Polymicrogyria with optic nerve hypoplasia (PMGOH; MONDO:0013172) is a recognized clinical entity, but its originally proposed relationship to TUBA8 is DISPUTED. ClinGen's Brain Malformations Gene Curation Expert Panel reached that classification in 2023 and concluded that no valid evidence remained to support the TUBA8-PMGOH claim. In 2009 an autosomal recessive syndrome of generalized polymicrogyria with optic nerve hypoplasia was mapped by autozygosity to a 7.42-Mb interval containing TUBA8, and a homozygous hypomorphic splice variant in TUBA8 was prioritized. The proposed mechanism drew on TUBA8's unusual alanine at position 40, where other alpha-tubulins carry a modifiable lysine, and on an apparent expression pattern in developing cerebral cortex. The latter evidence was subsequently weakened when TUBA8-specific probes found only very low expression in developing mouse and human brain. That relationship has since been substantially undercut, and by the original authors. A Tuba8 knockout mouse confirmed to lack Tuba8 protein did not display polymicrogyria and appeared neurologically normal. In response, the authors re-analysed the original human subjects by whole exome sequencing and found an additional homozygous loss-of-function mutation in SNAP29 - concluding that SNAP29 deficiency, rather than TUBA8 deficiency, may underlie most or all of the neurodevelopmental anomalies in those subjects. That is not a failure to replicate; it is a competing causal variant identified in the founding subjects on whom the gene-disease claim rests. Tuba8 nevertheless has demonstrable neurodevelopmental roles that should not be mistaken for evidence of PMGOH causality. It drives differentiation of cortical radial glia into apical intermediate progenitors by tuning tubulin C-terminal modifications. A 2026 Purkinje-cell-specific knockout also showed impaired dendrite development and maintenance with age-dependent locomotor and anxiety-like changes. These findings establish biological function in particular neural contexts, not a generalized cortical polymicrogyria mechanism or a human TUBA8-PMGOH association. This entry binds the MONDO disease identity while keeping the gene-disease claim explicitly disputed: ontology identity and causal validity are separate assertions. It exists so that a curator meeting TUBA8 on a polymicrogyria panel finds the expert-panel classification and competing SNAP29 explanation rather than an apparent gap or an unqualified causal claim.
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name: TUBA8-related Polymicrogyria with Optic Nerve Hypoplasia
creation_date: "2026-08-20T18:00:00Z"
category: Mendelian
disease_term:
preferred_term: Polymicrogyria with optic nerve hypoplasia
term:
id: MONDO:0013172
label: polymicrogyria with optic nerve hypoplasia
description: >-
Polymicrogyria with optic nerve hypoplasia (PMGOH; MONDO:0013172) is a
recognized clinical entity, but its originally proposed relationship to TUBA8
is DISPUTED. ClinGen's Brain Malformations Gene Curation Expert Panel reached
that classification in 2023 and concluded that no valid evidence remained to
support the TUBA8-PMGOH claim. In 2009 an autosomal recessive syndrome of generalized
polymicrogyria with optic nerve hypoplasia was mapped by autozygosity to
a 7.42-Mb interval containing TUBA8, and a homozygous hypomorphic splice
variant in TUBA8 was prioritized. The proposed mechanism drew on TUBA8's
unusual alanine at position 40, where other alpha-tubulins carry a modifiable
lysine, and on an apparent expression pattern in developing cerebral cortex.
The latter evidence was subsequently weakened when TUBA8-specific probes
found only very low expression in developing mouse and human brain.
That relationship has since been substantially undercut, and by the original
authors. A Tuba8 knockout mouse confirmed to lack Tuba8 protein did not display
polymicrogyria and appeared neurologically normal. In response, the authors
re-analysed the original human subjects by whole exome sequencing and found an
additional homozygous loss-of-function mutation in SNAP29 - concluding that
SNAP29 deficiency, rather than TUBA8 deficiency, may underlie most or all of
the neurodevelopmental anomalies in those subjects. That is not a failure to
replicate; it is a competing causal variant identified in the founding
subjects on whom the gene-disease claim rests.
Tuba8 nevertheless has demonstrable neurodevelopmental roles that should not
be mistaken for evidence of PMGOH causality. It drives differentiation of
cortical radial glia into apical intermediate progenitors by tuning tubulin
C-terminal modifications. A 2026 Purkinje-cell-specific knockout also showed
impaired dendrite development and maintenance with age-dependent locomotor
and anxiety-like changes. These findings establish biological function in
particular neural contexts, not a generalized cortical polymicrogyria
mechanism or a human TUBA8-PMGOH association.
