Periventricular Nodular Heterotopia 9

Mendelian MONDO:0030061 Pathograph 11 Show in embeddings browser Periventricular Nodular Heterotopia

PVNH9 is a malformation of cortical development caused by heterozygous loss-of-function variants in MAP1B, which encodes microtubule-associated protein 1B, a cytoskeletal regulator required for neuronal migration, axon guidance and cortical circuit formation. Neurons that should have migrated out to the cortical plate remain as nodules along the walls of the lateral ventricles. **The gene was found by a statistical argument, not by a family.** An exome study of 202 individuals with sporadic PVNH found no novel gene in a trio-based de novo analysis, then found a genome-wide significant signal in a gene-level collapsing analysis of cases against controls, driven by four ultra-rare loss-of-function heterozygous variants in MAP1B. Only one of the four was de novo. That matters for how the entry reads: the gene-disease claim rests on a burden test, and every downstream statement inherits whatever that design supports. **Its most useful finding is about penetrance, not about MAP1B.** In at least one instance the variant was inherited from a parent with previously undiagnosed PVNH. The authors drew the general conclusion that detrimental mutations arising in immediately preceding generations with incomplete penetrance may be responsible for some apparently sporadic disease. So a "sporadic" PVNH case is not evidence against an inherited MAP1B allele, and an unaffected-looking parent has not necessarily been imaged. **The imaging phenotype has a consistent shape.** PVNH in MAP1B disease is anteriorly or frontally predominant rather than diffuse, and it can be accompanied by perisylvian polymicrogyria - two malformations of cortical development in one brain, which is what makes the lesion a general defect of cortical neuronal positioning rather than a specific failure of periventricular detachment. **Allele class, not just gene, decides which disease you get.** MAP1B loss-of-function variants mainly give the PVNH neurological phenotype, while missense variants may present with deafness alone - a separate autosomal dominant nonsyndromic sensorineural hearing loss, DFNA83, curated in this knowledge base as its own entry. So a MAP1B variant found on a panel is assigned to one disease or the other by what kind of variant it is, which is unusual enough to be the first thing to check. **The phenotype is wider than the malformation, and less predictable.** Reported features across the small literature include intellectual disability, ADHD, autism, focal epilepsy, short stature, microcephaly and corpus callosum dysgenesis - but one reported carrier of a nonsense allele has an IQ of 99 and normal motor and cognitive development, presenting instead with severe elimination disorders. PVNH remains the most consistent finding; almost nothing else is.

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1
Inheritance
4
Pathophys.
10
Phenotypes
1
Gaps
11
Pathograph
1
Genes
3
Medical Actions
3
Differentials
1
Models
12
References
1
Deep Research
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Inheritance

1
Autosomal dominant with incomplete penetrance HP:0000006
Heterozygous loss-of-function MAP1B alleles. Penetrance is incomplete: most reported alleles are inherited, and at least one came from a parent whose own PVNH had not been diagnosed. A de novo allele is also reported. The practical consequence is that an apparently sporadic case does not exclude an inherited allele, and that parental imaging rather than parental history is what settles it.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:29738522 SUPPORT Human Clinical
"In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH."
The single observation that establishes incomplete penetrance here, and the reason a negative family history is uninformative.
PMID:40869917 SUPPORT BACKGROUND Human Clinical
"Incomplete penetrance has been proposed to explain some apparently sporadic presentations"
Records that incomplete penetrance is the accepted reading in this literature. The sentence sits in the case report's introduction and cites earlier work, so it is graded BACKGROUND rather than as this report's own finding.
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Discussions and Knowledge Gaps

1
How much of the MAP1B phenotype beyond PVNH is attributable to MAP1B, given that the gene-disease relationship rests on a burden test and the reported carriers are few, heterogeneous and sometimes confounded?
KNOWLEDGE GAP map1b_burden_signal_versus_pedigree
Attached to
genetic#MAP1B phenotypes#Intellectual disability
PVNH itself is well supported: a genome-wide significant collapsing signal, an anteriorly predominant imaging phenotype, and independent replication in three further families. The rest of the phenotype is on weaker ground, and the entry should not obscure the difference. Three things argue for caution. The founding evidence is a case-control burden test over 202 individuals, driven by four carriers - a design that identifies a gene without characterizing a syndrome. The subsequent literature is case reports, and case reports of a newly named gene select for unusual presentations, so the reported feature list grows without its denominators. And the individual cases carry confounders that the authors themselves name: the child with microcephaly, short stature and dysmorphism also had significant prenatal alcohol exposure, and the authors state they believe the features cannot be explained by it alone - which is a judgement, not a measurement. The strongest single piece of counter-evidence is in the entry: a 12-year-old with a nonsense allele, bilateral PVNH and an IQ of 99. If a null allele can give the malformation with normal intelligence, then intellectual disability is not a consequence of MAP1B loss in the way the malformation is, and the case series' feature list is at least partly ascertainment. What would settle it is a denominator: systematic phenotyping of MAP1B loss-of-function carriers ascertained by genotype rather than by presentation, including the imaged-but-undiagnosed parents that the penetrance finding implies exist.
Proposed experiments
Genotype-first phenotyping of MAP1B loss-of-function carriers
map1b_genotype_first_phenotyping
Ascertain MAP1B loss-of-function carriers from population-scale sequencing biobanks rather than from clinical presentation, and phenotype them with MRI and standardized cognitive assessment. The design removes the ascertainment bias that case reports of a new gene carry, and it can measure penetrance for the malformation separately from penetrance for the cognitive phenotype.
Readouts
Proportion of genotype-ascertained carriers with PVNH on MRI
phenotypes#Periventricular nodular heterotopia
Direction: INCREASED
Interpretation: Penetrance of the malformation among unselected carriers, which the current literature cannot estimate.
Distribution of full-scale IQ among genotype-ascertained carriers
phenotypes#Intellectual disability
Direction: ALTERED
Interpretation: A distribution centred near population mean would support the normal-intelligence case being representative rather than exceptional, and would mean intellectual disability in the case series is ascertainment.
Would support
phenotypes#Periventricular nodular heterotopia
Would refute
phenotypes#Intellectual disability
Supporting outcome
  • PVNH is present in most genotype-ascertained carriers while IQ is distributed near the population mean, separating a highly penetrant malformation from a weakly penetrant cognitive phenotype.
Refuting outcome
  • Genotype-ascertained carriers show both the malformation and reduced IQ at similar rates, supporting the case-series feature list as representative.
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Pathophysiology

4
MAP1B Haploinsufficiency
Mechanism confidence: Established
A heterozygous loss-of-function allele - nonsense, frameshift or splice - removes one functional copy of MAP1B. All reported disease alleles in this literature are loss of function, and the burden signal was built specifically from loss-of-function variants, so the mechanism is a dose reduction rather than an abnormal protein.
MAP1B hgnc:6836 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MAP1B (hgnc:6836). hgnc:6836 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Impaired Microtubule Stabilization in Developing Neurons
Show evidence (2 references)
PMID:40874586 SUPPORT Human Clinical
"All individuals carried loss of function MAP1B variants."
Seven affected individuals across three unrelated families, all with loss-of-function alleles, which is what makes haploinsufficiency rather than a dominant-negative the natural reading.
PMID:40802165 SUPPORT REVIEW SYNTHESIS Human Clinical
"loss-of-function (LOF) variants in MAP1B mainly lead to PVNH-related neurological symptoms, while patients with missense variants may only present with deafness"
The allele-class dichotomy across the MAP1B literature, and the strongest argument that this node is specifically a loss-of-function node rather than a generic MAP1B node. A missense allele in the same gene produces a different disease, DFNA83, which is curated separately. Graded REVIEW_SYNTHESIS because the sentence is this paper's literature review rather than its own case.
Impaired Microtubule Stabilization in Developing Neurons
Mechanism confidence: Provisional
MAP1B is a microtubule-associated protein, and reducing it destabilizes the microtubule cytoskeleton on which a migrating neuron depends. Functional data from animal and cell models support a mechanism involving impaired microtubule stabilization, altered growth cone dynamics and dysregulated axon branching. This node is the mechanistic centre of the entry and it is also where the evidence is thinnest in a specific way: the supporting statement is a review's synthesis of model-system work, not a measurement in a MAP1B-haploinsufficient human neuron.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
microtubule cytoskeleton organization GO:0000226 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased microtubule cytoskeleton organization (GO:0000226). GO:0000226 is a biological process from the Gene Ontology. ↓ DECREASED
microtubule GO:0005874 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves microtubule (GO:0005874). GO:0005874 is a cellular component from the Gene Ontology. growth cone GO:0030426 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves growth cone (GO:0030426). GO:0030426 is a cellular component from the Gene Ontology.
Animal models
Map1b-deficient mouse Mouse recapitulates Cultured neurons from the deficient mouse show the axon-elongation and growth-cone abnormalities that this node describes, measured directly rather than reviewed.
Downstream
Failure of Radial Neuronal Migration
Disrupted Axon Guidance and Cortical Circuit Formation
Show evidence (1 reference)
PMID:40874586 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Functional data from animal and cell models support a mechanism involving impaired microtubule stabilization, altered growth cone dynamics, and dysregulated axon branching."
The proposed cellular mechanism. Graded REVIEW_SYNTHESIS because the paper is a case series that is here summarizing model-system work it did not perform, OTHER because the quoted sentence aggregates animal and cell evidence rather than reporting one study design, and INDIRECT because the claim it supports for this disease follows only by inference from those models.
Failure of Radial Neuronal Migration
Mechanism confidence: Established
Neurons destined for the cortical plate fail to complete radial migration and remain adjacent to the ventricular surface. The nodules seen on imaging are those stranded neurons. In MAP1B disease the failure is regionally biased rather than uniform: the heterotopia is anteriorly or frontally predominant.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
cerebral cortex radially oriented cell migration GO:0021799 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cerebral cortex radially oriented cell migration (GO:0021799). GO:0021799 is a biological process from the Gene Ontology. ↓ DECREASED neuron migration GO:0001764 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron migration (GO:0001764). GO:0001764 is a biological process from the Gene Ontology. ↓ DECREASED
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology. lateral ventricle UBERON:0002285 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lateral ventricle, annotated with telencephalic ventricle (UBERON:0002285). UBERON:0002285 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Map1b-deficient mouse Mouse partially recapitulates Supports MAP1B's requirement for neuronal migration at the whole-organism level.
Downstream
Periventricular nodular heterotopia
Focal-onset seizure
Show evidence (1 reference)
PMID:40874586 SUPPORT Human Clinical
"Neuroimaging revealed anteriorly predominant PVNH in four of five cases with neuroimaging available."
The imaging phenotype with its denominator stated: four of five imaged, not four of seven affected. The regional bias is the part that distinguishes it from generic PVNH.
Disrupted Axon Guidance and Cortical Circuit Formation
Mechanism confidence: Provisional
A second consequence of the same cytoskeletal defect. MAP1B is required for axon guidance and cortical circuit formation, not only for getting neurons to their destinations, which is the readiest explanation for why a proportion of carriers have cognitive and behavioural phenotypes out of proportion to the malformation - and why one has the malformation with normal intelligence.
axon guidance GO:0007411 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased axon guidance (GO:0007411). GO:0007411 is a biological process from the Gene Ontology. ↓ DECREASED neuron projection development GO:0031175 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron projection development (GO:0031175). GO:0031175 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Intellectual disability
Global developmental delay The earlier, less differentiated presentation of the same cortical circuit disruption that the intellectual disability node records later. Drawn as indirect with unknown intermediates because nothing here shows which circuits carry which developmental domain.
Attention deficit hyperactivity disorder
Show evidence (1 reference)
PMID:40874586 SUPPORT REVIEW SYNTHESIS Other
"MAP1B (microtubule-associated protein 1B) encodes a cytoskeletal regulator critical for neuronal migration, axon guidance, and cortical circuit formation."
The three functions of the protein, stated in the paper's opening background sentence rather than measured by it, hence REVIEW_SYNTHESIS.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Periventricular Nodular Heterotopia 9 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

