
Developmental Regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33458610 SUPPORT Human Clinical
"She presented with severe developmental delay, hypotonia, and intractable epilepsy at age 6 months and lost all motor and cognitive abilities gradually by 4 years of age."
Exact patient-level evidence for loss of acquired abilities.
EEG Abnormality HP:0002353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG abnormality (HP:0002353). HP:0002353 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"Among the seven patients with seizures, five (71.4%) had abnormal EEG results, illustrating continuous slow background activity and epileptiform discharges."
Supports the EEG abnormality and its subgroup denominator.
Other 6
Pachygyria OBLIGATE HP:0001302 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pachygyria (HP:0001302). HP:0001302 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40017707 SUPPORT Human Clinical
"All eight patients had abnormal brain MRI findings, including pachygyria in eight (100%)"
8/8 = 100% in the explicitly scoped 2025 review set, which is OBLIGATE.
PMID:40448381 SUPPORT Human Clinical
"Brain MRI revealed cortical malformations consistent with the pachygyria-polymicrogyria complex, as well as a thickened corpus callosum."
A later case extends the morphology but is not added to the 8-person frequency denominator.
Subcortical Band Heterotopia OCCASIONAL HP:0032409 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Subcortical band heterotopia (HP:0032409). HP:0032409 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31630790 SUPPORT Human Clinical
"Brain imaging from all five affected individuals revealed varying degrees of cortical malformations including pachygyria and subcortical band heterotopia"
Establishes subcortical band heterotopia as part of the cortical spectrum in the delineating cohort.
PMID:40017707 SUPPORT Human Clinical
"SBH, subependymal cyst, thin brainstem, and cystic foci in white matter in two each (25%)"
2/8 = 25% in the 2025 review set, which is OCCASIONAL.
Subependymal Cysts OCCASIONAL HP:0002416 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Subependymal cysts (HP:0002416). HP:0002416 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"SBH, subependymal cyst, thin brainstem, and cystic foci in white matter in two each (25%)"
2/8 = 25% in the 2025 review set, which is OCCASIONAL.
Brainstem Hypoplasia OCCASIONAL Hypoplasia of the brainstem HP:0002365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the brainstem (HP:0002365). HP:0002365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"SBH, subependymal cyst, thin brainstem, and cystic foci in white matter in two each (25%)"
2/8 = 25% in the 2025 review set, which is OCCASIONAL.
Thick Corpus Callosum HP:0007074 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thick corpus callosum (HP:0007074). HP:0007074 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40448381 SUPPORT Human Clinical
"Brain MRI revealed cortical malformations consistent with the pachygyria-polymicrogyria complex, as well as a thickened corpus callosum."
Direct evidence for the opposite callosal direction in one later case.
Cerebral Visual Impairment HP:0100704 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral visual impairment (HP:0100704). HP:0100704 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"Moreover, a few patients present with visual system abnormalities, including optic atrophy and cortical blindness."
Supports a central visual-system phenotype without a count-based frequency.
🧬

Genetic Associations

1
TUBGCP2 (Causative)
Gene: TUBGCP2 (gamma-tubulin complex component 2) hgnc:18599 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TUBGCP2 (gamma-tubulin complex component 2), annotated with TUBGCP2 (hgnc:18599). hgnc:18599 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:31630790 SUPPORT Human Clinical
"Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder"
The founding gene-disease observation.
PMID:40017707 SUPPORT Human Clinical
"In this study, we reported a 6-year-old patient with LIS caused by a hemizygous variant in TUBGCP2 (two paternal missense variants: c.178 C>T, c.538T>C and one maternal exon variant: 2–14 deletion)."
Documents the later mixed missense/deletion configuration.
PMID:40448381 SUPPORT Human Clinical
"Exome sequencing identified a homozygous NM_006659.4:c.2647dupC p.(Gln883Profs*62) variant in the TUBGCP2 gene, which was confirmed by Sanger sequencing."
Documents the later homozygous frameshift allele.
💊

Medical Actions

3
Antiseizure Pharmacotherapy
Category: Therapeutic 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
Anti-seizure medication is selected according to seizure type. This is phenotype-based management extrapolated from general tubulinopathy guidance; no TUBGCP2-specific comparative treatment evidence is available.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf SUPPORT Other
"Seizures are treated with anti-seizure medications based on the specific seizure type."
PARTIAL because this GeneReviews overview does not discuss TUBGCP2 and is used only as phenotype-based management extrapolation.
Supportive and Rehabilitative Care
Category: Therapeutic 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. NCIT:C15747
An individualized plan may include physical, occupational, speech, and vision therapy, with physical therapy addressing complications of spasticity. This is general tubulinopathy guidance rather than a measured TUBGCP2-specific outcome.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf SUPPORT Other
"Supportive management, including an individualized therapy plan that includes physical therapy to manage the complications of spasticity, occupational therapy, speech therapy, and vision therapy for oculomotor deficits and/or strabismus should begin at the time of diagnosis to ensure the best..."
PARTIAL because this general tubulinopathy guidance does not mention TUBGCP2 and supplies no disorder-specific outcome data.
Genetic Counseling
Category: Counseling / Informational 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
Counseling should communicate autosomal recessive inheritance and interpret recurrence in light of confirmed familial variants and parental phase. The cited disease paper does not directly support a numerical recurrence-risk or carrier-testing outcome claim.
Show evidence (1 reference)
PMID:31630790 SUPPORT Human Clinical
"Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder"
PARTIAL support: the source establishes recessive inheritance but does not report a counseling intervention or outcome.
🔬

Diagnosis

2
Brain MRI
Brain MRI defines the malformation spectrum. Pachygyria was present in all eight people in the 2025 review, while subcortical band heterotopia and callosal, cerebellar, brainstem, and white-matter findings were variable. Imaging supports recognition but does not establish the molecular diagnosis.
magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"All eight patients had abnormal brain MRI findings, including pachygyria in eight (100%)"
Directly supports MRI as a consistent clinical investigation in the scoped review set.
Trio exome sequencing with segregation and copy-number validation
In the 2025 case, trio whole-exome sequencing detected sequence and deletion candidates, followed by Sanger validation and qPCR of selected TUBGCP2 exons. This exact workflow supports testing both sequence and copy-number variation; broader panel or genome claims are not inferred from that report.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40017707 SUPPORT Human Clinical
"The pathogenic variants detected using trio-WES were further validated by Sanger sequencing and qPCR."
Exact support for trio-WES followed by orthogonal sequence and copy-number validation.
🧫