This entry binds the MONDO disease identity while keeping the gene-disease
claim explicitly disputed: ontology identity and causal validity are separate
assertions. It exists so that a curator meeting TUBA8 on a polymicrogyria
panel finds the expert-panel classification and competing SNAP29 explanation
rather than an apparent gap or an unqualified causal claim.
parents:
- congenital nervous system disorder
- disorder of development or morphogenesis
references:
- reference: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
title: TUBA8 / polymicrogyria with optic nerve hypoplasia (Disputed)
- reference: ORPHA:250972
title: Polymicrogyria with optic nerve hypoplasia
- reference: PMID:19896110
title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
- reference: PMID:20466094
title: Tuba8 is expressed at low levels in the developing mouse and human brain.
- reference: PMID:28388629
title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
- reference: PMID:32097653
title: Tuba8 Drives Differentiation of Cortical Radial Glia into Apical Intermediate Progenitors by Tuning Modifications of Tubulin C Termini.
- reference: PMID:36211152
title: The Genetic Landscape of Polymicrogyria.
- reference: PMID:41105144
title: TUBA8 promotes neuronal dendrite development through its 40th alanine.
external_assertions:
- name: ClinGen TUBA8-PMGOH gene-disease validity assertion
source: ClinGen
assertion_type: gene_disease_validity
external_id: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
description: >-
ClinGen's Brain Malformations Gene Curation Expert Panel classifies the
autosomal recessive TUBA8-polymicrogyria with optic nerve hypoplasia
relationship as Disputed. The curation found that none of the reported
variants could be scored and that no valid evidence remained after the
homozygous SNAP29 frameshift in the founding subjects, the negative Tuba8
knockout, and the phenotypically discordant additional proband were
considered.
evidence:
- reference: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
reference_title: TUBA8 / polymicrogyria with optic nerve hypoplasia (Disputed)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
TUBA8 | HGNC:12410 | polymicrogyria with optic nerve hypoplasia |
MONDO:0013172 | AR | Disputed
explanation: >-
The authoritative ClinGen row identifies the disease, inheritance mode,
and disputed validity classification.
- reference: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
reference_title: TUBA8 / polymicrogyria with optic nerve hypoplasia (Disputed)
supports: REFUTE
evidence_source: OTHER
snippet: >-
In summary, the evidence supporting the relationship between TUBA8 and
autosomal recessive PMGOH has been disputed and no valid evidence remains
to support the claim.
explanation: >-
ClinGen's evidence summary directly rejects treating the reported
TUBA8-PMGOH relationship as established.
- name: Orphanet polymicrogyria with optic nerve hypoplasia record
source: Orphanet
assertion_type: structured_disease_record
external_id: ORPHA:250972
url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=250972
description: >-
Orphanet's structured record supplies the MONDO mapping, inheritance, and
source-backed phenotype spectrum. Its gene table still labels TUBA8 as a
disease-causing germline association; that unqualified assertion conflicts
with the later ClinGen Disputed classification and is recorded here as an
external-source discrepancy, not adopted as the entry's validity judgment.
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: MONDO:0013172 | Exact
explanation: Orphanet exactly maps its PMGOH record to the bound MONDO identity.
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: >-
TUBA8 | tubulin alpha 8 | hgnc:12410 | Disease-causing germline
mutation(s) in
explanation: >-
Captures Orphanet's causal gene assertion, marked PARTIAL because ClinGen's
later expert-panel review disputes the relationship and found no valid
supporting evidence.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Reported as autosomal recessive, established by autozygosity mapping in a
consanguineous setting. This is itself a difference from the dominant
tubulin-isotype cortical malformation disorders.
evidence:
- reference: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
reference_title: TUBA8 / polymicrogyria with optic nerve hypoplasia (Disputed)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
TUBA8 | HGNC:12410 | polymicrogyria with optic nerve hypoplasia |
MONDO:0013172 | AR | Disputed
explanation: >-
ClinGen records AR as the asserted inheritance mode while disputing the
underlying gene-disease relationship, so the support is necessarily
partial.
- reference: PMID:19896110
reference_title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we describe a recognizable autosomal recessive syndrome,
characterized by generalized polymicrogyria in association with optic nerve
hypoplasia (PMGOH).
explanation: >-
States the recessive inheritance and defines the reported syndrome.
pathophysiology:
- name: Reported Hypomorphic TUBA8 Splice Defect
role: TRIGGER
biological_scale: MOLECULAR
description: >-
The reported allele is a homozygous 14-bp deletion in the intron-1 splice
acceptor polypyrimidine tract. Patient lymphoblastoid cells retained a low
level of full-length transcript, so the allele is hypomorphic rather than a
proven null. Its molecular effect can be classified independently of the
disputed disease attribution: partial loss of TUBA8 function is supported,
but causation of PMGOH is not. TUBA8 is an unusual alpha-tubulin with alanine
rather than the modifiable lysine found at position 40 in other isotypes.