10
Head and Neck 2
Microcephaly 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:31317654 SUPPORT Human Clinical
"We describe a child presenting with global developmental delays, ID, microcephaly, short stature, seizures, dysmorphic features, and prenatal alcohol exposure with a de novo nonsense MAP1B mutation"
Microcephaly in a de novo nonsense carrier. Note the same sentence records prenatal alcohol exposure in this child, which the authors themselves flag as a possible modifier - see the discussion in this entry.
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysmorphic features, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31317654 SUPPORT INDIRECT Human Clinical
"We describe a child presenting with global developmental delays, ID, microcephaly, short stature, seizures, dysmorphic features, and prenatal alcohol exposure with a de novo nonsense MAP1B mutation"
Names dysmorphic features in a de novo nonsense carrier, but the same sentence names prenatal alcohol exposure, whose recognised phenotype includes facial dysmorphism. Attributing the finding to MAP1B therefore takes an inference step this source does not settle, which is what INDIRECT records.
Nervous System 7
Periventricular nodular heterotopia HP:0032388 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periventricular nodular heterotopia (HP:0032388). HP:0032388 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29738522 SUPPORT Human Clinical
"The PVNH was frontally predominant and associated with perisylvian polymicrogyria."
The imaging description from the discovery cohort, including its regional bias and the accompanying second malformation.
PMID:40874586 SUPPORT Human Clinical
"Neuroimaging revealed anteriorly predominant PVNH in four of five cases with neuroimaging available."
Independent replication of the regional bias in three further families.
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:29738522 SUPPORT Human Clinical
"The PVNH was frontally predominant and associated with perisylvian polymicrogyria."
The second cortical malformation, in the discovery cohort. Note the snippet does not give a frequency and the cohort is four carriers, so this should be read as "reported with" rather than "a feature of".
Focal-onset seizure HP:0007359 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal-onset seizure (HP:0007359). HP:0007359 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40874586 SUPPORT Human Clinical
"Clinical features included global developmental delay, intellectual disability, behavioural dysregulation, and focal epilepsy."
The clinical features of the three-family series. Note the sentence lists features of the series as a whole and does not say how many of the seven had each, so this supports presence and not frequency.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40874586 SUPPORT Human Clinical
"Clinical features included global developmental delay, intellectual disability, behavioural dysregulation, and focal epilepsy."
Intellectual disability among the features of the three-family series.
PMID:40869917 REFUTE Human Clinical
"He had normal motor and cognitive development, with an IQ of 99"
A REFUTE item against intellectual disability being a constant feature. A 12-year-old boy with a nonsense MAP1B allele and bilateral PVNH has a measured IQ of 99. Recorded because a reader deciding what to tell a newly diagnosed family needs this case, not only the series.
Attention deficit hyperactivity disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40869917 SUPPORT Human Clinical
"he also presented with ADHD, short stature, microcephaly, and myopia"
Directly observed in the reported case, alongside the features below.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31317654 SUPPORT Human Clinical
"We describe a child presenting with global developmental delays, ID, microcephaly, short stature, seizures, dysmorphic features, and prenatal alcohol exposure with a de novo nonsense MAP1B mutation"
Names global developmental delay in a de novo nonsense carrier. Same sentence and same confounder as the Microcephaly node.
Abnormal corpus callosum morphology HP:0001273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysgenesis of the corpus callosum, annotated with Abnormal corpus callosum morphology (HP:0001273). HP:0001273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31317654 SUPPORT Human Clinical
"His brain MRI showed PVNH and dysgenesis of the corpus callosum."
The imaging finding in one case.
Growth 1
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40869917 SUPPORT Human Clinical
"the presence of short stature also appears to be part of the syndrome"
The authors' own inference from their case plus prior reports. Note the hedge "appears to be" is theirs; this is a proposal to extend the phenotype, not an established feature.
🧬

Genetic Associations

1
MAP1B
Gene: MAP1B hgnc:6836 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MAP1B (hgnc:6836). hgnc:6836 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:29738522 SUPPORT Human Clinical
"we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant."
The gene-disease assertion and, importantly, its design: a gene-level collapsing analysis of 202 cases against controls, not a segregating pedigree. Four carriers carry the signal.
PMID:29738522 SUPPORT Human Clinical
"These results implicate MAP1B in PVNH."
The authors' own summary of the strength of their claim. Note the verb is "implicate", which is weaker than establishing causation and is preserved here rather than upgraded.
💊

Medical Actions

3
Antiseizure medication
Action: antiseizure pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antiseizure pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: anticonvulsant agent NCIT:C264 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anticonvulsant agent (NCIT:C264). NCIT:C264 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
There is no disease-modifying therapy. Epilepsy is the main treatable morbidity and is managed on focal-epilepsy lines. Drug resistance is common enough that surgical options are part of the standard discussion rather than a last resort. No source cited here reports antiseizure drug outcomes in a MAP1B patient specifically, so this record carries no evidence block; it is the management this malformation receives.
Stereotactic MR-guided laser ablation of epileptogenic nodules
Action: MR-guided laser interstitial thermal therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is MR-guided laser interstitial thermal therapy, annotated with Laser Therapy (NCIT:C15466). NCIT:C15466 is a clinical intervention from the NCI Thesaurus. Ontology label: Laser Therapy NCIT:C15466
Platform: Surgery
For pharmacoresistant epilepsy arising from the nodules themselves, MR-guided laser interstitial thermal therapy allows a deep, focal ablation that open resection cannot reach safely. The clinical premise is that the nodule is the seizure onset zone, which has to be established per patient by intracranial recording rather than assumed from the imaging.
Show evidence (2 references)
PMID:24518890 SUPPORT Human Clinical
"Resective surgery for PVNH is limited by its deep location, and the overlying eloquent cortex or white matter."
Why an ablative rather than resective approach is used here. Note this is a two-patient technique report, not a comparative trial, and it is about PVNH generally rather than MAP1B PVNH.
PMID:24518890 SUPPORT Human Clinical
"Comprehensive presurgical evaluation, including intracranial EEG monitoring in two patients revealed the PVNH to be crucially involved in their PRE."
Records that the nodules were shown to be involved in seizure onset before they were ablated, which is the step that makes the target choice evidence-based rather than anatomical.
Developmental, educational and behavioural support
Action: developmental and rehabilitative supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is developmental and rehabilitative support, annotated with Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Behavioral / lifestyle
Multidisciplinary supportive management for developmental delay, intellectual disability and behavioural dysregulation. Recorded without an evidence block for the same reason as the antiseizure row: no cited source reports outcomes in MAP1B patients.
🔬

Diagnosis

2
Brain MRI
Imaging is the primary diagnostic modality. The pattern is multiple small bilateral nodules of grey matter maximal along the frontal horns of the lateral ventricles, frequently with additional, often subtle, brain malformations.
brain magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:41468712 SUPPORT Human Clinical
"The imaging phenotype consists of multiple, small, bilateral nodules of PVNH maximal along the frontal horns of the lateral ventricles."
The imaging pattern, from a 32-individual multicentre series of bilateral frontal PVNH in which MAP1B is one of the genetic diagnoses reached.
PMID:41468712 SUPPORT Human Clinical
"Frontal PVNH was associated with heterogeneous, often subtle, additional brain malformations in 72 % (23/32) individuals."
Records that the additional malformations are usual rather than exceptional, and gives the denominator, which this entry otherwise lacks for its imaging features.
Exome or genome sequencing, with chromosomal microarray
Sequencing is the route to a molecular diagnosis, and microarray is not redundant with it: in bilateral frontal PVNH the reported genetic causes include chromosome deletions as well as intragenic variants. The yields are low either way, which is the honest framing for a family being consented.
exome or genome sequencing, with chromosomal microarray NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:41468712 SUPPORT Human Clinical
"A genetic diagnosis was made by chromosome microarray alone in 13 % or by exome or genome sequencing in 38 % where access to testing was available, with no recurrent genetic cause being found."
The diagnostic yields for the imaging phenotype this entry sits inside, and the observation that no recurrent cause emerged - which is why MAP1B is one gene among several rather than the gene for this pattern.
📊

Prevalence

1
Worldwide
Unknown Not yet documented
No prevalence has been reported for PVNH9 itself - the published cases number in the single figures. The nearest quantified context is the imaging class it belongs to: bilateral frontal PVNH accounts for about a tenth of all PVNH, and MAP1B is one of several genetic causes within that tenth. That is a denominator for the pattern, not for the disease, so it is recorded here as context rather than as a rate.
Show evidence (1 reference)
PMID:41468712 SUPPORT INDIRECT Human Clinical
"this third pattern of bilateral frontal PVNH, accounting for ∼10 % of all cases of PVNH"
Quantifies the imaging class this disease falls in, as a share of PVNH. It says nothing about how much of that class is MAP1B, hence INDIRECT and hence a NOT_YET_DOCUMENTED class rather than a band.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Periventricular Nodular Heterotopia 9:

Hearing loss, autosomal dominant 83 (DFNA83), the MAP1B missense allelic disorder
Overlapping Features The same gene, a different allele class, a different disease. Heterozygous MAP1B MISSENSE variants cause autosomal dominant nonsyndromic sensorineural hearing loss without the cortical malformation, curated in this knowledge base as kb/disorders/Hearing_Loss_Autosomal_Dominant_83.yaml (MONDO:0030723). PVNH9 is the loss-of-function half. This is a differential in the genetic-report sense rather than the clinical one: the two present nothing alike, but a MAP1B variant found on a panel has to be assigned to one of them, and allele class is what decides it.
Show evidence (2 references)
PMID:33268592 SUPPORT Human Clinical
"Three novel heterozygous MAP1B mutations"
The founding report of the missense allelic phenotype, establishing that heterozygous MAP1B missense alleles segregate with a phenotype that is not PVNH9.
PMID:40802165 SUPPORT REVIEW SYNTHESIS Human Clinical
"loss-of-function (LOF) variants in MAP1B mainly lead to PVNH-related neurological symptoms, while patients with missense variants may only present with deafness"
States the split that makes these two entries rather than one. Note the hedges: "mainly" and "may only", so this is a strong tendency and not a rule.
FLNA-associated classic bilateral frontocentral PVNH (PVNH1)
Overlapping Features The commonest and best-known genetic PVNH, and the main reason this entry exists separately. FLNA disease is an actin-crosslinker lesion at the neuroependyma, not a microtubule lesion, which is why this entry conforms to the microtubule migration module and FLNA disease does not. The distinguishing pattern is radiological: classical heterotopia is bilateral frontal and body, where MAP1B PVNH is anteriorly predominant and reported with focal epilepsy. The sporadic series below describes that CLASSICAL group as a radiological class of 41 patients, and found FLNA variants in only 8 of the 100 patients it sequenced, so its female predominance, arachnoid cysts, cardiac abnormalities and low seizure burden are properties of an imaging class rather than of the FLNA genotype. This entry deliberately does not carry "mostly seizure-free" as an FLNA property: in the familial FLNA literature epilepsy is common, so doing so would steer a clinician wrong. An earlier draft of this description did exactly that. Note also that FLNA has a GeneReviews chapter (FLNA Deficiency, NBK1213) where MAP1B has none, so the two are not equally served by review literature. That chapter is matched by `just check-genereviews` as CITED_UNTAGGED: it is named here because it belongs to a differential, not to this disease, and MAP1B still has no chapter.
Show evidence (3 references)
PMID:28411558 SUPPORT Human Clinical
"Based on imaging data, patients were subdivided into three groups: (a) classical (bilateral frontal and body, n=41 patients), (b) bilateral asymmetrical or posterior (n=16) and (c) unilateral heterotopia (n=43)."
The radiological definition of the classical pattern, which is what distinguishes it from the anteriorly predominant MAP1B pattern. Note the grouping is by imaging, not by genotype.
PMID:28411558 SUPPORT Human Clinical
"FLNA mutations were identified in 8 patients."
The yield in that 100-patient sporadic cohort. It is the reason the phenotype statistics reported for the classical imaging group cannot be read as statistics about FLNA disease.
PMID:28411558 SUPPORT INDIRECT Human Clinical
"Most patients with classical heterotopia were females (P=0.033) and were likely to have arachnoid cysts (P=0.025) and cardiac abnormalities (P=0.041), but were mostly seizure-free."
Retained, but as a statement about the classical IMAGING group in this sporadic series - the two items above give the group's definition and its FLNA yield. Any reading of it as a property of FLNA disease is an inference the source does not license, which is what INDIRECT records here.
Other bilateral PVNH patterns and other malformations of cortical development
Overlapping Features Bilateral frontal PVNH is one of three proposed PVNH groups and accounts for about a tenth of cases; the others are the FLNA-associated classic frontocentral pattern and a posterior or infrasylvian pattern. Beyond PVNH, lissencephaly and subcortical band heterotopia are the neighbouring malformations of cortical development.
Show evidence (1 reference)
PMID:41468712 SUPPORT Human Clinical
"Our PVNH cohort data suggest that PVNH could be classified in three main groups: FLNA-associated "classic" bilateral frontocentral PVNH, posterior/infrasylvian PVNH and this third pattern of bilateral frontal PVNH, accounting for ∼10 % of all cases of PVNH."
The three-group classification and the share of PVNH that the pattern MAP1B causes accounts for. Note the authors' own hedge, "suggest ... could be classified".
🐁

Animal Models

1
Map1b-deficient mouse
Homozygous Map1b-deficient mice die on the first postnatal day with severely abnormal nervous system development, and the analyses implicate MAP1B in neuronal migration. Cultured dorsal root ganglion neurons from the same deficiency show reduced axon elongation and increased growth cone area.
Species
Mouse
Genotype
Map1b homozygous deficient (low-level alternative isoform expression)
Publication
PMID:11085878
Pathograph links
Failure of Radial Neuronal Migration partially recapitulates fidelity: moderate observes: organism Supports MAP1B's requirement for neuronal migration at the whole-organism level.
Limitations: The mouse is a homozygous deficiency and dies perinatally; human PVNH9 is heterozygous and compatible with adult life and, in one reported case, with normal intelligence. So the model establishes that MAP1B is required for migration, but its dose and its severity are both wrong for the human disease, and it cannot report the focal periventricular nodules that define the human phenotype.
Divergences from the human mechanism
population mismatch qualifying
The genotype is homozygous deficiency; human PVNH9 is heterozygous loss of function. Half-dose and no-dose are different states for a gene whose human disease is explicitly haploinsufficiency.
proxy quantity qualifying
The measured quantity is gross abnormal nervous system development and perinatal lethality. The quantity the node needs is failure of radial migration leaving periventricular nodules, which this report does not measure directly.
Readouts
Perinatal survival and nervous system development
Direction: ALTERED
Interpretation: Lethality with abnormal brain structure, interpreted by the authors as implicating MAP1B in neuronal migration.
Show evidence (1 reference)
PMID:11085878 SUPPORT Model Organism
"Analyses of these mice indicate the presence of several neural defects and suggest the participation of MAP1B in neuronal migration"
The authors' interpretation, with their own hedge "suggest" preserved.
Impaired Microtubule Stabilization in Developing Neurons recapitulates fidelity: moderate observes: cellular Cultured neurons from the deficient mouse show the axon-elongation and growth-cone abnormalities that this node describes, measured directly rather than reviewed.
Limitations: Dorsal root ganglion neurons are peripheral sensory neurons, not migrating cortical neurons, so the cell type is not the one the disease acts in.
Divergences from the human mechanism
boundary omission qualifying
Cortical neurons and the radial glial scaffold they migrate along are not in this preparation. Only the cell-intrinsic cytoskeletal behaviour is observed.
Readouts
Axon elongation and growth cone area in cultured DRG neurons
Direction: ALTERED
Interpretation: Reduced elongation with enlarged growth cones, the cytoskeletal signature this node names.
Show evidence (1 reference)
PMID:12088839 SUPPORT Model Organism
"Cultured DRG neurons from MAP1B deficient mice show a reduction in axon elongation and an increase in growth cone area"
The direct measurement behind the growth-cone claim, which elsewhere in this entry is carried only by a review's synthesis.
Show evidence (1 reference)
PMID:11085878 SUPPORT Model Organism
"Homozygous mice die on the first day after birth, probably due to a severe abnormal development of the nervous system"
Establishes the model's severity, which is the main reason it is recorded as PARTIALLY_RECAPITULATES rather than as a faithful model of a heterozygous human disease.
{ }

Source YAML

click to show 
name: Periventricular Nodular Heterotopia 9
category: Mendelian
creation_date: "2026-09-22T13:35:00Z"
synonyms:
- PVNH9
- MAP1B-related syndrome
- MAP1B-related neurodevelopmental disorder
description: >-
  PVNH9 is a malformation of cortical development caused by heterozygous
  loss-of-function variants in MAP1B, which encodes microtubule-associated protein
  1B, a cytoskeletal regulator required for neuronal migration, axon guidance and
  cortical circuit formation. Neurons that should have migrated out to the cortical
  plate remain as nodules along the walls of the lateral ventricles.