Experimental Models

1
p.Glu311Lys Patient Fibroblasts PRIMARY_CELL_CULTURE
Primary skin fibroblasts from an affected person homozygous for p.Glu311Lys, compared with control fibroblasts by immunofluorescence, immunoblotting, proteomics, proliferation, and cytotoxicity assays. This is an allele-specific peripheral-cell model rather than a neural model.
Untreated patient and control fibroblasts L-serine treatment arm
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Primary skin fibroblasts from a p.Glu311Lys patient and controls
Culture
Fibroblast monolayer culture
Publication
PMID:33458610
Pathograph links
Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation partially recapitulates fidelity: low Measures gamma-tubulin, HAUS6, and NEDD1 localization and GCP2 abundance for p.Glu311Lys in primary patient cells.
Limitations: The model is limited to one missense allele and a peripheral cell type; neuronal migration, developing-brain mitosis, and microtubule nucleation were not measured.
Readouts
Gamma-tubulin, HAUS6, and NEDD1 localization
Direction: ALTERED
Interpretation: Faint delocalization in patient fibroblasts supports an allele-specific localization defect.
Show evidence (1 reference)
PMID:33458610 SUPPORT In Vitro
"However, in mitosis, patient fibroblasts presented a faint delocalization of two components associated with the γ-TuRC complex, HAUS6 and NEDD1 (Figure 3A, lower panel, and 3C)."
Direct localization measurement in patient fibroblasts.
GCP2 protein abundance
Direction: UNCHANGED
Interpretation: Preserved abundance bounds the p.Glu311Lys cellular defect but does not classify other alleles.
Show evidence (1 reference)
PMID:33458610 SUPPORT In Vitro
"In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels."
Directly reports unchanged GCP2 abundance in the model.
Show evidence (1 reference)
PMID:33458610 SUPPORT In Vitro
"Fibroblasts may not be the best cell type representing neuronal cells."
The authors' own limitation supports the LOW fidelity assignment.
Findings
L-serine increased measured proliferation by 8% in both patient and control fibroblasts and reduced cytotoxicity by 26% versus 14%, but neither change was statistically significant; this is not clinical treatment evidence.
"L-serine treatment in cultured skin fibroblasts revealed an 8% increased proliferation in both TUBGCP2-patient and control, while a 26% reduction of cytotoxicity was detected in patient-derived cells compared to 14% in controls. These changes did not reach statistical significance."
Show evidence (1 reference)
PMID:33458610 SUPPORT In Vitro
"L-serine treatment in cultured skin fibroblasts revealed an 8% increased proliferation in both TUBGCP2-patient and control, while a 26% reduction of cytotoxicity was detected in patient-derived cells compared to 14% in controls. These changes did not reach statistical significance."
Records the exact nonsignificant model result without promoting L-serine to treatment.
Show evidence (1 reference)
PMID:33458610 SUPPORT In Vitro
"In this study, we used human primary fibroblasts of a patient with pathogenic mutations to reveal molecular insights into the pathomechanism of a severe childhood-onset neurological disease."
Establishes the source and purpose of the primary-cell model.
🐁

Animal Models

2
tubgcp2 Morpholino Zebrafish
Two independent transient depletion reagents produce small heads and altered developing-brain pH3-positive cell abundance. Wild-type mRNA partly rescues brain size. This is a depletion model without a patient allele.
Reduced brain size Increased pH3-positive developing-brain cells
Species
Danio rerio
Genotype
tubgcp2 translation-blocking or splice-blocking morpholino with p53-blocking morpholino; wild-type tubgcp2 mRNA co-injection rescue arm
Publication
PMID:36078134
Pathograph links
Altered Developing-Brain Mitotic State partially recapitulates fidelity: low Measures altered abundance of mitotic cells in the developing morphant brain.
Limitations: Transient morpholino depletion is not a patient-allele model, and increased pH3 staining cannot distinguish mitotic arrest from over-proliferation.
Readouts
Phospho-histone H3-positive developing-brain cells
Direction: INCREASED
Interpretation: The measured cell count is increased, but the direction of the underlying mitotic or proliferative process remains unresolved.
Show evidence (1 reference)
PMID:36078134 SUPPORT Model Organism
"Compared to the control group (Figure 3a), we find significant and similar accumulation of mitotic brain cells in the morphant small-brain groups for both splicing and translation disruption (Figure 3b–d). However, these data do not distinguish over-proliferation from mitotic arrest."
Direct pH3 readout with the source's directionality limitation.
Show evidence (1 reference)
PMID:36078134 SUPPORT Model Organism
"However, these data do not distinguish over-proliferation from mitotic arrest."
Supports only a direction-neutral mitotic-state link.
Reduced Brain Growth and Microcephaly partially recapitulates fidelity: low Reproduces reduced larval head width and demonstrates partial wild-type-mRNA rescue.
Limitations: The transient knockdown does not model a patient allele, and it does not assay lissencephaly, neuronal migration, or microtubule nucleation.
Readouts
Larval head width
Direction: DECREASED
Interpretation: Head width more than two standard deviations below controls defines the model phenotype.
Show evidence (1 reference)
PMID:36078134 SUPPORT Model Organism
"In larvae injected with splice- or translation-blocking MOs, an experimental average of 88% develop the microcephaly phenotype (defined as a reduction of head width by more than two standard deviations compared to controls) (Figure 2a)."
Quantifies reduced head width in both depletion arms.
Brain size after wild-type tubgcp2 mRNA co-injection
Direction: RESTORED
Interpretation: Wild-type mRNA partly restores brain size, supporting on-target depletion effects.
Show evidence (1 reference)
PMID:36078134 SUPPORT Model Organism
"After co-injecting MOs with wild type tubgcp2 mRNA, an average of 55% developing larvae (55.75% of trans MO group; 53.64% of splice MO group) developed almost normal brain size (Figure 1d,e; Figure 2c,d)."
Direct genetic rescue readout in the zebrafish model.
Show evidence (1 reference)
PMID:36078134 SUPPORT Model Organism
"In larvae injected with splice- or translation-blocking MOs, an experimental average of 88% develop the microcephaly phenotype (defined as a reduction of head width by more than two standard deviations compared to controls) (Figure 2a)."
Supports reduced brain size in this low-fidelity depletion model.
Show evidence (1 reference)
PMID:36078134 SUPPORT Model Organism
"We show that antisense morpholino knockdown (KD) of the Danio rerio homolog, tubgcp2, recapitulates human TUBGCP2-associated microcephaly."
Establishes the zebrafish model and its reported phenotype.
Grip84-cg7716 Double-Knockout Fly
A double-homolog knockout produces small larval brains, general microsomia, delayed development, and pupal lethality. It is a low-fidelity null model in a species with two TUBGCP2 homologs and does not model a human allele.
Reduced larval brain surface area General microsomia and delayed development
Species
Drosophila melanogaster
Genotype
Double knockout of the TUBGCP2 homologs Grip84 and cg7716
Publication
PMID:36078134
Pathograph links
Reduced Brain Growth and Microcephaly partially recapitulates fidelity: low Reproduces reduced brain surface area in a two-homolog null background.
Limitations: The model removes two fly homologs, has severe generalized developmental effects, and does not assay human cortical folding, neuronal migration, or microtubule nucleation.
Readouts
Larval brain surface area
Direction: DECREASED
Interpretation: Reduced surface area supports only the brain-growth node.
Show evidence (1 reference)
PMID:36078134 SUPPORT Model Organism
"Surface area (SA) quantification (Figure 5d) shows that day 5 mutant fly brain SA is 64% of WT, and reaches 79% of WT brain SA just before mutant pupation, at day 6."
Quantifies the reduced-brain-size readout.
Show evidence (1 reference)
PMID:36078134 SUPPORT Model Organism
"Surface area (SA) quantification (Figure 5d) shows that day 5 mutant fly brain SA is 64% of WT, and reaches 79% of WT brain SA just before mutant pupation, at day 6."
Supports only reduced brain growth in this low-fidelity model.
Show evidence (1 reference)
PMID:36078134 SUPPORT Model Organism
"Drosophila melanogaster double knockouts (KO) for TUBGCP2 homologs Grip84/cg7716 also develop microcephalic brains with general microsomia."
Establishes the fly model and its broad phenotype.
{ }

Source YAML

click to show 
name: TUBGCP2-related Lissencephaly Spectrum Disorder
creation_date: "2026-08-22T10:00:00Z"
category: Mendelian
disease_term:
  preferred_term: pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures
  term:
    id: MONDO:0032893
    label: pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures
description: >-
  TUBGCP2-related lissencephaly spectrum disorder is an autosomal recessive
  neurodevelopmental disease caused by biallelic TUBGCP2 variants. The 2025
  eight-person literature review found pachygyria, microcephaly, and
  developmental delay in all eight individuals, seizures and dysmorphic facial
  features in seven, and a variable set of callosal, cerebellar, brainstem, and
  white-matter abnormalities. Later reports added a
  pachygyria-polymicrogyria complex with a thick corpus callosum and cystic
  leukomalacia to the radiological spectrum.