Later experiments confirm that this alanine contributes to Purkinje-cell
dendrite development, but they do not demonstrate the generalized cortical
migration failure proposed for PMGOH.
genetic_context:
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
allele_type: intronic 14-bp splice-altering deletion
description: >-
A shared homozygous splice-altering deletion was reported in two
consanguineous Pakistani families whose autozygous intervals indicated a
likely common ancestral background. The allele reduced correctly spliced
transcript but did not eliminate it. This molecular classification does
not imply that the allele caused the subjects' PMGOH phenotype.
genes:
- preferred_term: TUBA8
term:
id: hgnc:12410
label: TUBA8
biological_processes:
- preferred_term: microtubule cytoskeleton organization
term:
id: GO:0000226
label: microtubule cytoskeleton organization
modifier: DYSREGULATED
evidence:
- reference: PMID:28388629
reference_title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We previously identified homozygous hypomorphic TUBA8 mutations in human
subjects with a polymicrogyria (PMG) syndrome
explanation: >-
Establishes that the reported human TUBA8 allele was hypomorphic; this
supports partial loss of molecular function, not PMGOH causality.
- reference: PMID:19896110
reference_title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
By autozygosity mapping, we show that the molecular basis for this
condition is mutation of the TUBA8 gene, encoding a variant alpha-tubulin of
unknown function that is not susceptible to the lysine 40 acetylation that
regulates microtubule function during cortical neuron migration.
explanation: >-
The founding genetic and mechanistic claim, including the distinctive
absence of the lysine 40 acetylation site.
- reference: PMID:19896110
reference_title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Together with the unique expression pattern of TUBA8 within the developing
cerebral cortex, these observations suggest a role for this atypical
microtubule component in regulating mammalian brain development.
explanation: >-
The authors' own framing is that the observations SUGGEST a role - recorded
as PARTIAL because a suggested role is not a demonstrated mechanism.
- reference: PMID:41105144
reference_title: TUBA8 promotes neuronal dendrite development through its 40th alanine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Loss of TUBA8 in Purkinje cells induces global dendritic height defects in
multiple lobules during development and aging.
explanation: >-
Demonstrates a genuine cell-restricted neural function for TUBA8, but not
generalized cortical polymicrogyria or human disease causality.
- reference: PMID:32097653
reference_title: Tuba8 Drives Differentiation of Cortical Radial Glia into Apical Intermediate Progenitors by Tuning Modifications of Tubulin C Termini.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We show that the non-canonical tubulin Tuba8, transiently expressed in
cortical progenitors, drives differentiation of RGs into apical
intermediate progenitors, a more restricted progenitor type lacking
attachment to the basal lamina.
explanation: >-
Reports a genuine cortical developmental role for Tuba8 - though a
progenitor differentiation role, not the neuronal migration role the
disease attribution assumes.
downstream:
- target: Disrupted Cortical Development
description: >-
Founding proposed consequence: partial TUBA8 loss was asserted to perturb
cortical development and produce polymicrogyria. ClinGen now classifies
that gene-disease link as disputed with no valid supporting evidence.
evidence:
- reference: PMID:19896110
reference_title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
By autozygosity mapping, we show that the molecular basis for this
condition is mutation of the TUBA8 gene
explanation: The original paper's causal assertion for this edge.
- reference: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
reference_title: TUBA8 / polymicrogyria with optic nerve hypoplasia (Disputed)
supports: REFUTE
evidence_source: OTHER
snippet: >-
no valid evidence remains to support the claim
explanation: >-
ClinGen's expert review refutes treating the proposed TUBA8-to-PMGOH
edge as established.
- name: Competing Homozygous SNAP29 Loss of Function
role: TRIGGER
biological_scale: MOLECULAR
description: >-
Exome reanalysis of two founding subjects identified a homozygous SNAP29
frameshift within the same autozygous interval. Biallelic SNAP29 loss causes
CEDNIK syndrome and provides a direct competing explanation for most or all
of the neurodevelopmental findings originally attributed to TUBA8.