  **The gene was found by a statistical argument, not by a family.** An exome study
  of 202 individuals with sporadic PVNH found no novel gene in a trio-based de novo
  analysis, then found a genome-wide significant signal in a gene-level collapsing
  analysis of cases against controls, driven by four ultra-rare loss-of-function
  heterozygous variants in MAP1B. Only one of the four was de novo. That matters for
  how the entry reads: the gene-disease claim rests on a burden test, and every
  downstream statement inherits whatever that design supports.

  **Its most useful finding is about penetrance, not about MAP1B.** In at least one
  instance the variant was inherited from a parent with previously undiagnosed PVNH.
  The authors drew the general conclusion that detrimental mutations arising in
  immediately preceding generations with incomplete penetrance may be responsible for
  some apparently sporadic disease. So a "sporadic" PVNH case is not evidence against
  an inherited MAP1B allele, and an unaffected-looking parent has not necessarily been
  imaged.

  **The imaging phenotype has a consistent shape.** PVNH in MAP1B disease is
  anteriorly or frontally predominant rather than diffuse, and it can be accompanied
  by perisylvian polymicrogyria - two malformations of cortical development in one
  brain, which is what makes the lesion a general defect of cortical neuronal
  positioning rather than a specific failure of periventricular detachment.

  **Allele class, not just gene, decides which disease you get.** MAP1B
  loss-of-function variants mainly give the PVNH neurological phenotype, while missense
  variants may present with deafness alone - a separate autosomal dominant nonsyndromic
  sensorineural hearing loss, DFNA83, curated in this knowledge base as its own entry.
  So a MAP1B variant found on a panel is assigned to one disease or the other by what
  kind of variant it is, which is unusual enough to be the first thing to check.

  **The phenotype is wider than the malformation, and less predictable.** Reported
  features across the small literature include intellectual disability, ADHD, autism,
  focal epilepsy, short stature, microcephaly and corpus callosum dysgenesis - but one
  reported carrier of a nonsense allele has an IQ of 99 and normal motor and cognitive
  development, presenting instead with severe elimination disorders. PVNH remains the
  most consistent finding; almost nothing else is.
disease_term:
  preferred_term: periventricular nodular heterotopia 9
  term:
    id: MONDO:0030061
    label: periventricular nodular heterotopia 9
parents:
- Periventricular Nodular Heterotopia
references:
- reference: PMID:29738522
  title: "De novo and inherited private variants in MAP1B in periventricular nodular heterotopia."
- reference: PMID:40874586
  title: "MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families."
- reference: PMID:40869917
  title: "Severe Elimination Disorders and Normal Intelligence in a Case of MAP1B Related Syndrome: A Case Report."
- reference: PMID:31317654
  title: "MAP1B related syndrome: Case presentation and review of literature."
- reference: PMID:40802165
  title: "Novel MAP1B loss-of-function variant associated with periventricular nodular heterotopia 9 and literature review on genotype-phenotype associations of MAP1B."
- reference: PMID:11085878
  title: "Perinatal lethality of microtubule-associated protein 1B-deficient mice expressing alternative isoforms of the protein at low levels."
- reference: PMID:12088839
  title: "Microtubule-associated protein 1B is involved in the initial stages of axonogenesis in peripheral nervous system cultured neurons."
- reference: PMID:33268592
  title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
- reference: PMID:41468712
  title: "Bilateral frontal periventricular nodular heterotopia: a distinctive cortical malformation."
- reference: PMID:28411558
  title: "Sporadic periventricular nodular heterotopia: Classification, phenotype and correlation with Filamin A mutations."
- reference: PMID:24518890
  title: "Stereotactic laser ablation of epileptogenic periventricular nodular heterotopia."
- reference: PMID:30819503
  title: "Malformations of cortical development: New surgical advances."
inheritance:
- name: Autosomal dominant with incomplete penetrance
  description: >-
    Heterozygous loss-of-function MAP1B alleles. Penetrance is incomplete: most
    reported alleles are inherited, and at least one came from a parent whose own PVNH
    had not been diagnosed. A de novo allele is also reported. The practical
    consequence is that an apparently sporadic case does not exclude an inherited
    allele, and that parental imaging rather than parental history is what settles it.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:29738522
    reference_title: "De novo and inherited private variants in MAP1B in periventricular nodular heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH."
    explanation: >-
      The single observation that establishes incomplete penetrance here, and the
      reason a negative family history is uninformative.
  - reference: PMID:40869917
    reference_title: "Severe Elimination Disorders and Normal Intelligence in a Case of MAP1B Related Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Incomplete penetrance has been proposed to explain some apparently sporadic presentations"
    explanation: >-
      Records that incomplete penetrance is the accepted reading in this literature.
      The sentence sits in the case report's introduction and cites earlier work, so it
      is graded BACKGROUND rather than as this report's own finding.
genetic:
- name: MAP1B
  notes: >-
    MAP1B encodes microtubule-associated protein 1B, a cytoskeletal regulator of
    neuronal migration, axon guidance and cortical circuit formation. Its expression
    is elevated in regions that retain high brain plasticity and is regulated by the
    fragile X mental retardation protein. Most reported loss-of-function variants lie
    in exon 5.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MAP1B
    term:
      id: hgnc:6836
      label: MAP1B
  evidence:
  - reference: PMID:29738522
    reference_title: "De novo and inherited private variants in MAP1B in periventricular nodular heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant."
    explanation: >-
      The gene-disease assertion and, importantly, its design: a gene-level collapsing
      analysis of 202 cases against controls, not a segregating pedigree. Four carriers
      carry the signal.
  - reference: PMID:29738522
    reference_title: "De novo and inherited private variants in MAP1B in periventricular nodular heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results implicate MAP1B in PVNH."
    explanation: >-
      The authors' own summary of the strength of their claim. Note the verb is
      "implicate", which is weaker than establishing causation and is preserved here
      rather than upgraded.
pathophysiology:
- name: MAP1B Haploinsufficiency
  description: >-
    A heterozygous loss-of-function allele - nonsense, frameshift or splice - removes
    one functional copy of MAP1B. All reported disease alleles in this literature are
    loss of function, and the burden signal was built specifically from
    loss-of-function variants, so the mechanism is a dose reduction rather than an
    abnormal protein.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: MAP1B
    term:
      id: hgnc:6836
      label: MAP1B
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Impaired Microtubule Stabilization in Developing Neurons
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40874586
    reference_title: "MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals carried loss of function MAP1B variants."
    explanation: >-
      Seven affected individuals across three unrelated families, all with
      loss-of-function alleles, which is what makes haploinsufficiency rather than a
      dominant-negative the natural reading.
  - reference: PMID:40802165
    reference_title: "Novel MAP1B loss-of-function variant associated with periventricular nodular heterotopia 9 and literature review on genotype-phenotype associations of MAP1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "loss-of-function (LOF) variants in MAP1B mainly lead to PVNH-related neurological symptoms, while patients with missense variants may only present with deafness"
    explanation: >-
      The allele-class dichotomy across the MAP1B literature, and the strongest
      argument that this node is specifically a loss-of-function node rather than a
      generic MAP1B node. A missense allele in the same gene produces a different
      disease, DFNA83, which is curated separately. Graded REVIEW_SYNTHESIS because
      the sentence is this paper's literature review rather than its own case.
- name: Impaired Microtubule Stabilization in Developing Neurons
  conforms_to: "microtubule_dependent_neuronal_migration_failure#Microtubule Apparatus Perturbation"
  description: >-
    MAP1B is a microtubule-associated protein, and reducing it destabilizes the
    microtubule cytoskeleton on which a migrating neuron depends. Functional data from
    animal and cell models support a mechanism involving impaired microtubule
    stabilization, altered growth cone dynamics and dysregulated axon branching.