  Mechanistic evidence is narrower than the clinical association. For the
  p.Glu311Lys allele, structural analysis predicts disruption of the GCP2-GCP3
  electrostatic interface, while patient fibroblasts show faint delocalization
  of gamma-tubulin, HAUS6, and NEDD1 but normal GCP2 abundance. Neither
  microtubule nucleation nor neuronal migration has been measured in patient
  neural cells. Depletion models in zebrafish and Drosophila reproduce reduced
  brain size; zebrafish pH3 staining establishes an altered developing-brain
  mitotic state but cannot distinguish mitotic arrest from over-proliferation.
parents:
- congenital nervous system disorder
- hereditary neurological disease
references:
- reference: PMID:31630790
  title: Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
- reference: PMID:33458610
  title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
- reference: PMID:36078134
  title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
- reference: PMID:40017707
  title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
- reference: PMID:40448381
  title: "Thick Corpus Callosum: An Unusual Finding of TUBGCP2-Related Tubulinopathy."
- reference: PMID:42472988
  title: "Genotypic and phenotypic heterogeneity in tubulinopathies: insights from a Turkish multicenter cohort."
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf
  title: "https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf"
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic TUBGCP2 variants have been reported in homozygous and compound
    configurations, including two paternal missense variants opposite a
    maternal multi-exon deletion. Recurrence counseling depends on confirming
    the familial variants and parental phase rather than assuming a single
    configuration for every family.
  evidence:
  - reference: PMID:31630790
    reference_title: Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal
      recessive neurodevelopmental trait consisting of a neuronal migration
      disorder
    explanation: >-
      The delineating study's own statement of the mode of inheritance and the
      disease class.
  - reference: PMID:31630790
    reference_title: Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By querying clinical exome sequencing cases and through
      GeneMatcher-facilitated collaborations, we found three additional families
      with bi-allelic variation and similarly affected phenotypes
    explanation: >-
      Documents both homozygous and compound heterozygous configurations across
      independent families.
pathophysiology:
- name: Biallelic TUBGCP2 Variation
  role: TRIGGER
  biological_scale: MOLECULAR
  description: >-
    The disease is associated with biallelic germline TUBGCP2 variants. Reported
    configurations include homozygous missense and frameshift variants,
    compound-heterozygous missense and splice-altering variants, and two
    paternal missense variants opposite a maternal deletion of exons 2-14. The
    functional class is left UNKNOWN because no study has compared the full
    allele series in a common functional assay.
  genetic_context:
    functional_impact_category: UNKNOWN
    variant_origin: GERMLINE
    allele_type: missense, splice-altering, frameshift, multi-exon deletion
    description: >-
      Disease-wide context spanning homozygous, compound-heterozygous, and
      hemizygous-by-deletion configurations; zygosity is intentionally omitted
      because the schema has no generic biallelic value. Truncating and deletion
      alleles are not assigned loss of function without a direct assay, and no
      dominant-negative mechanism has been demonstrated.
  genes:
  - preferred_term: TUBGCP2
    term:
      id: hgnc:18599
      label: TUBGCP2
  evidence:
  - reference: PMID:31630790
    reference_title: Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By querying clinical exome sequencing cases and through
      GeneMatcher-facilitated collaborations, we found three additional families
      with bi-allelic variation and similarly affected phenotypes
    explanation: >-
      Establishes the replicated biallelic gene-disease association without
      assigning a uniform molecular effect to the different alleles.
  downstream:
  - target: Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation
    causal_link_type: UNKNOWN
    description: >-
      The p.Glu311Lys allele has computational and patient-fibroblast evidence;
      whether the same proximal effect applies to every reported allele is not
      established.
  - target: Dysmorphic Facial Features
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The developmental route from TUBGCP2 variation to facial dysmorphism is unknown.
- name: Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation
  role: PATHWAY
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Evidence for this proximal cellular state is allele-specific. Structural
    analysis predicts that p.Glu311Lys disrupts electrostatic interaction at the
    GCP2-GCP3 interface. Primary fibroblasts carrying that allele have normal
    GCP2 abundance but faint delocalization of gamma-tubulin, HAUS6, and NEDD1,
    plus broader cytoskeletal proteomic changes. The study did not measure
    microtubule-nucleation rate, and fibroblasts are not a neural model.
  biological_processes:
  - preferred_term: microtubule cytoskeleton organization
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
    modifier: DYSREGULATED
  cellular_components:
  - preferred_term: gamma-tubulin ring complex
    term:
      id: GO:0000931
      label: gamma-tubulin ring complex
    modifier: DYSREGULATED
  - preferred_term: centrosome
    term:
      id: GO:0005813
      label: centrosome
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:33458610
    reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3.
    explanation: >-
      Computational support limited to the p.Glu311Lys interface prediction; it
      is not a cellular measurement and is not generalized to other alleles.
  - reference: PMID:33458610
    reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In primary fibroblasts carrying the variant, we observed a faint
      delocalization of γ-tubulin during the cell cycle but normal GCP2 protein
      levels.
    explanation: >-
      Directly measures altered gamma-tubulin localization and preserved GCP2
      abundance in p.Glu311Lys patient fibroblasts.
  - reference: PMID:33458610
    reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, in mitosis, patient fibroblasts presented a faint delocalization
      of two components associated with the γ-TuRC complex, HAUS6 and NEDD1
      (Figure 3A, lower panel, and 3C).
    explanation: >-
      Exact patient-fibroblast evidence for altered localization of two
      gamma-TuRC-associated proteins; it does not establish reduced nucleation.
  - reference: PMID:33458610
    reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Through mass spectrometry, we observed dysregulation of multiple proteins
      involved in the assembly and organization of the cytoskeleton and the
      extracellular matrix, controlling cellular adhesion and of proteins crucial
      for neuronal homeostasis including axon guidance.
    explanation: Proteomic support for broad cytoskeletal dysregulation in the same fibroblasts.
  downstream:
  - target: Altered Developing-Brain Mitotic State
    causal_link_type: UNKNOWN
    description: >-
      A mitotic-state abnormality is seen in a depletion model, but its route
      from the human variant-dependent fibroblast state is not established.
  - target: Neuronal Migration Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Migration is inferred from human cortical imaging; it has not been assayed
      in patient neural cells or either animal model.
  - target: Associated Non-Cortical Structural Brain Abnormalities
    causal_link_type: UNKNOWN
    description: The developmental route to the non-cortical MRI findings is unresolved.
- name: Altered Developing-Brain Mitotic State
  role: PATHWAY
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Zebrafish tubgcp2 morphants have increased phospho-histone H3-positive cells
    in the developing brain. This is direction-neutral mechanistic evidence:
    the experiment establishes altered mitotic cell abundance but explicitly
    cannot distinguish mitotic arrest from over-proliferation. No comparable
    measurement has been made in patient neural cells.
  evidence:
  - reference: PMID:36078134
    reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Compared to the control group (Figure 3a), we find significant and similar
      accumulation of mitotic brain cells in the morphant small-brain groups for
      both splicing and translation disruption (Figure 3b–d). However, these data
      do not distinguish over-proliferation from mitotic arrest.
    explanation: >-
      Supports a direction-neutral mitotic/proliferative disturbance in a
      low-fidelity depletion model, not decreased proliferation or migration.
  downstream:
  - target: Reduced Brain Growth and Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The model links altered mitotic-cell abundance with reduced brain size,
      but the intervening cell-fate and population dynamics remain unresolved.
- name: Reduced Brain Growth and Microcephaly
  role: CONSEQUENCE
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Microcephaly was present in all eight individuals summarized in the 2025
    review. Independent zebrafish and fly depletion/null models show reduced
    brain size, but those low-fidelity models do not establish the human cellular
    route or reproduce the cortical-folding phenotype.
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All eight patients (three females and five males, ages ranging from 1 to 10
      years) presented with LIS and microcephaly.
    explanation: Direct human support for universal microcephaly in the eight-person review set.
  - reference: PMID:36078134
    reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In larvae injected with splice- or translation-blocking MOs, an experimental