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
allele_type: frameshift variant (c.487dupA; p.Ser163Lysfs*6)
description: >-
Homozygous SNAP29 frameshift identified by whole-exome reanalysis in two
of the original TUBA8-mutated subjects.
genes:
- preferred_term: SNAP29
term:
id: hgnc:11133
label: SNAP29
evidence:
- reference: PMID:28388629
reference_title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This resulted in identification of an additional homozygous
loss-of-function mutation in SNAP29, suggesting that SNAP29 deficiency,
rather than TUBA8 deficiency, may underlie most or all of the
neurodevelopmental anomalies in these subjects.
explanation: >-
Directly establishes the competing biallelic SNAP29 finding and the
original authors' revised causal interpretation.
downstream:
- target: Disrupted Cortical Development
description: >-
Competing explanation for the founding subjects' polymicrogyria and
broader neurodevelopmental phenotype.
evidence:
- reference: PMID:28388629
reference_title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This new data indicated that the PMG in our patients was likely to be
due, in whole or in part, to the SNAP29 rather than the TUBA8 mutation.
explanation: >-
The full-text interpretation explicitly links the SNAP29 frameshift to
the observed polymicrogyria.
- name: Disrupted Cortical Development
biological_scale: TISSUE
description: >-
The reported tissue phenotype: generalized polymicrogyria - a cortex of
normal thickness with excessive, abnormally small gyri - together with optic
nerve hypoplasia. The combination is described as a recognizable syndrome.
Whether it is caused by the TUBA8 variant is the open question this entry
records; the phenotype itself is not in dispute.
biological_processes:
- preferred_term: cerebral cortex development
term:
id: GO:0021987
label: cerebral cortex development
modifier: DYSREGULATED
evidence:
- reference: PMID:19896110
reference_title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we describe a recognizable autosomal recessive syndrome,
characterized by generalized polymicrogyria in association with optic nerve
hypoplasia (PMGOH).
explanation: Defines the reported clinical-radiological syndrome.
downstream:
- target: Polymicrogyria
description: The cortical malformation.
- target: Optic Nerve Hypoplasia
description: The ocular component that names the syndrome.
- target: Severe Global Developmental Delay
description: The severe neurodevelopmental outcome in the founding cohort.
- target: Neonatal Hypotonia
description: Early low muscle tone reported in the syndrome.
- target: Seizures
description: Epileptic manifestations reported in the founding cohort.
- target: Agenesis of Corpus Callosum
description: Absent corpus callosum accompanying the PMG in most subjects.
- target: Dysplastic Corpus Callosum
description: Dysplastic corpus callosum in part of the reported spectrum.
- target: Absent Speech
description: Lack of speech accompanying the profound developmental impairment.
- target: Hyporeflexia
description: Reduced reflexes reported in the founding cohort.
- target: Bilateral Tonic-Clonic Seizures
description: A reported seizure subtype.
- target: Infantile Spasms
description: A reported early-life seizure subtype.
- target: Brainstem Hypoplasia
description: Hypoplastic and malformed brainstem in part of the syndrome.
- target: Colpocephaly
description: Ventricular configuration accompanying callosal agenesis.
phenotypes:
- name: Polymicrogyria
description: >-
Generalized polymicrogyria. TUBA8 continues to appear in surveys of the
genetic landscape of polymicrogyria, which is why the contested status
matters practically - the gene is on panels.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Polymicrogyria
term:
id: HP:0002126
label: Polymicrogyria
evidence:
- reference: PMID:19896110
reference_title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by generalized polymicrogyria in association with optic nerve
hypoplasia (PMGOH)
explanation: Reports generalized polymicrogyria as a defining feature.
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0002126 | Polymicrogyria | Very frequent (99-80%)
explanation: Orphanet records polymicrogyria as very frequent in PMGOH.
- reference: PMID:36211152
reference_title: The Genetic Landscape of Polymicrogyria.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Several genes including GPR56, TUBB2B, SRPX2, PAX6, EOMES, WDR62, TUBA8,
COL18A1, and KIAA1279 are known to be associated with PMG
explanation: >-
This 2022 review illustrates why the historical TUBA8 claim remains
visible in polymicrogyria surveys; it predates and does not override the
ClinGen Disputed classification.
- name: Optic Nerve Hypoplasia
description: >-
Optic nerve hypoplasia, the feature that distinguishes this syndrome from
other polymicrogyria presentations.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Optic nerve hypoplasia
term:
id: HP:0000609
label: Optic nerve hypoplasia
evidence:
- reference: PMID:19896110
reference_title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by generalized polymicrogyria in association with optic nerve
hypoplasia (PMGOH)
explanation: Reports optic nerve hypoplasia as the co-defining feature.