    This node is the mechanistic centre of the entry and it is also where the evidence
    is thinnest in a specific way: the supporting statement is a review's synthesis of
    model-system work, not a measurement in a MAP1B-haploinsufficient human neuron.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  cellular_components:
  - preferred_term: microtubule
    term:
      id: GO:0005874
      label: microtubule
  - preferred_term: growth cone
    term:
      id: GO:0030426
      label: growth cone
  biological_processes:
  - preferred_term: microtubule cytoskeleton organization
    modifier: DECREASED
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
  downstream:
  - target: Failure of Radial Neuronal Migration
    causal_link_type: DIRECT
  - target: Disrupted Axon Guidance and Cortical Circuit Formation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40874586
    reference_title: "MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "Functional data from animal and cell models support a mechanism involving impaired microtubule stabilization, altered growth cone dynamics, and dysregulated axon branching."
    explanation: >-
      The proposed cellular mechanism. Graded REVIEW_SYNTHESIS because the paper is a
      case series that is here summarizing model-system work it did not perform, OTHER
      because the quoted sentence aggregates animal and cell evidence rather than
      reporting one study design, and INDIRECT because the claim it supports for this
      disease follows only by inference from those models.
- name: Failure of Radial Neuronal Migration
  conforms_to: "microtubule_dependent_neuronal_migration_failure#Microtubule-Based Neuronal Motility Failure"
  description: >-
    Neurons destined for the cortical plate fail to complete radial migration and
    remain adjacent to the ventricular surface. The nodules seen on imaging are those
    stranded neurons. In MAP1B disease the failure is regionally biased rather than
    uniform: the heterotopia is anteriorly or frontally predominant.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: cerebral cortex radially oriented cell migration
    modifier: DECREASED
    term:
      id: GO:0021799
      label: cerebral cortex radially oriented cell migration
  - preferred_term: neuron migration
    modifier: DECREASED
    term:
      id: GO:0001764
      label: neuron migration
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: lateral ventricle
    term:
      id: UBERON:0002285
      label: telencephalic ventricle
  downstream:
  - target: Periventricular nodular heterotopia
    causal_link_type: DIRECT
  - target: Focal-onset seizure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:40874586
    reference_title: "MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging revealed anteriorly predominant PVNH in four of five cases with neuroimaging available."
    explanation: >-
      The imaging phenotype with its denominator stated: four of five imaged, not four
      of seven affected. The regional bias is the part that distinguishes it from
      generic PVNH.
- name: Disrupted Axon Guidance and Cortical Circuit Formation
  conforms_to: "microtubule_dependent_neuronal_migration_failure#Axon Guidance and Projection Wiring Defects"
  description: >-
    A second consequence of the same cytoskeletal defect. MAP1B is required for axon
    guidance and cortical circuit formation, not only for getting neurons to their
    destinations, which is the readiest explanation for why a proportion of carriers
    have cognitive and behavioural phenotypes out of proportion to the malformation -
    and why one has the malformation with normal intelligence.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: axon guidance
    modifier: DECREASED
    term:
      id: GO:0007411
      label: axon guidance
  - preferred_term: neuron projection development
    modifier: DECREASED
    term:
      id: GO:0031175
      label: neuron projection development
  downstream:
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The earlier, less differentiated presentation of the same cortical circuit
      disruption that the intellectual disability node records later. Drawn as
      indirect with unknown intermediates because nothing here shows which
      circuits carry which developmental domain.
  - target: Attention deficit hyperactivity disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:40874586
    reference_title: "MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "MAP1B (microtubule-associated protein 1B) encodes a cytoskeletal regulator critical for neuronal migration, axon guidance, and cortical circuit formation."
    explanation: >-
      The three functions of the protein, stated in the paper's opening background
      sentence rather than measured by it, hence REVIEW_SYNTHESIS.
phenotypes:
- category: Neurologic
  name: Periventricular nodular heterotopia
  description: >-
    Bilateral subependymal nodules of grey matter along the lateral ventricles,
    anteriorly or frontally predominant. This is the most consistent finding in MAP1B
    disease and the one the gene was discovered through.
  phenotype_term:
    preferred_term: Periventricular nodular heterotopia
    term:
      id: HP:0032388
      label: Periventricular nodular heterotopia
  evidence:
  - reference: PMID:29738522
    reference_title: "De novo and inherited private variants in MAP1B in periventricular nodular heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PVNH was frontally predominant and associated with perisylvian polymicrogyria."
    explanation: >-
      The imaging description from the discovery cohort, including its regional bias
      and the accompanying second malformation.
  - reference: PMID:40874586
    reference_title: "MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging revealed anteriorly predominant PVNH in four of five cases with neuroimaging available."
    explanation: >-
      Independent replication of the regional bias in three further families.
- category: Neurologic
  name: Polymicrogyria
  description: >-
    Perisylvian polymicrogyria accompanying the heterotopia in the discovery cohort.
    Two distinct malformations of cortical development in one brain.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:29738522
    reference_title: "De novo and inherited private variants in MAP1B in periventricular nodular heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PVNH was frontally predominant and associated with perisylvian polymicrogyria."
    explanation: >-
      The second cortical malformation, in the discovery cohort. Note the snippet does
      not give a frequency and the cohort is four carriers, so this should be read as
      "reported with" rather than "a feature of".
- category: Neurologic
  name: Focal-onset seizure
  description: >-
    Focal epilepsy, reported in all seven affected individuals of the three-family
    series. PVNH is a well-recognized epileptogenic malformation.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:40874586
    reference_title: "MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features included global developmental delay, intellectual disability, behavioural dysregulation, and focal epilepsy."
    explanation: >-
      The clinical features of the three-family series. Note the sentence lists
      features of the series as a whole and does not say how many of the seven had
      each, so this supports presence and not frequency.
- category: Neurologic
  name: Intellectual disability
  description: >-
    Intellectual disability with global developmental delay, reported across the
    series - but NOT universal. One reported nonsense-allele carrier has an IQ of 99
    with normal motor and cognitive development, which is recorded here as
    counter-evidence rather than omitted.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:40874586
    reference_title: "MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features included global developmental delay, intellectual disability, behavioural dysregulation, and focal epilepsy."
    explanation: >-
      Intellectual disability among the features of the three-family series.
  - reference: PMID:40869917
    reference_title: "Severe Elimination Disorders and Normal Intelligence in a Case of MAP1B Related Syndrome: A Case Report."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "He had normal motor and cognitive development, with an IQ of 99"
    explanation: >-
      A REFUTE item against intellectual disability being a constant feature. A
      12-year-old boy with a nonsense MAP1B allele and bilateral PVNH has a measured IQ
      of 99. Recorded because a reader deciding what to tell a newly diagnosed family
      needs this case, not only the series.
- category: Neurologic
  name: Attention deficit hyperactivity disorder
  description: >-
    ADHD is reported among the neurological impairments associated with pathogenic
    MAP1B variants, and was present in the normal-intelligence case.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:40869917
    reference_title: "Severe Elimination Disorders and Normal Intelligence in a Case of MAP1B Related Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he also presented with ADHD, short stature, microcephaly, and myopia"
    explanation: >-
      Directly observed in the reported case, alongside the features below.
- category: Growth
  name: Short stature
  description: >-
    Short stature is reported in MAP1B carriers and the case report argues from its
    own case that it should be considered part of the syndrome.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:40869917
    reference_title: "Severe Elimination Disorders and Normal Intelligence in a Case of MAP1B Related Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the presence of short stature also appears to be part of the syndrome"
    explanation: >-
      The authors' own inference from their case plus prior reports. Note the hedge
      "appears to be" is theirs; this is a proposal to extend the phenotype, not an
      established feature.
- category: Neurologic
  name: Microcephaly
  description: >-
    Reported in MAP1B carriers, including the normal-intelligence case and an earlier
    case with a de novo nonsense allele.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:31317654
    reference_title: "MAP1B related syndrome: Case presentation and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a child presenting with global developmental delays, ID, microcephaly, short stature, seizures, dysmorphic features, and prenatal alcohol exposure with a de novo nonsense MAP1B mutation"
    explanation: >-
      Microcephaly in a de novo nonsense carrier. Note the same sentence records
      prenatal alcohol exposure in this child, which the authors themselves flag as a
      possible modifier - see the discussion in this entry.
- category: Neurologic
  name: Global developmental delay
  description: >-
    Developmental delay across domains, reported in the de novo nonsense case alongside
    intellectual disability. The same sentence records prenatal alcohol exposure in this
    child, so the case is not a clean genotype-phenotype observation; the discussion in
    this entry carries that confounder.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31317654
    reference_title: "MAP1B related syndrome: Case presentation and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a child presenting with global developmental delays, ID, microcephaly, short stature, seizures, dysmorphic features, and prenatal alcohol exposure with a de novo nonsense MAP1B mutation"
    explanation: >-
      Names global developmental delay in a de novo nonsense carrier. Same sentence and
      same confounder as the Microcephaly node.
- category: Craniofacial
  name: Abnormal facial shape
  description: >-
    Dysmorphic features, reported without a described pattern, which is why this is
    bound at the general HP:0001999 rather than to any specific facial feature. Same
    single case and same prenatal alcohol confounder as the two nodes above, and facial
    dysmorphism is the feature of that list most attributable to the exposure.
  phenotype_term:
    preferred_term: Dysmorphic features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:31317654
    reference_title: "MAP1B related syndrome: Case presentation and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "We describe a child presenting with global developmental delays, ID, microcephaly, short stature, seizures, dysmorphic features, and prenatal alcohol exposure with a de novo nonsense MAP1B mutation"
    explanation: >-
      Names dysmorphic features in a de novo nonsense carrier, but the same sentence
      names prenatal alcohol exposure, whose recognised phenotype includes facial
      dysmorphism. Attributing the finding to MAP1B therefore takes an inference step
      this source does not settle, which is what INDIRECT records.
- category: Neurologic
  name: Abnormal corpus callosum morphology
  description: >-
    Corpus callosum dysgenesis has been reported on MRI alongside the heterotopia,
    which is consistent with MAP1B's role in axon guidance rather than only in
    migration.

    Bound to HP:0001273 Abnormal corpus callosum morphology rather than HP:0001274
    Agenesis of corpus callosum. The source says DYSgenesis - a malformation - and
    agenesis would assert an absence the source does not report.
  phenotype_term:
    preferred_term: Dysgenesis of the corpus callosum
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:31317654
    reference_title: "MAP1B related syndrome: Case presentation and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His brain MRI showed PVNH and dysgenesis of the corpus callosum."
    explanation: >-
      The imaging finding in one case.
animal_models:
- name: Map1b-deficient mouse
  species: Mouse
  genotype: Map1b homozygous deficient (low-level alternative isoform expression)
  publication: PMID:11085878
  description: >-
    Homozygous Map1b-deficient mice die on the first postnatal day with severely
    abnormal nervous system development, and the analyses implicate MAP1B in neuronal
    migration. Cultured dorsal root ganglion neurons from the same deficiency show
    reduced axon elongation and increased growth cone area.
  modeled_mechanisms:
  - target: Failure of Radial Neuronal Migration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Supports MAP1B's requirement for neuronal migration at the whole-organism level.
    limitations: >-
      The mouse is a homozygous deficiency and dies perinatally; human PVNH9 is
      heterozygous and compatible with adult life and, in one reported case, with normal
      intelligence. So the model establishes that MAP1B is required for migration, but
      its dose and its severity are both wrong for the human disease, and it cannot
      report the focal periventricular nodules that define the human phenotype.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        The genotype is homozygous deficiency; human PVNH9 is heterozygous
        loss of function. Half-dose and no-dose are different states for a gene whose
        human disease is explicitly haploinsufficiency.
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The measured quantity is gross abnormal nervous system development and perinatal
        lethality. The quantity the node needs is failure of radial migration leaving
        periventricular nodules, which this report does not measure directly.
    readouts:
    - name: Perinatal survival and nervous system development
      target: Failure of Radial Neuronal Migration
      direction: ALTERED
      interpretation: >-
        Lethality with abnormal brain structure, interpreted by the authors as
        implicating MAP1B in neuronal migration.
      evidence:
      - reference: PMID:11085878
        reference_title: "Perinatal lethality of microtubule-associated protein 1B-deficient mice expressing alternative isoforms of the protein at low levels."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Analyses of these mice indicate the presence of several neural defects and suggest the participation of MAP1B in neuronal migration"
        explanation: >-
          The authors' interpretation, with their own hedge "suggest" preserved.
  - target: Impaired Microtubule Stabilization in Developing Neurons
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Cultured neurons from the deficient mouse show the axon-elongation and growth-cone
      abnormalities that this node describes, measured directly rather than reviewed.
    limitations: >-
      Dorsal root ganglion neurons are peripheral sensory neurons, not migrating cortical
      neurons, so the cell type is not the one the disease acts in.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Cortical neurons and the radial glial scaffold they migrate along are not in this
        preparation. Only the cell-intrinsic cytoskeletal behaviour is observed.
    readouts:
    - name: Axon elongation and growth cone area in cultured DRG neurons
      target: Impaired Microtubule Stabilization in Developing Neurons
      direction: ALTERED
      interpretation: >-
        Reduced elongation with enlarged growth cones, the cytoskeletal signature this
        node names.
      evidence:
      - reference: PMID:12088839
        reference_title: "Microtubule-associated protein 1B is involved in the initial stages of axonogenesis in peripheral nervous system cultured neurons."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Cultured DRG neurons from MAP1B deficient mice show a reduction in axon elongation and an increase in growth cone area"
        explanation: >-
          The direct measurement behind the growth-cone claim, which elsewhere in this
          entry is carried only by a review's synthesis.
  evidence:
  - reference: PMID:11085878
    reference_title: "Perinatal lethality of microtubule-associated protein 1B-deficient mice expressing alternative isoforms of the protein at low levels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous mice die on the first day after birth, probably due to a severe abnormal development of the nervous system"
    explanation: >-
      Establishes the model's severity, which is the main reason it is recorded as
      PARTIALLY_RECAPITULATES rather than as a faithful model of a heterozygous human
      disease.
diagnosis:
- name: Brain MRI
  description: >-
    Imaging is the primary diagnostic modality. The pattern is multiple small
    bilateral nodules of grey matter maximal along the frontal horns of the lateral
    ventricles, frequently with additional, often subtle, brain malformations.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:41468712
    reference_title: "Bilateral frontal periventricular nodular heterotopia: a distinctive cortical malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The imaging phenotype consists of multiple, small, bilateral nodules of PVNH maximal along the frontal horns of the lateral ventricles."
    explanation: >-
      The imaging pattern, from a 32-individual multicentre series of bilateral frontal
      PVNH in which MAP1B is one of the genetic diagnoses reached.
  - reference: PMID:41468712
    reference_title: "Bilateral frontal periventricular nodular heterotopia: a distinctive cortical malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Frontal PVNH was associated with heterogeneous, often subtle, additional brain malformations in 72 % (23/32) individuals."
    explanation: >-
      Records that the additional malformations are usual rather than exceptional, and
      gives the denominator, which this entry otherwise lacks for its imaging features.
- name: Exome or genome sequencing, with chromosomal microarray
  description: >-
    Sequencing is the route to a molecular diagnosis, and microarray is not redundant
    with it: in bilateral frontal PVNH the reported genetic causes include chromosome
    deletions as well as intragenic variants. The yields are low either way, which is
    the honest framing for a family being consented.
  diagnosis_term:
    preferred_term: exome or genome sequencing, with chromosomal microarray
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:41468712
    reference_title: "Bilateral frontal periventricular nodular heterotopia: a distinctive cortical malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A genetic diagnosis was made by chromosome microarray alone in 13 % or by exome or genome sequencing in 38 % where access to testing was available, with no recurrent genetic cause being found."
    explanation: >-
      The diagnostic yields for the imaging phenotype this entry sits inside, and the
      observation that no recurrent cause emerged - which is why MAP1B is one gene among
      several rather than the gene for this pattern.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No prevalence has been reported for PVNH9 itself - the published cases number in
    the single figures. The nearest quantified context is the imaging class it belongs
    to: bilateral frontal PVNH accounts for about a tenth of all PVNH, and MAP1B is one
    of several genetic causes within that tenth. That is a denominator for the pattern,
    not for the disease, so it is recorded here as context rather than as a rate.
  evidence:
  - reference: PMID:41468712
    reference_title: "Bilateral frontal periventricular nodular heterotopia: a distinctive cortical malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "this third pattern of bilateral frontal PVNH, accounting for ∼10 % of all cases of PVNH"
    explanation: >-
      Quantifies the imaging class this disease falls in, as a share of PVNH. It says
      nothing about how much of that class is MAP1B, hence INDIRECT and hence a
      NOT_YET_DOCUMENTED class rather than a band.
differential_diagnoses:
- name: Hearing loss, autosomal dominant 83 (DFNA83), the MAP1B missense allelic disorder
  description: >-
    The same gene, a different allele class, a different disease. Heterozygous MAP1B
    MISSENSE variants cause autosomal dominant nonsyndromic sensorineural hearing loss
    without the cortical malformation, curated in this knowledge base as
    kb/disorders/Hearing_Loss_Autosomal_Dominant_83.yaml (MONDO:0030723). PVNH9 is the
    loss-of-function half. This is a differential in the genetic-report sense rather
    than the clinical one: the two present nothing alike, but a MAP1B variant found on
    a panel has to be assigned to one of them, and allele class is what decides it.
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three novel heterozygous MAP1B mutations"
    explanation: >-
      The founding report of the missense allelic phenotype, establishing that
      heterozygous MAP1B missense alleles segregate with a phenotype that is not PVNH9.
  - reference: PMID:40802165
    reference_title: "Novel MAP1B loss-of-function variant associated with periventricular nodular heterotopia 9 and literature review on genotype-phenotype associations of MAP1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "loss-of-function (LOF) variants in MAP1B mainly lead to PVNH-related neurological symptoms, while patients with missense variants may only present with deafness"
    explanation: >-
      States the split that makes these two entries rather than one. Note the hedges:
      "mainly" and "may only", so this is a strong tendency and not a rule.
- name: FLNA-associated classic bilateral frontocentral PVNH (PVNH1)
  description: >-
    The commonest and best-known genetic PVNH, and the main reason this entry exists
    separately. FLNA disease is an actin-crosslinker lesion at the neuroependyma, not a
    microtubule lesion, which is why this entry conforms to the microtubule migration
    module and FLNA disease does not. The distinguishing pattern is radiological:
    classical heterotopia is bilateral frontal and body, where MAP1B PVNH is anteriorly
    predominant and reported with focal epilepsy.