      average of 88% develop the microcephaly phenotype (defined as a reduction of
      head width by more than two standard deviations compared to controls)
      (Figure 2a).
    explanation: >-
      Supports reduced brain size in a zebrafish depletion model, with no claim
      that it reproduces the human cortical or allelic mechanism.
  downstream:
  - target: Microcephaly
    causal_link_type: DIRECT
    description: The tissue-level reduced-brain-growth state is expressed clinically as microcephaly.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The neurodevelopmental intermediates producing global delay are unresolved.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The epileptogenic circuit intermediates are unresolved.
  - target: Developmental Regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The mechanism of regression in the severely affected patient is unresolved.
  - target: Generalized Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The neural and motor-system intermediates producing hypotonia are unresolved.
  - target: Spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The corticospinal intermediates producing spasticity are unresolved.
- name: Neuronal Migration Failure
  role: PATHWAY
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  conforms_to: microtubule_dependent_neuronal_migration_failure#Microtubule-Based Neuronal Motility Failure
  description: >-
    The founding study interpreted pachygyria and subcortical band heterotopia as
    presumably caused by disrupted neuronal migration. Migration has not been
    directly measured in patient-derived neural cells, zebrafish, or fly, so this
    node remains a partially supported imaging-based hypothesis.
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:31630790
    reference_title: Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging from all five affected individuals revealed varying degrees
      of cortical malformations including pachygyria and subcortical band
      heterotopia, presumably caused by disruption of neuronal migration.
    explanation: >-
      The authors explicitly hedge the imaging-to-mechanism inference;
      migration itself was not assayed.
  downstream:
  - target: Lissencephaly Spectrum Cortical Malformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A migration defect is a plausible route to the cortical phenotype, but
      direct cellular validation and relevant intermediates are lacking.
- name: Lissencephaly Spectrum Cortical Malformation
  role: CONSEQUENCE
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  conforms_to: microtubule_dependent_neuronal_migration_failure#Cortical Dyslamination and Neuronal Ectopia
  description: >-
    The cortical phenotype spans pachygyria, agyria, subcortical band
    heterotopia, and a reported pachygyria-polymicrogyria complex. Pachygyria
    was present in all eight people summarized in the 2025 review. Cystic
    leukomalacia is kept separate as a non-cortical radiological extension.
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the TUBGCP2 variants were found to cause lissencephaly spectrum diseases,
      with the main clinical manifestations being microcephaly, lissencephaly
      (including agyria, pachygyria, or subcortical band heterotopia)
    explanation: Defines the human cortical-malformation spectrum.
  - reference: PMID:40448381
    reference_title: "Thick Corpus Callosum: An Unusual Finding of TUBGCP2-Related Tubulinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed cortical malformations consistent with the
      pachygyria-polymicrogyria complex, as well as a thickened corpus callosum.
    explanation: Extends the directly observed cortical phenotype to a pachygyria-polymicrogyria complex.
  downstream:
  - target: Pachygyria
    causal_link_type: DIRECT
    description: Pachygyria is the constant cortical imaging manifestation in the review set.
  - target: Subcortical Band Heterotopia
    causal_link_type: DIRECT
    description: Subcortical band heterotopia is a less frequent cortical manifestation.
  - target: Polymicrogyria
    causal_link_type: DIRECT
    description: Polymicrogyria was reported as part of a pachygyria-polymicrogyria complex.
- name: Associated Non-Cortical Structural Brain Abnormalities
  role: CONSEQUENCE
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Callosal, cerebellar, brainstem, white-matter, cystic, and visual-system
    abnormalities expand the structural spectrum beyond the cortex. Their
    developmental links to TUBGCP2 and to each other are not established.
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All eight patients had abnormal brain MRI findings, including pachygyria in
      eight (100%); thin corpus callosum in six (75%); cerebellar volume loss in
      three (37.5%); SBH, subependymal cyst, thin brainstem, and cystic foci in
      white matter in two each (25%); delayed myelination in one (12.5%); and
      periventricular leukomalacia in one (12.5%).
    explanation: Quantifies the non-cortical MRI findings in the eight-person review set.
  - reference: PMID:42472988
    reference_title: "Genotypic and phenotypic heterogeneity in tubulinopathies: insights from a Turkish multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a rare case of TUBGCP2-related tubulinopathy presenting with
      cystic leukomalacia, expanding the known radiological spectrum.
    explanation: >-
      Supports cystic leukomalacia as a later non-cortical radiological extension,
      not as evidence for the cortical-malformation mechanism.
  downstream:
  - target: Thin Corpus Callosum
    causal_link_type: UNKNOWN
  - target: Cerebellar Volume Loss
    causal_link_type: UNKNOWN
  - target: Subependymal Cysts
    causal_link_type: UNKNOWN
  - target: Brainstem Hypoplasia
    causal_link_type: UNKNOWN
  - target: Cerebral White Matter Abnormality
    causal_link_type: UNKNOWN
  - target: Thick Corpus Callosum
    causal_link_type: UNKNOWN
  - target: Optic Atrophy
    causal_link_type: UNKNOWN
  - target: Cerebral Visual Impairment
    causal_link_type: UNKNOWN
phenotypes:
- category: Neurological
  name: Pachygyria
  description: >-
    Pachygyria was present in 8/8 people in the 2025 cumulative review set. A
    later case report described a pachygyria-polymicrogyria complex; that later
    report is not included in this frequency denominator.
  phenotype_term:
    preferred_term: Pachygyria
    term:
      id: HP:0001302
      label: Pachygyria
  frequency: OBLIGATE
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All eight patients had abnormal brain MRI findings, including pachygyria in
      eight (100%)
    explanation: >-
      8/8 = 100% in the explicitly scoped 2025 review set, which is OBLIGATE.
  - reference: PMID:40448381
    reference_title: "Thick Corpus Callosum: An Unusual Finding of TUBGCP2-Related Tubulinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed cortical malformations consistent with the
      pachygyria-polymicrogyria complex, as well as a thickened corpus callosum.
    explanation: >-
      A later case extends the morphology but is not added to the 8-person
      frequency denominator.
- category: Neurological
  name: Subcortical Band Heterotopia
  description: >-
    Present in 2/8 people in the 2025 cumulative review set and part of the
    lissencephaly-spectrum cortical phenotype.
  phenotype_term:
    preferred_term: Subcortical band heterotopia
    term:
      id: HP:0032409
      label: Subcortical band heterotopia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31630790
    reference_title: Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging from all five affected individuals revealed varying degrees
      of cortical malformations including pachygyria and subcortical band
      heterotopia
    explanation: >-
      Establishes subcortical band heterotopia as part of the cortical spectrum
      in the delineating cohort.
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SBH, subependymal cyst, thin brainstem, and cystic foci in white matter in
      two each (25%)
    explanation: >-
      2/8 = 25% in the 2025 review set, which is OCCASIONAL.
- category: Neurological
  name: Polymicrogyria
  description: >-
    Reported in a later case as part of a pachygyria-polymicrogyria complex. No
    frequency is assigned because that case falls outside the 8-person review
    denominator.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:40448381
    reference_title: "Thick Corpus Callosum: An Unusual Finding of TUBGCP2-Related Tubulinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed cortical malformations consistent with the
      pachygyria-polymicrogyria complex, as well as a thickened corpus callosum.
    explanation: Direct case-report support for polymicrogyria in the cortical spectrum.
- category: Neurological
  name: Microcephaly
  description: >-
    Present in 8/8 people in the 2025 cumulative review set. Later case reports
    are not included in this denominator.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  frequency: OBLIGATE
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All eight patients (three females and five males, ages ranging from 1 to 10
      years) presented with LIS and microcephaly.
    explanation: >-
      8/8 in the 2025 review set is direct support for the OBLIGATE band.
- category: Neurological
  name: Global Developmental Delay
  description: >-
    Present in 8/8 people in the 2025 cumulative review set, most often affecting
    both speech and motor domains.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: OBLIGATE
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All eight patients exhibited DD, with six (75%) having speech and motor
      delay
    explanation: >-
      8/8 in the 2025 review set is OBLIGATE; the same sentence supplies the
      developmental-domain breakdown.
- category: Neurological
  name: Seizures
  description: >-
    Present in 7/8 people in the 2025 review set, with onset from 5 months to 4