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0000609 | Optic nerve hypoplasia | Very frequent (99-80%)
explanation: Orphanet records optic nerve hypoplasia as very frequent in PMGOH.
- name: Severe Global Developmental Delay
description: >-
Profound developmental impairment was part of the phenotype in the founding
subjects. This is a feature of the clinical syndrome and does not establish
that TUBA8 caused it.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Severe global developmental delay
term:
id: HP:0011344
label: Severe global developmental delay
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0011344 | Severe global developmental delay | Very frequent (99-80%)
explanation: Orphanet records severe global developmental delay as very frequent.
- name: Neonatal Hypotonia
description: >-
Low muscle tone beginning in infancy was part of the reported PMGOH
phenotype, irrespective of which homozygous variant caused it.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Neonatal hypotonia
term:
id: HP:0001319
label: Neonatal hypotonia
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0001319 | Neonatal hypotonia | Very frequent (99-80%)
explanation: Orphanet records the exact neonatal hypotonia term as very frequent.
- name: Seizures
description: >-
Seizures were a core manifestation in the founding subjects; an additional
individual with TUBA8 variants had epilepsy but lacked PMG and optic nerve
hypoplasia, so epilepsy alone does not rescue the disputed syndrome claim.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
reference_title: TUBA8 / polymicrogyria with optic nerve hypoplasia (Disputed)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
profound developmental delay, low muscle tone in infancy, seizures, and
optic nerve hypoplasia
explanation: ClinGen's evidence summary records seizures in PMGOH.
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0001250 | Seizure | Very frequent (99-80%)
explanation: Orphanet records seizures as very frequent in PMGOH.
- name: Agenesis of Corpus Callosum
description: >-
The corpus callosum was absent in most reported subjects.
frequency: FREQUENT
phenotype_term:
preferred_term: Agenesis of corpus callosum
term:
id: HP:0001274
label: Agenesis of corpus callosum
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0001274 | Agenesis of corpus callosum | Frequent (79-30%)
explanation: Orphanet records callosal agenesis as frequent in PMGOH.
- name: Dysplastic Corpus Callosum
description: Dysplastic corpus callosum is also part of the reported spectrum.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Dysplastic corpus callosum
term:
id: HP:0006989
label: Dysplastic corpus callosum
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0006989 | Dysplastic corpus callosum | Occasional (29-5%)
explanation: Orphanet records dysplastic corpus callosum as occasional.
- name: Absent Speech
description: Absent speech accompanies the severe developmental impairment.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Absent speech
term:
id: HP:0001344
label: Absent speech
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0001344 | Absent speech | Very frequent (99-80%)
explanation: Orphanet records absent speech as very frequent.
- name: Hyporeflexia
description: Reduced deep-tendon reflexes were part of the reported syndrome.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Hyporeflexia
term:
id: HP:0001265
label: Hyporeflexia
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0001265 | Hyporeflexia | Very frequent (99-80%)
explanation: Orphanet records hyporeflexia as very frequent.
- name: Bilateral Tonic-Clonic Seizures
description: Bilateral tonic-clonic seizures are one reported seizure subtype.
frequency: FREQUENT
phenotype_term:
preferred_term: Bilateral tonic-clonic seizure
term:
id: HP:0002069
label: Bilateral tonic-clonic seizure
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0002069 | Bilateral tonic-clonic seizure | Frequent (79-30%)
explanation: Orphanet records this seizure subtype as frequent.
- name: Infantile Spasms
description: Infantile spasms are an occasional early seizure presentation.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Infantile spasms
term:
id: HP:0012469
label: Infantile spasms
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0012469 | Infantile spasms | Occasional (29-5%)
explanation: Orphanet records infantile spasms as occasional.
- name: Brainstem Hypoplasia
description: >-
Brainstem hypoplasia and loss of normal pontomedullary demarcation were
reported in part of the syndrome.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Hypoplasia of the brainstem
term:
id: HP:0002365
label: Hypoplasia of the brainstem
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0002365 | Hypoplasia of the brainstem | Occasional (29-5%)
explanation: Orphanet records brainstem hypoplasia as occasional.