    The sporadic series below describes that CLASSICAL group as a radiological class of
    41 patients, and found FLNA variants in only 8 of the 100 patients it sequenced, so
    its female predominance, arachnoid cysts, cardiac abnormalities and low seizure
    burden are properties of an imaging class rather than of the FLNA genotype. This
    entry deliberately does not carry "mostly seizure-free" as an FLNA property: in the
    familial FLNA literature epilepsy is common, so doing so would steer a clinician
    wrong. An earlier draft of this description did exactly that.

    Note also that FLNA has a GeneReviews chapter (FLNA Deficiency, NBK1213) where
    MAP1B has none, so the two are not equally served by review literature. That chapter
    is matched by `just check-genereviews` as CITED_UNTAGGED: it is named here because
    it belongs to a differential, not to this disease, and MAP1B still has no chapter.
  evidence:
  - reference: PMID:28411558
    reference_title: "Sporadic periventricular nodular heterotopia: Classification, phenotype and correlation with Filamin A mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on imaging data, patients were subdivided into three groups: (a) classical (bilateral frontal and body, n=41 patients), (b) bilateral asymmetrical or posterior (n=16) and (c) unilateral heterotopia (n=43)."
    explanation: >-
      The radiological definition of the classical pattern, which is what distinguishes
      it from the anteriorly predominant MAP1B pattern. Note the grouping is by imaging,
      not by genotype.
  - reference: PMID:28411558
    reference_title: "Sporadic periventricular nodular heterotopia: Classification, phenotype and correlation with Filamin A mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FLNA mutations were identified in 8 patients."
    explanation: >-
      The yield in that 100-patient sporadic cohort. It is the reason the phenotype
      statistics reported for the classical imaging group cannot be read as statistics
      about FLNA disease.
  - reference: PMID:28411558
    reference_title: "Sporadic periventricular nodular heterotopia: Classification, phenotype and correlation with Filamin A mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Most patients with classical heterotopia were females (P=0.033) and were likely to have arachnoid cysts (P=0.025) and cardiac abnormalities (P=0.041), but were mostly seizure-free."
    explanation: >-
      Retained, but as a statement about the classical IMAGING group in this sporadic
      series - the two items above give the group's definition and its FLNA yield. Any
      reading of it as a property of FLNA disease is an inference the source does not
      license, which is what INDIRECT records here.
- name: Other bilateral PVNH patterns and other malformations of cortical development
  description: >-
    Bilateral frontal PVNH is one of three proposed PVNH groups and accounts for about
    a tenth of cases; the others are the FLNA-associated classic frontocentral pattern
    and a posterior or infrasylvian pattern. Beyond PVNH, lissencephaly and subcortical
    band heterotopia are the neighbouring malformations of cortical development.
  evidence:
  - reference: PMID:41468712
    reference_title: "Bilateral frontal periventricular nodular heterotopia: a distinctive cortical malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our PVNH cohort data suggest that PVNH could be classified in three main groups: FLNA-associated \"classic\" bilateral frontocentral PVNH, posterior/infrasylvian PVNH and this third pattern of bilateral frontal PVNH, accounting for ∼10 % of all cases of PVNH."
    explanation: >-
      The three-group classification and the share of PVNH that the pattern MAP1B causes
      accounts for. Note the authors' own hedge, "suggest ... could be classified".
treatments:
- name: Antiseizure medication
  description: >-
    There is no disease-modifying therapy. Epilepsy is the main treatable morbidity and
    is managed on focal-epilepsy lines. Drug resistance is common enough that surgical
    options are part of the standard discussion rather than a last resort.

    No source cited here reports antiseizure drug outcomes in a MAP1B patient
    specifically, so this record carries no evidence block; it is the management this
    malformation receives.
  treatment_term:
    preferred_term: antiseizure pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  therapeutic_modality: SMALL_MOLECULE
- name: Stereotactic MR-guided laser ablation of epileptogenic nodules
  description: >-
    For pharmacoresistant epilepsy arising from the nodules themselves, MR-guided laser
    interstitial thermal therapy allows a deep, focal ablation that open resection
    cannot reach safely. The clinical premise is that the nodule is the seizure onset
    zone, which has to be established per patient by intracranial recording rather than
    assumed from the imaging.
  treatment_term:
    preferred_term: MR-guided laser interstitial thermal therapy
    term:
      id: NCIT:C15466
      label: Laser Therapy
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:24518890
    reference_title: "Stereotactic laser ablation of epileptogenic periventricular nodular heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Resective surgery for PVNH is limited by its deep location, and the overlying eloquent cortex or white matter."
    explanation: >-
      Why an ablative rather than resective approach is used here. Note this is a
      two-patient technique report, not a comparative trial, and it is about PVNH
      generally rather than MAP1B PVNH.
  - reference: PMID:24518890
    reference_title: "Stereotactic laser ablation of epileptogenic periventricular nodular heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comprehensive presurgical evaluation, including intracranial EEG monitoring in two patients revealed the PVNH to be crucially involved in their PRE."
    explanation: >-
      Records that the nodules were shown to be involved in seizure onset before they
      were ablated, which is the step that makes the target choice evidence-based rather
      than anatomical.
- name: Developmental, educational and behavioural support
  description: >-
    Multidisciplinary supportive management for developmental delay, intellectual
    disability and behavioural dysregulation. Recorded without an evidence block for the
    same reason as the antiseizure row: no cited source reports outcomes in MAP1B
    patients.
  treatment_term:
    preferred_term: developmental and rehabilitative support
    term:
      id: NCIT:C15315
      label: Rehabilitation
  therapeutic_modality: BEHAVIORAL
discussions:
- discussion_id: map1b_burden_signal_versus_pedigree
  kind: KNOWLEDGE_GAP
  prompt: >-
    How much of the MAP1B phenotype beyond PVNH is attributable to MAP1B, given that
    the gene-disease relationship rests on a burden test and the reported carriers
    are few, heterogeneous and sometimes confounded?
  attaches_to:
  - genetic#MAP1B
  - phenotypes#Intellectual disability
  rationale: >-
    PVNH itself is well supported: a genome-wide significant collapsing signal, an
    anteriorly predominant imaging phenotype, and independent replication in three
    further families. The rest of the phenotype is on weaker ground, and the entry
    should not obscure the difference.

    Three things argue for caution. The founding evidence is a case-control burden
    test over 202 individuals, driven by four carriers - a design that identifies a
    gene without characterizing a syndrome. The subsequent literature is case reports,
    and case reports of a newly named gene select for unusual presentations, so the
    reported feature list grows without its denominators. And the individual cases
    carry confounders that the authors themselves name: the child with microcephaly,
    short stature and dysmorphism also had significant prenatal alcohol exposure, and
    the authors state they believe the features cannot be explained by it alone -
    which is a judgement, not a measurement.

    The strongest single piece of counter-evidence is in the entry: a 12-year-old with
    a nonsense allele, bilateral PVNH and an IQ of 99. If a null allele can give the
    malformation with normal intelligence, then intellectual disability is not a
    consequence of MAP1B loss in the way the malformation is, and the case series'
    feature list is at least partly ascertainment.

    What would settle it is a denominator: systematic phenotyping of MAP1B
    loss-of-function carriers ascertained by genotype rather than by presentation,
    including the imaged-but-undiagnosed parents that the penetrance finding implies
    exist.
  proposed_experiments:
  - experiment_id: map1b_genotype_first_phenotyping
    name: Genotype-first phenotyping of MAP1B loss-of-function carriers
    description: >-
      Ascertain MAP1B loss-of-function carriers from population-scale sequencing
      biobanks rather than from clinical presentation, and phenotype them with MRI and
      standardized cognitive assessment. The design removes the ascertainment bias that
      case reports of a new gene carry, and it can measure penetrance for the
      malformation separately from penetrance for the cognitive phenotype.
    readouts:
    - name: Proportion of genotype-ascertained carriers with PVNH on MRI
      target: phenotypes#Periventricular nodular heterotopia
      direction: INCREASED
      interpretation: >-
        Penetrance of the malformation among unselected carriers, which the current
        literature cannot estimate.
    - name: Distribution of full-scale IQ among genotype-ascertained carriers
      target: phenotypes#Intellectual disability
      direction: ALTERED
      interpretation: >-
        A distribution centred near population mean would support the
        normal-intelligence case being representative rather than exceptional, and
        would mean intellectual disability in the case series is ascertainment.
    would_support:
    - phenotypes#Periventricular nodular heterotopia
    would_refute:
    - phenotypes#Intellectual disability
    supporting_outcome:
    - >-
      PVNH is present in most genotype-ascertained carriers while IQ is distributed
      near the population mean, separating a highly penetrant malformation from a
      weakly penetrant cognitive phenotype.
    refuting_outcome:
    - >-
      Genotype-ascertained carriers show both the malformation and reduced IQ at
      similar rates, supporting the case-series feature list as representative.
notes: >-
  Ontology gaps and binding choices.

  Lateral ventricle is bound as UBERON:0002285 telencephalic ventricle, which is the
  term the cache holds; cache/uberon/terms.csv has no "lateral ventricle" row. The
  telencephalic ventricle is the correct anatomical structure and the common name is
  carried in `preferred_term`.

  Allelic disorder cross-reference. kb/disorders/Hearing_Loss_Autosomal_Dominant_83.yaml
  (DFNA83, MONDO:0030723) curates the MAP1B missense phenotype and already names PVNH9
  as its loss-of-function counterpart. The two entries now point at each other. That
  entry also notes the same caution recorded here about the Map1b mouse: it is a null,
  and the deafness alleles are missense.

  No GeneReviews chapter exists for this disorder. Verified offline against
  cache/bookshelf/genereviews.csv: grep for "MAP1B", "periventricular", "heterotopia"
  and "nodular" returns no chapter, so the phenotype baseline here is the primary
  literature.

  An earlier draft added a second sentence claiming there was no FLNA periventricular
  heterotopia chapter in the committed index either. That was WRONG - the index holds
  `20301392,NBK1213,0,1993,FLNA Deficiency.` - and review caught it. It is the second
  false negative-existence claim in this entry's history and the same mistake as the
  GO term in the sibling PR #12512: a claim about what a source does not contain,
  written without running the query against it. The claim that matters here, that no
  chapter covers PVNH9 or MAP1B, was run and is correct. FLNA Deficiency is now cited
  in `differential_diagnoses:` instead of being wrongly said not to exist.
review_notes: >-
  Evidence base, stated plainly because it governs how the entry should be read. The
  gene-disease relationship rests on a case-control gene-level collapsing analysis of
  202 sporadic PVNH exomes, driven by four ultra-rare loss-of-function carriers, plus
  a later three-family case series and two single case reports. That is enough for the
  malformation and thin for everything else, and the `discussions` block says so
  rather than the entry implying uniform support.

  One evidence item is graded REFUTE on purpose. PMID:40869917 reports a nonsense-allele
  carrier with bilateral PVNH and an IQ of 99, which refutes intellectual disability as
  a constant feature. It is recorded on the phenotype it contradicts rather than
  omitted, because the phenotype list of a newly described gene is exactly where
  counter-evidence gets lost.

  Round 2 corrections, recorded rather than quietly applied. Three prose blocks still
  described the HP:0001274 binding that round 1 replaced with HP:0001273 - an evidence
  explanation, a notes paragraph, and a review_notes paragraph asking a reviewer to
  repoint a term that had already been repointed. All three are deleted. The FLNA
  differential attributed female predominance, arachnoid cysts, cardiac abnormalities
  and a low seizure burden to the FLNA genotype; PMID:28411558 defines its classical
  group radiologically (n=41) in a sporadic cohort where FLNA variants were found in 8
  of 100, so those are properties of an imaging class. The description is rescoped, the
  8/100 yield is quoted, and "mostly seizure-free" is no longer carried as an FLNA
  property - in the familial FLNA literature epilepsy is common, so that one would have
  steered a clinician wrong.

  Of the two phenotypes added this round, only one is wired. Global developmental delay
  hangs off Disrupted Axon Guidance and Cortical Circuit Formation, as the earlier and
  less differentiated form of what the intellectual disability node records later.
  Abnormal facial shape is deliberately left unconnected: MAP1B is a
  microtubule-associated protein with no craniofacial role anything here shows, the
  only source is one child with documented prenatal alcohol exposure, and drawing an
  edge from a neuronal migration lesion to facial dysmorphism would assert a mechanism
  in order to clear a connectivity report. Entry connectivity is 5/10 after both,
  against 4/8 before.

  Inserting that edge also reproduced, in this file, the defect review had just caught
  in a sibling PR: the new downstream item landed between an existing target and its own
  causal_link_type, capturing it. Here the result was a duplicate key and
  `just check-duplicate-keys` refused the file; in the sibling the captured slot was a
  description, no key repeated, and nothing caught it but a reader. Same edit, same
  mistake, and whether any gate sees it depends only on which slot happens to follow.

  One further error of mine in the same round, caught by a gate: the sequencing
  diagnosis first carried a qualifier predicate bound to NCIT:C25218 with the label
  "Intervention or Procedure", written from memory. The canonical label is "Clinical
  Intervention or Procedure". `just check-qualifier-terms` caught it only because
  NCIT:C25218 was already in cache/ncit/terms.csv from elsewhere in the KB - an
  uncached CURIE in that slot gets no opinion from the offline gate, and
  `just validate-terms` never reaches inside `qualifiers` at all. The qualifier is
  dropped: the predicate was also a stretch, since "also performed" is not what
  NCIT:C25218 means. The microarray stays named in the entry's description.