    years and a median of 21.5 months.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures occurred in seven of the eight (87.5%) patients, with the age at
      seizure onset ranging from 5 months to 4 years and a median age of 21.5
      months.
    explanation: >-
      7/8 = 87.5% in the 2025 review set, which is VERY_FREQUENT, and the same
      sentence supplies the onset window.
- category: Craniofacial
  name: Dysmorphic Facial Features
  description: >-
    Broad facial dysmorphism was present in 7/8 people in the 2025 review set.
    Individual features were less frequent, so the record is mapped to abnormal
    facial shape rather than to narrow forehead alone.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      seven patients (87.5%) had dysmorphic facial features, including
      recruitment in the ear of five (71.4%); narrow forehead, thick eyebrows,
      and smooth philtrum in four each (57.1%)
    explanation: >-
      7/8 = 87.5% broad dysmorphism in the 2025 review set, which is
      VERY_FREQUENT; narrow forehead occurred in only four of those seven.
- category: Neurological
  name: Thin Corpus Callosum
  description: >-
    Present in 6/8 people in the 2025 cumulative review set. A later report of a
    thick corpus callosum is recorded separately and is outside this denominator.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  frequency: FREQUENT
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All eight patients had abnormal brain MRI findings, including pachygyria in
      eight (100%); thin corpus callosum in six (75%)
    explanation: >-
      6/8 = 75% in the 2025 review set, which is FREQUENT.
- category: Neurological
  name: Cerebellar Volume Loss
  description: >-
    Cerebellar volume loss was reported in 3/8 people in the 2025 cumulative
    review set.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  frequency: FREQUENT
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cerebellar volume loss in three (37.5%)
    explanation: >-
      3/8 = 37.5% in the 2025 review set, which is FREQUENT (30-79%).
- category: Neurological
  name: Subependymal Cysts
  description: >-
    Subependymal cysts were reported in 2/8 people in the 2025 cumulative review
    set.
  phenotype_term:
    preferred_term: Subependymal cysts
    term:
      id: HP:0002416
      label: Subependymal cysts
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SBH, subependymal cyst, thin brainstem, and cystic foci in white matter in
      two each (25%)
    explanation: 2/8 = 25% in the 2025 review set, which is OCCASIONAL.
- category: Neurological
  name: Brainstem Hypoplasia
  description: >-
    A thin brainstem was reported in 2/8 people in the 2025 cumulative review
    set and is represented by the broader canonical HPO term for brainstem
    hypoplasia.
  phenotype_term:
    preferred_term: Hypoplasia of the brainstem
    term:
      id: HP:0002365
      label: Hypoplasia of the brainstem
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SBH, subependymal cyst, thin brainstem, and cystic foci in white matter in
      two each (25%)
    explanation: 2/8 = 25% in the 2025 review set, which is OCCASIONAL.
- category: Neurological
  name: Cerebral White Matter Abnormality
  description: >-
    Cystic white-matter foci were reported in 2/8 people in the 2025 cumulative
    review set. The broad HPO mapping avoids equating these foci with the later
    cystic-leukomalacia report.
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SBH, subependymal cyst, thin brainstem, and cystic foci in white matter in
      two each (25%)
    explanation: 2/8 = 25% in the 2025 review set, which is OCCASIONAL.
- category: Neurological
  name: Thick Corpus Callosum
  description: >-
    A later case with a homozygous frameshift variant had a thick corpus
    callosum. No frequency is assigned because this report is outside the
    8-person denominator.
  phenotype_term:
    preferred_term: Thick corpus callosum
    term:
      id: HP:0007074
      label: Thick corpus callosum
  evidence:
  - reference: PMID:40448381
    reference_title: "Thick Corpus Callosum: An Unusual Finding of TUBGCP2-Related Tubulinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed cortical malformations consistent with the
      pachygyria-polymicrogyria complex, as well as a thickened corpus callosum.
    explanation: Direct evidence for the opposite callosal direction in one later case.
- category: Neurological
  name: Generalized Hypotonia
  description: >-
    Severe hypotonia was documented in one p.Glu311Lys sibling. No frequency is
    assigned because the cited case sentence does not define a cumulative
    denominator.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:33458610
    reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She presented with severe developmental delay, hypotonia, and intractable
      epilepsy at age 6 months and lost all motor and cognitive abilities
      gradually by 4 years of age.
    explanation: >-
      Exact patient-level evidence for hypotonia; it also documents regression,
      which is curated separately.
- category: Neurological
  name: Spasticity
  description: >-
    Spasticity with brisk reflexes and limb contractures was documented in a
    p.Glu311Lys sibling. No cumulative frequency is assigned.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:33458610
    reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination revealed microcephaly, atrophy, and contractures
      of the extremities with brisk deep tendon reflexes and spasticity.
    explanation: Exact patient-examination evidence for spasticity.
- category: Neurological
  name: Developmental Regression
  description: >-
    One severely affected p.Glu311Lys sibling lost previously acquired motor and
    cognitive abilities by four years. No cumulative frequency is assigned.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:33458610
    reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She presented with severe developmental delay, hypotonia, and intractable
      epilepsy at age 6 months and lost all motor and cognitive abilities
      gradually by 4 years of age.
    explanation: Exact patient-level evidence for loss of acquired abilities.
- category: Ophthalmic
  name: Optic Atrophy
  description: >-
    Optic atrophy has been reported in a few patients, but the review did not
    provide a denominator suitable for frequency assignment.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, a few patients present with visual system abnormalities,
      including optic atrophy and cortical blindness.
    explanation: Supports optic atrophy without a count-based frequency.
- category: Ophthalmic
  name: Cerebral Visual Impairment
  description: >-
    The review reports cortical blindness in a few patients. This is mapped to
    cerebral visual impairment without assigning a frequency.
  phenotype_term:
    preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, a few patients present with visual system abnormalities,
      including optic atrophy and cortical blindness.
    explanation: Supports a central visual-system phenotype without a count-based frequency.
- category: Neurological
  name: EEG Abnormality
  description: >-
    Five of seven patients with seizures had slow background activity and
    epileptiform discharges. No disease-level frequency is assigned because the
    denominator is restricted to the seizure subgroup.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  reports_on:
  - target: Seizures
    relationship: READOUT_OF
    interpretation: EEG abnormality is an investigation readout within the seizure subgroup.
    evidence:
    - reference: PMID:40017707
      reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Among the seven patients with seizures, five (71.4%) had abnormal EEG
        results, illustrating continuous slow background activity and
        epileptiform discharges.
      explanation: Directly links the EEG finding to the seizure subgroup.
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the seven patients with seizures, five (71.4%) had abnormal EEG
      results, illustrating continuous slow background activity and epileptiform
      discharges.
    explanation: Supports the EEG abnormality and its subgroup denominator.
genetic:
- name: TUBGCP2
  association: Causative
  gene_term:
    preferred_term: TUBGCP2 (gamma-tubulin complex component 2)
    term:
      id: hgnc:18599
      label: TUBGCP2
  notes: >-
    TUBGCP2 encodes GCP2, a core gamma-tubulin ring-complex component. The
    founding families carried homozygous p.Arg333Cys or p.Ala615Pro, or
    compound-heterozygous p.Arg297Cys and c.2025-2A>G alleles. Subsequent reports
    added homozygous p.Glu311Lys; a Chinese configuration with paternal c.178C>T
    and c.538T>C/p.Trp180Arg variants opposite a maternal exons 2-14 deletion;
    and homozygous c.2647dupC/p.Gln883Profs*62. Functional consequences cannot
    be generalized across this mixed allele series.
  evidence:
  - reference: PMID:31630790
    reference_title: Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal
      recessive neurodevelopmental trait consisting of a neuronal migration
      disorder
    explanation: >-
      The founding gene-disease observation.
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we reported a 6-year-old patient with LIS caused by a
      hemizygous variant in TUBGCP2 (two paternal missense variants: c.178 C>T,
      c.538T>C and one maternal exon variant: 2–14 deletion).
    explanation: Documents the later mixed missense/deletion configuration.
  - reference: PMID:40448381
    reference_title: "Thick Corpus Callosum: An Unusual Finding of TUBGCP2-Related Tubulinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing identified a homozygous NM_006659.4:c.2647dupC
      p.(Gln883Profs*62) variant in the TUBGCP2 gene, which was confirmed by
      Sanger sequencing.
    explanation: Documents the later homozygous frameshift allele.
diagnosis:
- name: Brain MRI
  description: >-