- name: Colpocephaly
description: Colpocephaly accompanies the callosal malformation spectrum.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Colpocephaly
term:
id: HP:0030048
label: Colpocephaly
evidence:
- reference: ORPHA:250972
reference_title: Polymicrogyria with optic nerve hypoplasia
supports: SUPPORT
evidence_source: OTHER
snippet: HP:0030048 | Colpocephaly | Very frequent (99-80%)
explanation: Orphanet records colpocephaly as very frequent.
genetic:
- name: TUBA8
association: Disputed
relationship_type: DISPUTED
gene_term:
preferred_term: TUBA8 (atypical alpha-tubulin 8)
term:
id: hgnc:12410
label: TUBA8
notes: >-
Recorded as Disputed, matching the 2023 ClinGen Brain Malformations GCEP
classification. The 2009 autozygosity mapping and molecularly hypomorphic
TUBA8 splice variant are real observations, but the shared interval contained
a homozygous SNAP29 loss-of-function variant, global Tuba8 knockout did not
produce PMG, the original broad cortical expression result was not reproduced
with TUBA8-specific probes, and an additional proband with compound
heterozygous TUBA8 missense variants lacked both PMG and optic nerve
hypoplasia. TUBA8 has experimentally supported neural functions, but those do
not establish this human gene-disease relationship.
evidence:
- reference: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
reference_title: TUBA8 / polymicrogyria with optic nerve hypoplasia (Disputed)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
TUBA8 | HGNC:12410 | polymicrogyria with optic nerve hypoplasia |
MONDO:0013172 | AR | Disputed
explanation: >-
ClinGen's expert-panel classification directly supports recording this
association as Disputed.
- reference: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
reference_title: TUBA8 / polymicrogyria with optic nerve hypoplasia (Disputed)
supports: REFUTE
evidence_source: OTHER
snippet: >-
Another proband, who had compound heterozygous missense variants in trans
in TUBA8, had epilepsy but no brain structural anomalies or optic nerve
hypoplasia
explanation: >-
The only additional reported proband was phenotypically discordant with
PMGOH, so it does not provide replication of the founding association.
- reference: PMID:19896110
reference_title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
By autozygosity mapping, we show that the molecular basis for this
condition is mutation of the TUBA8 gene
explanation: The founding human genetic evidence for the association.
- reference: PMID:28388629
reference_title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: >-
Homozygous mice were confirmed to lack Tuba8 protein in the testis, but
did not display PMG and appeared to be neurologically normal.
explanation: >-
The knockout mice lack Tuba8 protein yet have no polymicrogyria and are
neurologically normal - the central evidence against a brain developmental
role for this gene.
diagnosis:
- name: Exome-scale reanalysis including SNAP29
description: >-
A TUBA8 finding in a patient with PMG and optic nerve hypoplasia should not
be treated as diagnostic. Exome-scale analysis must evaluate SNAP29 and
other causes of cortical malformation; reanalysis of the founding subjects
identified homozygous SNAP29 loss of function consistent with CEDNIK.
evidence:
- reference: PMID:28388629
reference_title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In response to this finding, we re-analyzed the human PMG subjects using
whole exome sequencing. This resulted in identification of an additional
homozygous loss-of-function mutation in SNAP29
explanation: >-
Directly supports broad molecular reanalysis and explicit assessment of
SNAP29 rather than diagnosis from the historical TUBA8 finding alone.
- name: Apply the ClinGen disputed validity classification
description: >-
Variant interpretation and panel reporting should state that the
TUBA8-PMGOH relationship is disputed and that no valid supporting evidence
remained in the 2023 expert-panel assessment.
evidence:
- reference: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
reference_title: TUBA8 / polymicrogyria with optic nerve hypoplasia (Disputed)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
no valid evidence remains to support the claim
explanation: >-
Establishes the evidence-status warning required when interpreting a
TUBA8 variant in this phenotype.
animal_models:
- name: Global Tuba8 exon-3 knockout mouse
species: Mouse (Mus musculus)
genotype: Homozygous deletion of Tuba8 exon 3 with nonsense-mediated transcript decay and absent Tuba8 protein
publication: PMID:28388629
description: >-
A validated global Tuba8-null mouse developed normally, showed no
polymicrogyria or cortical-layering defect, and appeared neurologically
normal. It is the principal negative model for the proposed human cortical
mechanism, although species differences and the distinction between a mouse
null and the human hypomorphic splice allele limit complete refutation.
evidence:
- reference: PMID:28388629
reference_title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Homozygous mice were confirmed to lack Tuba8 protein in the testis, but
did not display PMG and appeared to be neurologically normal.
explanation: Defines the null model and its negative neurological phenotype.
modeled_mechanisms:
- target: Disrupted Cortical Development
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
The null model fails to reproduce polymicrogyria or abnormal cortical
development, weakening the proposed TUBA8-to-PMGOH mechanism.
limitations: >-
A negative mouse result cannot by itself exclude a human-specific effect,
and the human allele retained some full-length transcript rather than
being a proven null. The competing SNAP29 variant makes the negative model
more probative but does not eliminate those cross-species limitations.
evidence:
- reference: PMID:28388629
reference_title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
No consistent differences in the embryonic cortex was detected between
the control and knockout samples
explanation: >-
The embryonic cortical analysis did not reproduce the proposed human
cortical-development defect.