  Two pathophysiology nodes carry mechanism_confidence PROVISIONAL and evidence graded
  REVIEW_SYNTHESIS + OTHER. Both describe MAP1B's cellular role from a case series'
  summary of animal and cell work, with no measurement in a MAP1B-haploinsufficient
  human neuron anywhere in this literature. Grading them ESTABLISHED would have
  asserted a mechanism nobody has shown in this disease.

  The prenatal alcohol confounder in PMID:31317654 is carried in the evidence
  explanation for Microcephaly rather than dropped, because that case is one of very
  few and its features are among the ones the entry is least sure about.
📚

References & Deep Research

References

12
PMID:29738522
De novo and inherited private variants in MAP1B in periventricular nodular heterotopia.
No top-level findings curated for this source.
PMID:40874586
MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families.
No top-level findings curated for this source.
PMID:40869917
Severe Elimination Disorders and Normal Intelligence in a Case of MAP1B Related Syndrome: A Case Report.
No top-level findings curated for this source.
PMID:31317654
MAP1B related syndrome: Case presentation and review of literature.
No top-level findings curated for this source.
PMID:40802165
Novel MAP1B loss-of-function variant associated with periventricular nodular heterotopia 9 and literature review on genotype-phenotype associations of MAP1B.
No top-level findings curated for this source.
PMID:11085878
Perinatal lethality of microtubule-associated protein 1B-deficient mice expressing alternative isoforms of the protein at low levels.
No top-level findings curated for this source.
PMID:12088839
Microtubule-associated protein 1B is involved in the initial stages of axonogenesis in peripheral nervous system cultured neurons.
No top-level findings curated for this source.
PMID:33268592
Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss.
No top-level findings curated for this source.
PMID:41468712
Bilateral frontal periventricular nodular heterotopia: a distinctive cortical malformation.
No top-level findings curated for this source.
PMID:28411558
Sporadic periventricular nodular heterotopia: Classification, phenotype and correlation with Filamin A mutations.
No top-level findings curated for this source.
PMID:24518890
Stereotactic laser ablation of epileptogenic periventricular nodular heterotopia.
No top-level findings curated for this source.
PMID:30819503
Malformations of cortical development: New surgical advances.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Periventricular Nodular Heterotopia 9 (MONDO:0030061) · 2026-09-22T13:32:44Z · View source

De novo curation of PVNH9 / MAP1B-related syndrome (MONDO:0030061), claimed in #12508. This claim replaced #12501 (hypertrophic cardiomyopathy 18), which was withdrawn as a duplicate of the assigned genetics-gap batch #12252 after an automated duplicate notice. The original preflight searched kb/ on origin/main and open PRs and found nothing, because MONDO:0013475 is named only in an open issue body and in stubs/. entry_type decision: DISEASE. A single-gene leaf under periventricular nodular heterotopia. Pathograph: five nodes from MAP1B haploinsufficiency through impaired microtubule stabilization to two arms - failure of radial neuronal migration, and disrupted axon guidance and cortical circuit formation. Evidence discipline is the substance of this entry. The gene-disease relationship rests on a gene-level collapsing analysis of 202 sporadic PVNH exomes driven by four ultra-rare loss-of-function carriers, not on a segregating pedigree, and the entry says so in the description, in the gene evidence explanation, and in a knowledge gap. The authors' own verb, 'implicate', is quoted and not upgraded. Two pathophysiology nodes carry mechanism_confidence PROVISIONAL with evidence graded REVIEW_SYNTHESIS + OTHER + INDIRECT, because the mechanism comes from a case series' summary of animal and cell work with no measurement in a MAP1B-haploinsufficient human neuron. One REFUTE item: PMID:40869917 reports a nonsense-allele carrier with bilateral PVNH and an IQ of 99, which refutes intellectual disability as a constant feature. Recorded on the phenotype it contradicts. Confounder preserved: PMID:31317654's case had significant prenatal alcohol exposure, which the authors flag; this is carried in the Microcephaly evidence explanation rather than dropped. Binding flagged as weak: HP:0001274 Agenesis of corpus callosum is bound to a source that says dysgenesis. No dysgenesis term is in the term cache; the mismatch is recorded in notes and review_notes for a reviewer to repoint or remove. Validation: just validate, just validate-terms, just count-verified-snippets (18/18), check-duplicate-keys, check-entity-refs, check-causal-targets, check-coarse-phenotypes. Review round 1 (PR #12510). CRITICAL, taken. HP:0001274 Agenesis of corpus callosum rebound to HP:0001273 Abnormal corpus callosum morphology. The source says dysgenesis, agenesis asserts absence, and HP:0001273 was in the same cache the notes cited as justification for saying no suitable term existed. The reviewer and the deep-research report reached the same term independently. Second false negative-existence claim corrected. The notes had added that the FLNA periventricular heterotopia chapter was not in the committed Bookshelf index; it is, as 20301392 NBK1213 FLNA Deficiency. The primary claim, that no chapter covers PVNH9 or MAP1B, was run and is correct. FLNA Deficiency is now cited in differential_diagnoses rather than wrongly said not to exist. conforms_to added against microtubule_dependent_neuronal_migration_failure on three nodes. The module's exclusion list names apical neuroependyma integrity failure, which is the FLNA mechanism, not MAP1B's, and MAP1B is a microtubule-associated protein, so the module fits. Clinical sections added from the committed report, all re-verified against freshly fetched caches: diagnosis (brain MRI pattern, exome/genome with microarray and the 13 percent / 38 percent yields), three differential diagnoses (DFNA83 as the allelic disorder, FLNA classic frontocentral PVNH with its discriminating features, the three-group PVNH classification), and three treatments (antiseizure pharmacotherapy, MR-guided laser ablation of epileptogenic nodules, developmental support). Two of the three treatments carry no evidence block and say so.

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Periventricular Nodular Heterotopia 9 (PVNH9): A Comprehensive Disease Characterization Report
openscientist-autonomous 25 citations 2026-09-22T13:31:46.051875

Periventricular Nodular Heterotopia 9 (PVNH9): A Comprehensive Disease Characterization Report

Target disease: Periventricular Nodular Heterotopia 9 (PVNH9) MONDO ID: MONDO:0030061 · OMIM: #618918 · Causal gene: MAP1B (HGNC:6836; 5q13.2) Report type: Disease knowledge-base entry compiled from primary literature (41 papers reviewed, 8 findings confirmed)

Summary

Periventricular Nodular Heterotopia 9 (PVNH9) is a rare, autosomal dominant malformation of cortical development caused by heterozygous loss-of-function (LoF) variants in MAP1B, the gene encoding the neuron-specific microtubule-associated protein 1B. PVNH is defined by nodular masses of neurons and glia ectopically retained along the walls of the lateral ventricles because they fail to complete radial migration to the cortex. In PVNH9 the nodules are characteristically frontally (anteriorly) predominant and are frequently accompanied by perisylvian polymicrogyria and corpus callosum abnormalities. The clinical presentation typically emerges in childhood and includes global developmental delay, intellectual disability, focal epilepsy, and behavioural dysregulation, with variable dysmorphism, microcephaly and short stature reported in some individuals.

The mechanistic basis is well supported across human genetics, mouse genetics, and cell biology. MAP1B crosslinks and stabilizes microtubules, couples microtubules to the actin cytoskeleton, and regulates growth-cone dynamics and axon elongation; it is a downstream effector of Netrin-1 signalling and its translation is repressed by the fragile-X protein FMRP. Heterozygous LoF variants reduce MAP1B mRNA and protein (haploinsufficiency), impairing microtubule stabilization and radial neuronal migration and leaving neurons stranded in periventricular nodules. The founding genome-wide collapsing analysis (Heinzen et al., 2018) implicated MAP1B through four ultra-rare LoF variants, and independent families have since confirmed the association, demonstrating autosomal dominant inheritance with incomplete penetrance and variable expressivity (one variant was inherited from a parent with previously undiagnosed PVNH).

A striking allelic dichotomy distinguishes PVNH9 from another MAP1B phenotype: LoF variants cause PVNH-related neurological disease, whereas missense variants cause autosomal dominant nonsyndromic sensorineural hearing loss (SNHL) without brain malformation, reflecting MAP1B's high expression in cochlear spiral ganglion neurons. There is no disease-modifying therapy; management is symptomatic — antiseizure medication for epilepsy (often drug-resistant) and, for refractory focal epilepsy, ablative surgery such as MR-guided laser interstitial thermal therapy (MRgLITT) targeting epileptogenic nodules — alongside developmental, educational and rehabilitative support and genetic counselling.

Key Findings

Finding 1 — PVNH9 is caused by heterozygous loss-of-function variants in MAP1B

PVNH9 (OMIM #618918) is caused by heterozygous mutations in MAP1B (microtubule-associated protein 1B; HGNC:6836; chromosome 5q13.2). Multiple independent families with de novo or inherited LoF variants — nonsense, frameshift and splice-site — have been reported. Documented alleles include c.7091dup and c.2035G>T (p.Glu679). The mechanism is haploinsufficiency / loss of function: functional assays demonstrate significantly reduced MAP1B* mRNA and protein in mutant versus wild-type.

A 2025 report describing a novel MAP1B LoF variant states plainly that "PVNH9 is caused by a heterozygous mutation in the microtubule-associated protein 1B (MAP1B) gene" and that "the qPCR and western blot analyses demonstrated significantly reduced mRNA and protein expression, respectively, in the mutant compared with that in the wild-type" PMID: 40802165. A de novo nonsense variant, "a de novo nonsense MAP1B mutation (c.2035G>T, p.Glu679X) detected on whole exome sequencing," anchors the LoF class PMID: 31317654. Evidence source: human clinical + in vitro functional.

Finding 2 — Genotype–phenotype correlation: LoF → PVNH; missense → isolated deafness

A review of MAP1B genotype–phenotype associations found that LoF variants (nonsense, frameshift, splice) predominantly cause PVNH-related neurological disease (intellectual disability, epilepsy, developmental delay, dysmorphism), whereas missense variants may present with only deafness (nonsyndromic SNHL). As stated: "loss-of-function (LOF) variants in MAP1B mainly lead to PVNH-related neurological symptoms, while patients with missense variants may only present with deafness" PMID: 40802165. This dichotomy is mechanistically important: it suggests the two allele classes exert distinct molecular consequences (haploinsufficiency versus a tissue-restricted or altered-function effect). Evidence source: human clinical review.

Finding 3 — Clinical spectrum: anteriorly-predominant PVNH, developmental delay, intellectual disability, epilepsy

In a case series of 7 affected individuals from 3 unrelated families carrying pathogenic MAP1B variants (all LoF), features included global developmental delay, intellectual disability, behavioural dysregulation and focal epilepsy. Neuroimaging revealed anteriorly (frontally) predominant PVNH in 4 of 5 cases with imaging available; some patients additionally showed polymicrogyria (PMG) and dysgenesis/agenesis of the corpus callosum. Additional reported features include microcephaly, short stature and dysmorphic facial features.

The primary description reports: "Clinical features included global developmental delay, intellectual disability, behavioural dysregulation, and focal epilepsy. Neuroimaging revealed anteriorly predominant PVNH in four of five cases" PMID: 40874586. An earlier review summarizes the recurrent presentation as "a phenotype including periventricular nodular heterotopia (PVNH), intellectual disability (ID), seizures, and dysmorphic features" PMID: 31317654. Evidence source: human clinical.

Finding 4 — Mechanism: MAP1B is a microtubule stabilizer essential for neuronal migration and axon growth, and is FMRP-regulated

MAP1B is a neuron-specific microtubule-associated protein that crosslinks microtubules and actin filaments, stabilizes microtubules, and controls growth-cone dynamics and axon branching/elongation. It is a downstream effector of Netrin-1 signalling (via GSK3/CDK5-dependent phosphorylation); MAP1B-deficient neurons show reduced chemoattractant responses to Netrin-1, and mice show axon-tract and pontine-nuclei defects. MAP1B translation is repressed by FMRP, and FMRP regulates postnatal neuronal migration via MAP1B. MAP1B acts synergistically with MAP2 and tau — double-knockout mice show delayed neuronal migration and disorganized cortical layering. A newly described nuclear pool of MAP1B interacts with the BRG1 chromatin-remodelling complex; increasing the nuclear/cytosol ratio disrupts neuronal positioning, reminiscent of MAP1B patients, and mutant human brain organoids show neuronal ectopia.

Supporting quotes: "Functional data from animal and cell models support a mechanism involving impaired microtubule stabilization, altered growth cone dynamics, and dysregulated axon branching" PMID: 40874586; "map1B-deficient neurons from the lower rhombic lip and other brain regions have reduced chemoattractive responses to Netrin 1 in vitro" PMID: 15186740; "FMRP regulates postnatal neuronal migration via MAP1B" PMID: 38757694; "increasing the nuclear/cytosol ratio disrupts neuronal positioning, reminiscent of patients with MAP1B mutations" PMID: 42276043; and "disrupted cortical patterning caused by retarded neuronal migration" PMID: 11581286. Evidence source: model organism + in vitro + computational.

Finding 5 — Map1b-deficient mice recapitulate neuronal migration and axon defects

Map1b-deficient mice (gene-trap/knockout; Mus musculus; ortholog Map1b, NCBI Gene 17755) show severe abnormal nervous-system development. Homozygous mutants die on the first postnatal day with altered structure of several brain regions, and analyses "suggest the participation of MAP1B in neuronal migration." Cultured DRG neurons from MAP1B-deficient mice show reduced axon elongation (~half the elongation speed of controls) and increased growth-cone area. Map2/Map1b and tau/Map1b double-knockouts show delayed neuronal migration and disorganized cortical layering, indicating partial redundancy with other MAPs.

Quotes: "Homozygous mice die on the first day after birth, probably due to a severe abnormal development of the nervous system" and "Analyses of these mice indicate the presence of several neural defects and suggest the participation of MAP1B in neuronal migration" PMID: 11085878; "Cultured DRG neurons from MAP1B deficient mice show a reduction in axon elongation and an increase in growth cone area" PMID: 12088839. Evidence source: model organism.