    Brain MRI defines the malformation spectrum. Pachygyria was present in all
    eight people in the 2025 review, while subcortical band heterotopia and
    callosal, cerebellar, brainstem, and white-matter findings were variable.
    Imaging supports recognition but does not establish the molecular diagnosis.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All eight patients had abnormal brain MRI findings, including pachygyria in
      eight (100%)
    explanation: >-
      Directly supports MRI as a consistent clinical investigation in the scoped
      review set.
- name: Trio exome sequencing with segregation and copy-number validation
  description: >-
    In the 2025 case, trio whole-exome sequencing detected sequence and deletion
    candidates, followed by Sanger validation and qPCR of selected TUBGCP2 exons.
    This exact workflow supports testing both sequence and copy-number variation;
    broader panel or genome claims are not inferred from that report.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathogenic variants detected using trio-WES were further validated by
      Sanger sequencing and qPCR.
    explanation: >-
      Exact support for trio-WES followed by orthogonal sequence and copy-number
      validation.
treatments:
- name: Antiseizure Pharmacotherapy
  action_category: THERAPEUTIC
  description: >-
    Anti-seizure medication is selected according to seizure type. This is
    phenotype-based management extrapolated from general tubulinopathy guidance;
    no TUBGCP2-specific comparative treatment evidence is available.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Seizures are treated with anti-seizure medications based on the specific
      seizure type.
    explanation: >-
      PARTIAL because this GeneReviews overview does not discuss TUBGCP2 and is
      used only as phenotype-based management extrapolation.
- name: Supportive and Rehabilitative Care
  action_category: THERAPEUTIC
  description: >-
    An individualized plan may include physical, occupational, speech, and
    vision therapy, with physical therapy addressing complications of
    spasticity. This is general tubulinopathy guidance rather than a measured
    TUBGCP2-specific outcome.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Supportive management, including an individualized therapy plan that
      includes physical therapy to manage the complications of spasticity,
      occupational therapy, speech therapy, and vision therapy for oculomotor
      deficits and/or strabismus should begin at the time of diagnosis to ensure
      the best possible functionality and developmental outcome.
    explanation: >-
      PARTIAL because this general tubulinopathy guidance does not mention
      TUBGCP2 and supplies no disorder-specific outcome data.
- name: Genetic Counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Counseling should communicate autosomal recessive inheritance and interpret
    recurrence in light of confirmed familial variants and parental phase. The
    cited disease paper does not directly support a numerical recurrence-risk or
    carrier-testing outcome claim.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31630790
    reference_title: Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal
      recessive neurodevelopmental trait consisting of a neuronal migration
      disorder
    explanation: >-
      PARTIAL support: the source establishes recessive inheritance but does not
      report a counseling intervention or outcome.
experimental_models:
- name: p.Glu311Lys Patient Fibroblasts
  description: >-
    Primary skin fibroblasts from an affected person homozygous for p.Glu311Lys,
    compared with control fibroblasts by immunofluorescence, immunoblotting,
    proteomics, proliferation, and cytotoxicity assays. This is an allele-specific
    peripheral-cell model rather than a neural model.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Primary skin fibroblasts from a p.Glu311Lys patient and controls
  culture_system: Fibroblast monolayer culture
  conditions:
  - Untreated patient and control fibroblasts
  - L-serine treatment arm
  publication: PMID:33458610
  modeled_mechanisms:
  - target: Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Measures gamma-tubulin, HAUS6, and NEDD1 localization and GCP2 abundance
      for p.Glu311Lys in primary patient cells.
    limitations: >-
      The model is limited to one missense allele and a peripheral cell type;
      neuronal migration, developing-brain mitosis, and microtubule nucleation
      were not measured.
    readouts:
    - name: Gamma-tubulin, HAUS6, and NEDD1 localization
      target: Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation
      direction: ALTERED
      interpretation: Faint delocalization in patient fibroblasts supports an allele-specific localization defect.
      evidence:
      - reference: PMID:33458610
        reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          However, in mitosis, patient fibroblasts presented a faint delocalization
          of two components associated with the γ-TuRC complex, HAUS6 and NEDD1
          (Figure 3A, lower panel, and 3C).
        explanation: Direct localization measurement in patient fibroblasts.
    - name: GCP2 protein abundance
      target: Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation
      direction: UNCHANGED
      interpretation: Preserved abundance bounds the p.Glu311Lys cellular defect but does not classify other alleles.
      evidence:
      - reference: PMID:33458610
        reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          In primary fibroblasts carrying the variant, we observed a faint
          delocalization of γ-tubulin during the cell cycle but normal GCP2
          protein levels.
        explanation: Directly reports unchanged GCP2 abundance in the model.
    evidence:
    - reference: PMID:33458610
      reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Fibroblasts may not be the best cell type representing neuronal cells.
      explanation: The authors' own limitation supports the LOW fidelity assignment.
  findings:
  - statement: >-
      L-serine increased measured proliferation by 8% in both patient and control
      fibroblasts and reduced cytotoxicity by 26% versus 14%, but neither change
      was statistically significant; this is not clinical treatment evidence.
    supporting_text: >-
      L-serine treatment in cultured skin fibroblasts revealed an 8% increased
      proliferation in both TUBGCP2-patient and control, while a 26% reduction of
      cytotoxicity was detected in patient-derived cells compared to 14% in
      controls. These changes did not reach statistical significance.
    evidence:
    - reference: PMID:33458610
      reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        L-serine treatment in cultured skin fibroblasts revealed an 8% increased
        proliferation in both TUBGCP2-patient and control, while a 26% reduction
        of cytotoxicity was detected in patient-derived cells compared to 14% in
        controls. These changes did not reach statistical significance.
      explanation: Records the exact nonsignificant model result without promoting L-serine to treatment.
  evidence:
  - reference: PMID:33458610
    reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this study, we used human primary fibroblasts of a patient with
      pathogenic mutations to reveal molecular insights into the pathomechanism
      of a severe childhood-onset neurological disease.
    explanation: Establishes the source and purpose of the primary-cell model.
animal_models:
- name: tubgcp2 Morpholino Zebrafish
  species: Danio rerio
  genotype: >-
    tubgcp2 translation-blocking or splice-blocking morpholino with p53-blocking
    morpholino; wild-type tubgcp2 mRNA co-injection rescue arm
  publication: PMID:36078134
  description: >-
    Two independent transient depletion reagents produce small heads and altered
    developing-brain pH3-positive cell abundance. Wild-type mRNA partly rescues
    brain size. This is a depletion model without a patient allele.
  associated_phenotypes:
  - Reduced brain size
  - Increased pH3-positive developing-brain cells
  modeled_mechanisms:
  - target: Altered Developing-Brain Mitotic State
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Measures altered abundance of mitotic cells in the developing morphant brain.
    limitations: >-
      Transient morpholino depletion is not a patient-allele model, and increased
      pH3 staining cannot distinguish mitotic arrest from over-proliferation.
    readouts:
    - name: Phospho-histone H3-positive developing-brain cells
      target: Altered Developing-Brain Mitotic State
      direction: INCREASED
      interpretation: >-
        The measured cell count is increased, but the direction of the underlying
        mitotic or proliferative process remains unresolved.
      evidence:
      - reference: PMID:36078134
        reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Compared to the control group (Figure 3a), we find significant and
          similar accumulation of mitotic brain cells in the morphant small-brain
          groups for both splicing and translation disruption (Figure 3b–d).
          However, these data do not distinguish over-proliferation from mitotic
          arrest.
        explanation: Direct pH3 readout with the source's directionality limitation.
    evidence:
    - reference: PMID:36078134
      reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        However, these data do not distinguish over-proliferation from mitotic
        arrest.
      explanation: Supports only a direction-neutral mitotic-state link.
  - target: Reduced Brain Growth and Microcephaly
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Reproduces reduced larval head width and demonstrates partial wild-type-mRNA rescue.
    limitations: >-
      The transient knockdown does not model a patient allele, and it does not
      assay lissencephaly, neuronal migration, or microtubule nucleation.
    readouts:
    - name: Larval head width
      target: Reduced Brain Growth and Microcephaly
      direction: DECREASED
      interpretation: Head width more than two standard deviations below controls defines the model phenotype.
      evidence:
      - reference: PMID:36078134
        reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In larvae injected with splice- or translation-blocking MOs, an
          experimental average of 88% develop the microcephaly phenotype (defined
          as a reduction of head width by more than two standard deviations
          compared to controls) (Figure 2a).
        explanation: Quantifies reduced head width in both depletion arms.
    - name: Brain size after wild-type tubgcp2 mRNA co-injection
      target: Reduced Brain Growth and Microcephaly
      direction: RESTORED
      interpretation: Wild-type mRNA partly restores brain size, supporting on-target depletion effects.
      evidence:
      - reference: PMID:36078134
        reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          After co-injecting MOs with wild type tubgcp2 mRNA, an average of 55%
          developing larvae (55.75% of trans MO group; 53.64% of splice MO group)
          developed almost normal brain size (Figure 1d,e; Figure 2c,d).
        explanation: Direct genetic rescue readout in the zebrafish model.
    evidence:
    - reference: PMID:36078134
      reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In larvae injected with splice- or translation-blocking MOs, an
        experimental average of 88% develop the microcephaly phenotype (defined
        as a reduction of head width by more than two standard deviations
        compared to controls) (Figure 2a).
      explanation: Supports reduced brain size in this low-fidelity depletion model.
  evidence:
  - reference: PMID:36078134
    reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that antisense morpholino knockdown (KD) of the Danio rerio homolog,
      tubgcp2, recapitulates human TUBGCP2-associated microcephaly.
    explanation: Establishes the zebrafish model and its reported phenotype.
- name: Grip84-cg7716 Double-Knockout Fly
  species: Drosophila melanogaster
  genotype: Double knockout of the TUBGCP2 homologs Grip84 and cg7716
  publication: PMID:36078134
  description: >-
    A double-homolog knockout produces small larval brains, general microsomia,
    delayed development, and pupal lethality. It is a low-fidelity null model in
    a species with two TUBGCP2 homologs and does not model a human allele.
  associated_phenotypes:
  - Reduced larval brain surface area
  - General microsomia and delayed development
  modeled_mechanisms:
  - target: Reduced Brain Growth and Microcephaly
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Reproduces reduced brain surface area in a two-homolog null background.
    limitations: >-
      The model removes two fly homologs, has severe generalized developmental
      effects, and does not assay human cortical folding, neuronal migration, or
      microtubule nucleation.
    readouts:
    - name: Larval brain surface area
      target: Reduced Brain Growth and Microcephaly
      direction: DECREASED
      interpretation: Reduced surface area supports only the brain-growth node.
      evidence:
      - reference: PMID:36078134
        reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Surface area (SA) quantification (Figure 5d) shows that day 5 mutant fly
          brain SA is 64% of WT, and reaches 79% of WT brain SA just before mutant
          pupation, at day 6.
        explanation: Quantifies the reduced-brain-size readout.
    evidence:
    - reference: PMID:36078134
      reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Surface area (SA) quantification (Figure 5d) shows that day 5 mutant fly
        brain SA is 64% of WT, and reaches 79% of WT brain SA just before mutant
        pupation, at day 6.
      explanation: Supports only reduced brain growth in this low-fidelity model.
  evidence:
  - reference: PMID:36078134
    reference_title: A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Drosophila melanogaster double knockouts (KO) for TUBGCP2 homologs
      Grip84/cg7716 also develop microcephalic brains with general microsomia.
    explanation: Establishes the fly model and its broad phenotype.
discussions:
- discussion_id: gap_tubgcp2_functional_impact_class
  status: OPEN
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do TUBGCP2 disease alleles act by loss of function, or by interfering with
    gamma-TuRC assembly while the subunit remains present?
  rationale: >-
    The mixed allele series includes missense, splice-altering, frameshift, and
    multi-exon deletion variants, but no common assay establishes their effects.
    For p.Glu311Lys, GCP2 abundance is preserved while gamma-tubulin, HAUS6, and
    NEDD1 localization changes. That allele-specific result does not classify the
    truncating, splice, or deletion alleles and does not demonstrate a
    dominant-negative mechanism. Functional impact therefore remains UNKNOWN.
  attaches_to:
  - pathophysiology#Biallelic TUBGCP2 Variation
  proposed_experiments:
  - experiment_id: exp_tubgcp2_allele_series_rescue
    name: Allele-series rescue in TUBGCP2-null cells
    description: >-
      Re-express each reported allele in a TUBGCP2 knockout background and score
      gamma-TuRC assembly, nucleation rate, and HAUS6/NEDD1 localization. A
      matched allele series would distinguish preserved, partial, and absent
      function without inferring an effect from variant class alone.
- discussion_id: gap_tubgcp2_human_neural_validation
  status: OPEN
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do patient neural progenitors show altered gamma-TuRC localization,
    microtubule nucleation, mitotic dynamics, or neuronal migration?
  rationale: >-
    Current functional evidence comes from p.Glu311Lys skin fibroblasts and
    low-fidelity depletion/null animal models. The human cortical imaging
    suggests a migration disorder, but no patient-derived neural system measures
    migration, mitosis, or nucleation. This missing bridge prevents a causal
    assignment from the fibroblast localization phenotype to cortical
    malformation.
  attaches_to:
  - pathophysiology#Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation
  - pathophysiology#Altered Developing-Brain Mitotic State
  - pathophysiology#Neuronal Migration Failure
  evidence:
  - reference: PMID:40017707
    reference_title: "TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Currently, functional and proteomic studies on TUBGCP2 gene variants in
      human neurons are lacking.
    explanation: The review explicitly identifies the human-neural evidence gap.
  proposed_experiments:
  - experiment_id: exp_tubgcp2_patient_neural_models
    name: Isogenic patient iPSC neural-progenitor and migration assays
    description: >-
      Generate patient and corrected iPSC-derived neural progenitors and cortical
      organoids; quantify gamma-TuRC localization, microtubule nucleation,
      live-cell mitotic timing, progenitor survival, and radial migration.
- discussion_id: gap_tubgcp2_corpus_callosum_direction
  status: OPEN
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does TUBGCP2 disease produce a thin corpus callosum in most patients but
    a thick one in at least one, and does the direction track the allele?
  rationale: >-
    Thin corpus callosum occurred in 6/8 people in the 2025 review, while a later
    patient with homozygous c.2647dupC/p.Gln883Profs*62 had a thick corpus
    callosum. With one thick-callosum report, it is unknown whether direction
    tracks genotype, age, a modifier, or measurement differences.
  attaches_to:
  - phenotypes#Thin Corpus Callosum
  - phenotypes#Thick Corpus Callosum
  evidence:
  - reference: PMID:40448381
    reference_title: "Thick Corpus Callosum: An Unusual Finding of TUBGCP2-Related Tubulinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed cortical malformations consistent with the
      pachygyria-polymicrogyria complex, as well as a thickened corpus callosum.
    explanation: Direct evidence for the later opposite-direction callosal finding.
  proposed_experiments:
  - experiment_id: exp_tubgcp2_callosal_morphometry
    name: Genotype-stratified callosal morphometry across reported cases
    description: >-
      Pool published TUBGCP2 MRIs, measure callosal cross-sectional area against
      age norms, and test whether truncating alleles separate from missense
      alleles on that measure.
- discussion_id: gap_tubgcp2_l_serine_translation
  status: OPEN
  kind: OPEN_QUESTION
  prompt: >-
    Does L-serine alter a disease-relevant phenotype in TUBGCP2 neural models?
  rationale: >-
    A patient-fibroblast experiment found an 8% proliferation increase in both
    patient and control cells and a larger numerical reduction in cytotoxicity in
    patient cells, but neither result reached statistical significance. There is
    no animal or human treatment evidence, so L-serine remains a model-only
    observation rather than a treatment.
  attaches_to:
  - pathophysiology#Variant-Dependent Gamma-TuRC Localization and Cytoskeletal Dysregulation
  evidence:
  - reference: PMID:33458610
    reference_title: Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      L-serine treatment in cultured skin fibroblasts revealed an 8% increased
      proliferation in both TUBGCP2-patient and control, while a 26% reduction of
      cytotoxicity was detected in patient-derived cells compared to 14% in
      controls. These changes did not reach statistical significance.
    explanation: The exact nonsignificant in-vitro result that motivates, but does not answer, the question.
notes: >-
  Reviewed against six disease-focused PubMed records (PMID:31630790,
  PMID:33458610, PMID:36078134, PMID:40017707, PMID:40448381, and
  PMID:42472988). Frequency bands are scoped to the eight-person cumulative
  review in PMID:40017707; later cases extend the spectrum but are not silently
  added to that denominator.