- name: Purkinje-cell-specific Tuba8 conditional knockout mouse
species: Mouse (Mus musculus)
genotype: Pcp2-Cre/Tuba8fl/fl with Tuba8 ablated in Purkinje cells from P6
publication: PMID:41105144
description: >-
This postnatal, cell-restricted knockout resolves a real Tuba8 function that
the earlier global study did not detect: impaired Purkinje-cell dendrite
development and maintenance, followed by age-dependent locomotor and
anxiety-like changes. It supports a narrow cerebellar role but is not a
model of PMG, optic nerve hypoplasia, the human splice allele, or the
prenatal generalized cortical phenotype.
evidence:
- reference: PMID:41105144
reference_title: TUBA8 promotes neuronal dendrite development through its 40th alanine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
With Pcp2-driven conditional knockout (cKO) of TUBA8 and TUBA4A in
Purkinje cells, we found that loss of TUBA8 resulted in developmental
defects in dendritic morphology and function
explanation: Defines the conditional model and its principal neural result.
modeled_mechanisms:
- target: Reported Hypomorphic TUBA8 Splice Defect
relationship: PERTURBS
fidelity: LOW
description: >-
Purkinje-cell Tuba8 loss perturbs a genuine neural function of the gene,
separating biological plausibility from evidence for the disputed human
syndrome.
limitations: >-
The model deletes Tuba8 after birth in one cerebellar cell type; it neither
carries the human hypomorphic splice allele nor tests prenatal cerebral
cortical organization or optic nerve development.
evidence:
- reference: PMID:41105144
reference_title: TUBA8 promotes neuronal dendrite development through its 40th alanine.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Loss of TUBA8 in Purkinje cells induces global dendritic height defects
in multiple lobules during development and aging.
explanation: >-
Demonstrates a Tuba8-dependent neural phenotype while remaining
mechanistically remote from human PMGOH.
discussions:
- discussion_id: gap_tuba8_gene_disease_validity
prompt: >-
Is TUBA8 a genuine cause of polymicrogyria with optic nerve hypoplasia, or
was the 2009 autozygosity finding a linked bystander?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Reported Hypomorphic TUBA8 Splice Defect
- pathophysiology#Competing Homozygous SNAP29 Loss of Function
- pathophysiology#Disrupted Cortical Development
rationale: >-
ClinGen's 2023 Brain Malformations GCEP assessment is the controlling
validity judgment: the TUBA8-PMGOH relationship is Disputed and no valid
evidence remained to support it. The founding observation still deserves
accurate representation. Two consanguineous Pakistani families, probably
sharing an ancestral autozygous interval, carried the same molecularly
hypomorphic TUBA8 splice variant, and TUBA8 has experimentally supported
functions in radial-glial differentiation and Purkinje-cell dendrite
development.
Those observations do not establish the syndrome relationship. The 7.42-Mb
autozygous interval contained more than TUBA8, and exome reanalysis found a
homozygous SNAP29 frameshift that the original authors judged likely to
explain most or all of the neurodevelopmental phenotype. A validated global
Tuba8 knockout had no PMG or consistent cortical defect. The founding broad
cortical expression pattern was not reproduced by later TUBA8-specific
probes, which found very low expression during mouse and human neuronal
migration. ClinGen also considered a fifth proband with compound
heterozygous TUBA8 missense variants; that individual had epilepsy but no
brain structural anomaly or optic nerve hypoplasia and therefore did not
replicate PMGOH.
The remaining question is narrow: whether independently ascertained,
phenotypically concordant families without a competing cause could overturn
the disputed classification, or whether TUBA8 only modifies particular
neural functions while SNAP29 explains the founding syndrome. The MONDO
disease identity is bound because the clinical entity exists; the TUBA8
association remains Disputed and the entry is not a Tubulinopathies grouping
member.
proposed_experiments:
- experiment_id: exp_tuba8_independent_family_ascertainment
name: Ascertainment of additional biallelic TUBA8 families
description: >-
Query large polymicrogyria and cortical malformation sequencing cohorts for
biallelic TUBA8 variants, and where found, assess segregation and phenotype
concordance with the reported PMGOH syndrome.