Finding 6 — PVNH9 within the PVNH spectrum: genetic heterogeneity and epilepsy burden

PVNH is a malformation of cortical development caused by impaired neuronal migration producing nodular masses of neurons/glia along the lateral ventricle walls. It is genetically heterogeneous: the most common single-gene cause is X-linked FLNA (PVNH1, predominantly females, male prenatal lethality); other loci include ARFGEF2 (PVNH2, autosomal recessive) and MAP1B (PVNH9, autosomal dominant). In FLNA-negative bilateral PVNH cohorts (n = 71), focal-onset seizures were most common (79.3%), developmental delay was present in 21.8%, family history of epilepsy in 36.9%, and febrile seizures in 16.6%. Epilepsy is frequently drug-resistant; surgical options include stereotactic MRgLITT targeting epileptogenic nodules.

Quotes: "Periventricular nodular heterotopia (PVNH) is a malformation of cortical development due to impaired neuronal migration resulting in the formation of nodular masses of neurons and glial cells in close proximity to the ventricular walls" and "Focal onset seizures were the most common type of seizure presentation (79.3%)" PMID: 26340046; "Stereotactic MR guided laser interstitial thermal therapy (MRgLITT) has recently become available for controlled focal ablation, enabling us to target these lesions" PMID: 24518890. Evidence source: human clinical.

Finding 7 — MAP1B implicated by genome-wide significant collapsing analysis, with incomplete penetrance

The founding study exome-sequenced 202 individuals with sporadic PVNH. A gene-level collapsing analysis identified a genome-wide significant signal driven by four ultra-rare LoF heterozygous variants in MAP1B (including one de novo). PVNH cases overall showed a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27×10⁻⁷). The PVNH was frontally predominant and associated with perisylvian polymicrogyria. In at least one instance the variant was inherited from a parent with previously undiagnosed PVNH, demonstrating incomplete penetrance/variable expressivity. A subsequent family (Arya et al., 2021) with a novel heterozygous frameshift variant showed seizures (febrile, fever-triggered, afebrile), photosensitivity, mild developmental delay, obsessive-compulsive behaviours and poor attention, with periventricular heterotopia, corpus callosum abnormalities and perisylvian polymicrogyria.

Quotes: "we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant"; "In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH"; "The PVNH was frontally predominant and associated with perisylvian polymicrogyria" PMID: 29738522. Confirmatory imaging: "Neuroimaging showed PVH, corpus callosum abnormalities, and perisylvian polymicrogyria" PMID: 33772511. Evidence source: human genetics (statistical).

Finding 8 — MAP1B missense variants cause autosomal dominant nonsyndromic sensorineural hearing loss (distinct allelic phenotype)

Three novel heterozygous MAP1B missense mutations (c.4198A>G p.Ser1400Gly; c.2768T>C p.Ile923Thr; c.5512T>C p.Phe1838Leu) cosegregated with autosomal dominant nonsyndromic SNHL in three unrelated Chinese families. MAP1B is highly expressed in cochlear spiral ganglion neurons. Patient iPSC-derived otic sensory neuron-like cells carrying p.Ser1400Gly showed reduced MAP1B levels/phosphorylation, disturbed microtubule dynamics, impaired axonal elongation and electrophysiological defects — rescued by CRISPR/Cas9 correction. Map1b heterozygous knockout mice displayed late-onset progressive SNHL, more pronounced at high frequencies.

Quotes: "Three novel heterozygous MAP1B mutations (c.4198A>G, p.1400S>G; c.2768T>C, p.923I>T; c.5512T>C, p.1838F>L) were cosegregated with autosomal dominant inheritance of nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families"; "Map1b heterozygous KO mice displayed late-onset progressive sensorineural hearing loss that was more pronounced in the high frequencies"; "MAP1B is highly expressed in the spiral ganglion neurons in the mouse cochlea" PMID: 33268592. Evidence source: human genetics + iPSC + mouse.

Report by Requested Section

1. Disease Information

PVNH9 is a rare, genetically-defined subtype of periventricular nodular heterotopia — a malformation of cortical development in which nodules of neurons and glia are ectopically retained along the lateral ventricular walls due to failed radial neuronal migration PMID: 26340046. It is defined at the molecular level by heterozygous LoF variants in MAP1B PMID: 40802165.

Key identifiers: OMIM #618918; MONDO:0030061; causal gene MAP1B (HGNC:6836; OMIM 157129; NCBI Gene 4131; chromosome 5q13.2). Orphanet groups the disorder under periventricular nodular heterotopia; a dedicated ICD-11 code is not established, but the broad category is congenital malformation of the brain (ICD-11 LA05; ICD-10 Q04.8, "other specified congenital malformations of brain"). MeSH: "Periventricular Nodular Heterotopia." Synonyms/alternative names:* PVNH9; PNH9; MAP1B-related periventricular nodular heterotopia; MAP1B-related brain malformation/syndrome.

Information source: The evidence is derived from aggregated disease-level resources and small case series/cohorts (OMIM, published families, exome/genome cohorts), not large EHR datasets.

2. Etiology

Causal factors — genetic. The primary cause is a heterozygous germline LoF variant in MAP1B (nonsense, frameshift, splice-site) acting through haploinsufficiency PMID: 40802165; PMID: 29738522. No environmental or infectious cause is implicated; PVNH9 is a monogenic neurodevelopmental malformation.

Genetic risk factors. The causal variant is itself the risk determinant. Broader PVNH is genetically heterogeneous (see §4/§9), and rare genomic copy-number variants contribute to the wider PVNH population — array-CGH shows an enrichment of pathogenic CNVs in PVNH versus polymicrogyria (35.7% vs 9.1%) PMID: 30683929.

Environmental / lifestyle risk factors. None established for PVNH9 specifically. As a de novo or inherited monogenic malformation, it is not attributable to toxins, occupational exposure, diet, smoking or alcohol.

Protective factors. None identified (genetic or environmental). Not available for this disease.

Gene–environment interactions. No documented GxE interactions. Phenotypic variability appears driven by genetic/modifier and stochastic developmental factors rather than environment; note fever-triggered seizures in one family PMID: 33772511 as a possible symptomatic trigger rather than a disease-causing interaction.

3. Phenotypes

Phenotype Type Suggested HPO Onset Severity Frequency
Periventricular nodular heterotopia (frontally predominant) Imaging/structural HP:0032388 (periventricular nodular heterotopia) Congenital — ~core (4/5 imaged)
Global developmental delay Clinical sign HP:0001263 Infancy/childhood Mild–moderate Common
Intellectual disability Clinical sign HP:0001249 Childhood Mild–moderate Common
Focal epilepsy / seizures Clinical sign HP:0007359 / HP:0001250 Childhood Variable, often drug-resistant Common
Behavioural dysregulation / OCD features / poor attention Behavioural HP:0000708 / HP:0000722 / HP:0000736 Childhood Variable Subset
Polymicrogyria (perisylvian) Imaging/structural HP:0002126 Congenital — Subset
Corpus callosum dysgenesis/agenesis Imaging/structural HP:0001274 / HP:0001273 Congenital — Subset
Microcephaly Physical HP:0000252 Congenital/childhood Variable Subset
Short stature Physical HP:0004322 Childhood Variable Subset
Dysmorphic facial features Physical HP:0001999 Congenital Variable Subset
Sensorineural hearing loss (missense alleles only) Clinical sign HP:0000407 Late-onset, progressive High-frequency predominant Missense subgroup

Core features are supported by PMID: 40874586 and PMID: 31317654; the missense/deafness phenotype by PMID: 33268592. Progression: the structural malformation is static (congenital), while epilepsy and cognitive/behavioural features constitute the chronic clinical burden. Quality-of-life impact: driven principally by epilepsy (often drug-resistant), intellectual disability and behavioural dysregulation, which affect education, independence and daily functioning; disease-specific QoL instruments have not been applied. Bilateral frontal PVNH generally carries "milder sequelae than other forms of bilateral PVNH" PMID: 41468712.

4. Genetic / Molecular Information

  • Causal gene: MAP1B (HGNC:6836; OMIM *157129; NCBI Gene 4131; UniProt P46821; 5q13.2).
  • Pathogenic variants: Nonsense (e.g., c.2035G>T p.Glu679* PMID: 31317654), frameshift/duplication (e.g., c.7091dup), and splice variants; classified pathogenic/likely pathogenic per ACMG (de novo occurrence, LoF in a constrained gene, segregation). Four ultra-rare heterozygous LoF variants underpinned the founding genome-wide signal PMID: 29738522.
  • Variant class / functional consequence: LoF → haploinsufficiency (reduced mRNA and protein) PMID: 40802165. By contrast, missense variants (p.Ser1400Gly, p.Ile923Thr, p.Phe1838Leu) cause SNHL and behave as a distinct allelic series PMID: 33268592.
  • Allele frequency: Pathogenic variants are ultra-rare/private in population databases (gnomAD); MAP1B is a highly constrained gene, consistent with LoF intolerance.
  • Somatic vs germline: Germline (de novo or inherited).
  • Modifier genes: Functional redundancy with MAP2 and MAPT (tau) PMID: 11581286; EB1/MAPRE1 can partially complement MAP1B loss PMID: 15789376 — candidate genetic modifiers of expressivity, though not clinically validated.
  • Epigenetic information: No disease-specific methylation/histone signature reported. Not available.
  • Chromosomal abnormalities: PVNH broadly is associated with recurrent CNVs (e.g., 7q11.23, 7p22.1) and extreme genetic heterogeneity PMID: 30683929; PMID: 41468712, but PVNH9 itself is defined by intragenic MAP1B LoF.

5. Environmental Information

No environmental factors, lifestyle factors, or infectious agents are implicated in PVNH9. It is a monogenic developmental disorder. Not applicable.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. A heterozygous LoF variant in MAP1B (nonsense/frameshift/splice) results in reduced MAP1B mRNA and protein — haploinsufficiency PMID: 40802165.
  2. Reduced MAP1B leads to impaired microtubule stabilization and impaired crosslinking of microtubules to actin, disrupting growth-cone dynamics and axon branching/elongation PMID: 40874586; PMID: 12088839.
  3. Because MAP1B is a downstream effector of Netrin-1 signalling (GSK3/CDK5-phosphorylation), reduced MAP1B blunts chemoattractant responses guiding migrating neurons and axons PMID: 15186740. (Upstream regulation: FMRP normally represses MAP1B translation and regulates migration via MAP1B PMID: 38757694; a nuclear MAP1B pool interacting with BRG1 chromatin remodelling also influences positioning PMID: 42276043.)
  4. Impaired cytoskeletal dynamics cause retarded radial neuronal migration during corticogenesis (demonstrated in mouse; partially buffered by MAP2/tau redundancy) PMID: 11581286; PMID: 11085878.
  5. Neurons that fail to migrate are retained as ectopic nodules along the lateral ventricle walls — periventricular nodular heterotopia, frontally predominant PMID: 26340046; PMID: 29738522.
  6. Branch A: Cortical dysgenesis co-occurs as perisylvian polymicrogyria and corpus callosum abnormalities (axon-guidance component) PMID: 29738522; PMID: 33772511.
  7. Branch B (missense alleles): in cochlear spiral ganglion neurons, altered MAP1B causes sensorineural hearing loss rather than migration failure PMID: 33268592.
  8. Ectopic nodules and abnormal cortical circuitry produce an epileptogenic substrate and disordered network function, which results in focal epilepsy, developmental delay, intellectual disability and behavioural dysregulation PMID: 40874586; PMID: 26340046.
MAP1B LoF variant
      │ (haploinsufficiency: down mRNA / down protein)
      ▼
down microtubule stabilization / MT-actin crosslinking
      │  (blunted Netrin-1 response; FMRP / nuclear-BRG1 regulation upstream)
      ▼
impaired growth-cone dynamics & axon elongation
      ▼
retarded radial neuronal migration ──► Branch A: perisylvian polymicrogyria + corpus callosum anomalies
      ▼                                 Branch B (missense): spiral ganglion neurons → SNHL
ectopic periventricular nodules (frontal-predominant PVNH)
      ▼
epileptogenic cortical network
      ▼
epilepsy · developmental delay · intellectual disability · behaviour

Molecular pathways: microtubule/cytoskeletal regulation; Netrin-1/DCC guidance; JNK-MAPK signalling phosphorylates MAP1B (MKK4/MKK7→JNK), linking stress-kinase pathways to migration/axon elongation PMID: 22090513; PMID: 40594443. Cellular processes: neuronal migration (GO:0001764), axon guidance (GO:0007411), microtubule cytoskeleton organization (GO:0000226), growth-cone dynamics. Protein dysfunction: loss of function/haploinsufficiency of a microtubule-stabilizing MAP. Immune/metabolic involvement: not implicated. Cell types: migrating cortical projection neurons (CL:0000679 glutamatergic neuron; migrating post-mitotic neurons), and — for the missense branch — cochlear spiral ganglion neurons (CL:0000100).

7. Anatomical Structures Affected

  • Organ/system: central nervous system — cerebral cortex and periventricular white matter (UBERON:0000956 cerebral cortex; UBERON:0002285 periventricular region; UBERON:0002436 lateral ventricle). Body system: nervous system.
  • Localization: heterotopic nodules along the lateral ventricle walls, frontally (anteriorly) predominant, typically bilateral PMID: 29738522; PMID: 41468712. Associated: perisylvian cortex (polymicrogyria) and corpus callosum (UBERON:0002336).
  • Tissue/cell level: nervous tissue; ectopic post-mitotic neurons and glia forming nodules. For the missense/deafness branch: cochlear spiral ganglion neurons.
  • Subcellular level: cytoskeleton — microtubules (GO:0005874) and the microtubule–actin interface; a nuclear MAP1B pool is also implicated (GO:0005634) PMID: 42276043; presynaptic terminals in mature neurons PMID: 27425640.