  OLS4/MONDO was checked live on 2026-08-25 against the MONDO 2026-08-04 release.
  MONDO:0032893 was active and non-obsolete with the exact label "pachygyria,
  microcephaly, developmental delay, and dysmorphic facies, with or without
  seizures". This supersedes the entry's prior ontology-gap note.

  The literature sometimes calls TUBGCP2 disease a tubulinopathy. GCP2 is a
  gamma-tubulin-complex component rather than a tubulin isotype, so grouping
  membership remains a separate curation-boundary decision. Mechanistically,
  the entry retains only the migration-module nodes that are supported or
  explicitly hypothetical; it does not claim measured nucleation failure.

  GeneReviews NBK350554 does not mention TUBGCP2. Its seizure and rehabilitation
  guidance is included only as PARTIAL, OTHER-source phenotype-based
  extrapolation. L-serine has only a nonsignificant patient-fibroblast result and
  is not curated as treatment.
📚

References & Deep Research

References

7
PMID:31630790
Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
No top-level findings curated for this source.
PMID:33458610
Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.
No top-level findings curated for this source.
PMID:36078134
A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
No top-level findings curated for this source.
PMID:40017707
TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review.
No top-level findings curated for this source.
PMID:40448381
Thick Corpus Callosum: An Unusual Finding of TUBGCP2-Related Tubulinopathy.
No top-level findings curated for this source.
PMID:42472988
Genotypic and phenotypic heterogeneity in tubulinopathies: insights from a Turkish multicenter cohort.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf
https://www.ncbi.nlm.nih.gov/books/NBK350554/pdf/Bookshelf_NBK350554.pdf
No top-level findings curated for this source.