decision_criterion: >-
Two or more unrelated families with biallelic TUBA8 variants and concordant
polymicrogyria with optic nerve hypoplasia, no competing causal variant,
convincing segregation, and variant-level functional evidence would
materially support re-evaluation by ClinGen and reconsideration for the
Tubulinopathies grouping. Continued absence across well-powered cohorts
would reinforce the disputed classification.
would_support:
- pathophysiology#Reported Hypomorphic TUBA8 Splice Defect
evidence:
- reference: CGGV:assertion_9bd5681e-2a42-4bbb-be5f-dabe6efa5334-2023-12-19T170000.000Z
reference_title: TUBA8 / polymicrogyria with optic nerve hypoplasia (Disputed)
supports: REFUTE
evidence_source: OTHER
snippet: >-
In summary, the evidence supporting the relationship between TUBA8 and
autosomal recessive PMGOH has been disputed and no valid evidence remains
to support the claim.
explanation: >-
The expert-panel synthesis establishes the current gene-disease validity
state around which the knowledge gap is framed.
- reference: PMID:19896110
reference_title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
By autozygosity mapping, we show that the molecular basis for this
condition is mutation of the TUBA8 gene, encoding a variant alpha-tubulin of
unknown function that is not susceptible to the lysine 40 acetylation that
regulates microtubule function during cortical neuron migration.
explanation: >-
The case for the association, including the specific mechanistic
hypothesis.
- reference: PMID:28388629
reference_title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: >-
Homozygous mice were confirmed to lack Tuba8 protein in the testis, but
did not display PMG and appeared to be neurologically normal.
explanation: >-
The negative brain phenotype in a confirmed protein-null animal, which is
the strongest single piece of evidence against the association.
- reference: PMID:28388629
reference_title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
This resulted in identification of an additional homozygous
loss-of-function mutation in SNAP29, suggesting that SNAP29 deficiency,
rather than TUBA8 deficiency, may underlie most or all of the
neurodevelopmental anomalies in these subjects.
explanation: >-
A competing causal variant identified in the founding family itself - the
linked-bystander scenario confirmed rather than merely hypothesized.
- reference: PMID:28388629
reference_title: A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Nonetheless, in the mouse brain, Tuba8 specifically localised to the
cerebellar Purkinje cells, suggesting that the human mutations may affect
or modify motor control.
explanation: >-
The narrow residual case for a TUBA8 neurological contribution, offered by
the same authors who undercut the primary claim.
- reference: PMID:41105144
reference_title: TUBA8 promotes neuronal dendrite development through its 40th alanine.
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: >-
A previous study using in situ hybridization with an optimized Tuba8 RNA
probe showed that a very low level of Tuba8 was expressed in the
developing cerebral cortex and specifically localized in cerebellar
Purkinje cells (Braun et al., 2010).
explanation: >-
Provides a quotable full-text restatement of the TUBA8-specific expression
result that weakened the founding broad cortical-expression rationale.
- reference: PMID:32097653
reference_title: Tuba8 Drives Differentiation of Cortical Radial Glia into Apical Intermediate Progenitors by Tuning Modifications of Tubulin C Termini.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We show that the non-canonical tubulin Tuba8, transiently expressed in
cortical progenitors, drives differentiation of RGs into apical
intermediate progenitors, a more restricted progenitor type lacking
attachment to the basal lamina.
explanation: >-
Shows Tuba8 does have a cortical developmental role - but a
progenitor-differentiation one rather than the migration role the disease
attribution would require.
notes: >-
Created 2026-08-20 while closing out tubulin-family disease coverage following
docs/reports/tubulinopathies-grouping-review-2026-08-20.md, which flagged TUBA8
as a contested candidate that should be recorded rather than silently omitted.
Review on 2026-08-26 found that ClinGen had already classified the exact
TUBA8-polymicrogyria with optic nerve hypoplasia relationship as Disputed in
2023. The entry now binds MONDO:0013172 because disease identity does not assert
gene causality, records genetic[].relationship_type as DISPUTED, and exposes
the expert-panel assertion structurally.
NOT a member of the Tubulinopathies grouping and NOT conformed to
microtubule_dependent_neuronal_migration_failure. Conformance would assert
exactly the migration mechanism that the mouse knockout fails to support, so
declaring it would import the disputed claim through the module layer.
Molecular function and disease validity are kept separate. The founding TUBA8
allele is a demonstrated hypomorphic splice defect, and newer models support
radial-glial and Purkinje-cell functions, but none of that establishes PMGOH
causality. Conversely, the competing SNAP29 variant and negative global mouse
model are machine-visible rather than buried in prose. The central unresolved
question is whether any independently ascertained, phenotypically concordant
TUBA8 families without a second diagnosis exist.