8. Temporal Development

  • Onset: the malformation is congenital (arises during fetal corticogenesis); clinical features (seizures, developmental delay) manifest in infancy/childhood PMID: 40874586.
  • Progression: the structural lesion is static/stable; epilepsy and neurodevelopmental features follow a chronic, lifelong course. Missense-associated SNHL is late-onset and progressive PMID: 33268592.
  • Critical period: the window of vulnerability is prenatal neuronal migration (~weeks 8–24 of gestation); there is no postnatal window to reverse the malformation, so intervention is symptomatic.

9. Inheritance and Population

  • Inheritance: Autosomal dominant, de novo or inherited PMID: 29738522.
  • Penetrance/expressivity: incomplete penetrance and variable expressivity — a variant was inherited from a parent with previously undiagnosed PVNH PMID: 29738522.
  • Epidemiology: PVNH9 is ultra-rare with no formal prevalence/incidence estimate; it represents a small fraction of overall PVNH (itself dominated by FLNA). Bilateral frontal PVNH — the pattern within which MAP1B falls — accounts for ~10% of all PVNH PMID: 41468712. Precise PVNH9 prevalence: not available.
  • Sex ratio: No strong sex bias reported for PVNH9 (unlike X-linked FLNA PVNH1, which predominates in females with male prenatal lethality) PMID: 23622213.
  • Founder effects / consanguinity / anticipation / mosaicism: none established; not a repeat-expansion disorder. Not applicable/not available.

10. Diagnostics

  • Imaging (primary diagnostic modality): brain MRI shows bilateral frontally-predominant periventricular nodules isointense to grey matter, often with perisylvian polymicrogyria and corpus callosum anomalies PMID: 29738522; PMID: 41468712.
  • Genetic testing: exome or genome sequencing is the diagnostic mainstay (variant detected on WES PMID: 31317654); PVNH gene panels including MAP1B, FLNA, ARFGEF2 and others; chromosomal microarray (CMA) for CNVs given genetic heterogeneity — CMA yields a diagnosis in ~13% and exome/genome in ~38% of bilateral frontal PVNH where tested PMID: 41468712.
  • Electrophysiology: EEG for seizure characterization (focal-onset predominant PMID: 26340046).
  • Differential diagnosis: other PVNH genetic subtypes (notably FLNA PVNH1 — classic bilateral frontocentral, female-predominant; ARFGEF2 PVNH2), and other malformations of cortical development (lissencephaly/SBH from LIS1/DCX, polymicrogyria syndromes) PMID: 23622213; PMID: 28411558.
  • Biomarkers / omics / newborn screening: no molecular biomarker or newborn-screening test exists; diagnosis is imaging + sequencing.

11. Outcome / Prognosis

PVNH9 is a chronic, non-progressive structural disorder; life expectancy is generally not shortened in humans (in contrast to the perinatal lethality of homozygous mouse knockouts, which reflects biallelic loss not seen in patients PMID: 11085878). Morbidity is driven by epilepsy (frequently drug-resistant PMID: 30819503), intellectual disability, and behavioural dysregulation. Bilateral frontal PVNH tends to have milder sequelae than other bilateral PVNH forms PMID: 41468712. Prognostic factors: seizure control, severity of associated malformations (polymicrogyria, corpus callosum agenesis) and degree of cognitive impairment. No validated prognostic biomarkers. Quality-of-life instruments have not been formally applied.

12. Treatment

There is no disease-modifying/curative therapy; management is symptomatic and multidisciplinary.

  • Pharmacotherapy: antiseizure medications for epilepsy (NCIT: Anticonvulsant Agent). Choice follows focal-epilepsy guidelines; drug resistance is common PMID: 30819503.
  • Surgical/interventional: for refractory focal epilepsy arising from epileptogenic nodules, stereotactic MR-guided laser interstitial thermal therapy (MRgLITT) enables focal ablation of nodules PMID: 24518890; PMID: 28370739; resective/stereotactic epilepsy surgery is an option in selected cases PMID: 30819503.
  • Supportive/rehabilitative: developmental and educational support, physical/occupational/speech therapy, and behavioural/psychiatric management (NCIT: Rehabilitation Therapy; Supportive Care).
  • Advanced/experimental therapeutics (gene, cell, RNA, targeted, immuno): none reported for PVNH9. Not available.
  • Pharmacogenomics / personalized medicine: none specific to PVNH9. Not available.
  • For the missense/deafness allelic phenotype: management is hearing rehabilitation (amplification/cochlear implantation as indicated) — outside the PVNH9 malformation itself PMID: 33268592.

13. Prevention

Because PVNH9 is a monogenic developmental malformation, prevention is limited to reproductive/genetic strategies: genetic counselling for autosomal dominant transmission with incomplete penetrance, cascade testing of at-risk relatives, and options for prenatal diagnosis or preimplantation genetic testing when a familial variant is known. Tertiary prevention — preventing complications — centres on optimizing seizure control and developmental support. There is no primary prevention (no modifiable environmental risk), no immunization, and no population screening. Primary/behavioural/public-health prevention: not applicable.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: Mus musculus Map1b (NCBI Gene 17755; NCBI Taxon 10090) is the principal experimental ortholog; a Drosophila ortholog Futsch exists (relevant to fragile-X/MAP1B biology) PMID: 15498496.
  • Natural disease in other species: no naturally-occurring companion-animal or wildlife PVNH9 equivalent is documented in OMIA. Not available. Disease knowledge derives from engineered models, not natural animal disease.
  • Comparative biology: MAP1B's role in neuronal migration and axon growth is evolutionarily conserved from Drosophila (Futsch) to mouse to human, supporting cross-species mechanistic inference PMID: 15498496; PMID: 11085878.
  • Zoonotic potential: none (genetic disorder). Not applicable.

15. Model Organisms

Model Type Key phenotype Recapitulation Reference
Map1b KO / gene-trap mouse (homozygous) Mammalian, germline KO Perinatal (P1) lethality; severe abnormal CNS development; neuronal migration defects Confirms migration mechanism; homozygous lethality exceeds heterozygous human phenotype PMID: 11085878
Map1b heterozygous KO mouse Mammalian Late-onset progressive high-frequency SNHL Models the missense/deafness allelic branch PMID: 33268592
Map1b / Map2 and Map1b / Mapt(tau) double KO Mammalian Delayed neuronal migration, disorganized cortical layering Reveals MAP redundancy; unmasks migration role PMID: 11581286
MAP1B-deficient DRG/hippocampal neurons In vitro (mouse) Reduced axon elongation, increased growth-cone area, presynaptic deficits Cellular mechanism of axon growth defect PMID: 12088839; PMID: 27425640
Patient iPSC-derived otic sensory neuron-like cells In vitro (human) Reduced MAP1B/phospho-MAP1B, disturbed microtubule dynamics, impaired axon elongation; rescued by CRISPR correction Directly models human missense allele PMID: 33268592
Human brain organoids (MAP1B mutant / nuclear ratio) In vitro (human) Neuronal ectopia; disrupted positioning Models cortical mispositioning PMID: 42276043
Drosophila (Futsch; fmr1 context) Invertebrate Altered synaptic/neuronal elaboration Conserved MAP1B/FMRP axis PMID: 15498496

Model resources: MGI (mouse Map1b), IMPC/IMSR (KO alleles), Cellosaurus (iPSC lines), FlyBase (futsch). Limitation: homozygous mouse lethality and the SNHL-focused heterozygous phenotype mean no single model fully recapitulates human heterozygous LoF PVNH9 cortical heterotopia; organoids are the most direct human-relevant system.

Mechanistic Model / Interpretation

The findings converge into a single coherent model: PVNH9 is a microtubule-cytoskeletal disorder of neuronal migration caused by MAP1B haploinsufficiency. MAP1B is expressed early in nervous-system development where it stabilizes microtubules and links them to actin, powering the growth-cone motility and axon elongation that migrating neurons and their processes require. When one MAP1B allele is lost, protein dosage falls below the threshold needed for timely radial migration (a threshold partly buffered by the redundant MAPs MAP2 and tau, and by EB1). Neurons that fail to reach the cortical plate remain as frontally-predominant periventricular nodules, while accompanying axon-guidance failures manifest as perisylvian polymicrogyria and corpus callosum anomalies. The resulting aberrant cortical circuitry is epileptogenic and cognitively/behaviourally disruptive.

The model is unusually well-triangulated: statistical human genetics (genome-wide significant collapsing signal), independent case series, functional demonstration of reduced expression, mouse genetics (migration defect, redundancy), and cellular/organoid biology all point the same way. The allelic dichotomy — LoF causing brain malformation versus missense causing isolated deafness — is the most intriguing feature and implies that missense alleles do not simply reduce dosage but exert a tissue-restricted or altered-function effect to which cochlear spiral ganglion neurons are selectively vulnerable, while LoF's dosage reduction preferentially derails cortical migration.

Evidence Base

PMID Contribution Evidence type
40802165 Causal gene + LoF/haploinsufficiency; genotype–phenotype dichotomy Human clinical + in vitro
40874586 Core clinical spectrum; anteriorly predominant PVNH; mechanism synthesis Human clinical
31317654 De novo nonsense variant; recurrent phenotype triad Human clinical
29738522 Founding genome-wide collapsing signal; incomplete penetrance; imaging Human genetics (statistical)
33772511 Confirmatory family; epilepsy + imaging triad Human clinical
15186740 MAP1B downstream of Netrin-1 in migration/guidance Model organism/in vitro
38757694 FMRP regulates migration via MAP1B (upstream) Model organism
42276043 Nuclear MAP1B/BRG1; organoid ectopia In vitro/human organoid
11581286 MAP1B/MAP2 redundancy; retarded migration Model organism
11085878 KO mouse lethality + migration defect Model organism
12088839 Axon elongation/growth-cone cellular phenotype In vitro
26340046 PVNH definition; epilepsy burden quantification Human clinical
24518890 MRgLITT surgical option Human clinical
33268592 Missense → SNHL allelic branch; iPSC + mouse Human genetics + iPSC + mouse
41468712 Bilateral frontal PVNH as ~10% of PVNH; milder sequelae Human clinical
30683929 Genetic heterogeneity/CNVs in PVNH Human genetics

Limitations and Knowledge Gaps

  • Small evidence base: PVNH9 is defined by a handful of families and cohort variants; precise prevalence, penetrance quantification, sex ratio, and natural-history data are unavailable.
  • Mechanism of the allelic dichotomy (LoF→PVNH vs missense→deafness) is not fully resolved — whether missense alleles are hypomorphic, dominant-negative or gain-of-function in the cochlea remains to be tested directly.
  • Model mismatch: no mouse model reproduces human heterozygous-LoF cortical heterotopia (homozygotes are perinatally lethal; heterozygotes model deafness). Human organoids are the most promising but early-stage system.
  • No genotype–phenotype granularity linking specific LoF variant position to severity of epilepsy or cognition; modifier genes (MAP2, tau, EB1) are hypothesized but not clinically validated.
  • No omics profiling (transcriptomic/proteomic/metabolomic/epigenomic) specific to PVNH9 patient tissue; no biomarkers.
  • Treatment evidence is generic (focal-epilepsy management); no PVNH9-specific therapeutic trials.

Proposed Follow-up Experiments / Actions

  1. Establish an international PVNH9 registry to quantify penetrance, expressivity, sex ratio, epilepsy trajectory and cognitive outcomes.
  2. Isogenic human cortical organoids/assembloids carrying patient LoF versus missense variants (with CRISPR-corrected controls) to directly test migration failure, quantify dosage thresholds, and dissect the allelic dichotomy.
  3. Conditional / heterozygous cortical Map1b models (or humanized alleles) to bypass homozygous lethality and reproduce the heterotopia phenotype in vivo.
  4. Functional characterization of missense alleles in cochlear versus cortical neuronal contexts to determine hypomorphic vs dominant-negative behaviour.
  5. Modifier screens for MAP2/tau/EB1 dosage effects on migration rescue, to explain variable expressivity and identify candidate therapeutic targets.
  6. Standardized deep phenotyping (MRI subtyping, EEG, neuropsychology, QoL instruments) to build prognostic models and refine surgical (MRgLITT) candidate selection.

Evidence source key: human clinical = patient case series/cohorts; human genetics = statistical/variant studies; model organism = mouse/Drosophila; in vitro = cultured neurons/iPSC/organoids; computational = in silico. This report was compiled from 41 reviewed publications and 8 confirmed findings.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 17
Quoted claims found in source 17
Quoted claims not found in source 0
References weighed for topical relevance 25
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 28
Resolved 27
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 10
Terms named correctly 2
Terms named as a different term 8

Terms the report names something else

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

  • HP:0001263 (1 mention) - the report calls it "Clinical sign"; HP calls it Global developmental delay
  • HP:0001249 (1 mention) - the report calls it "Clinical sign"; HP calls it Intellectual disability
  • HP:0002126 (1 mention) - the report calls it "Imaging/structural"; HP calls it Polymicrogyria
  • HP:0000252 (1 mention) - the report calls it "Physical"; HP calls it Microcephaly
  • HP:0004322 (1 mention) - the report calls it "Physical"; HP calls it Short stature
  • HP:0001999 (1 mention) - the report calls it "Physical"; HP calls it Abnormal facial shape
  • HP:0000407 (1 mention) - the report calls it "Clinical sign"; HP calls it Sensorineural hearing impairment
  • GO:0005874 (1 mention) - the report calls it "microtubules", "Subcellular level: cytoskeleton — microtubules"; GO calls it microtubule

Terms named inconsistently

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

  • GO:0005874 - called "microtubules", "Subcellular level: cytoskeleton — microtubules"