👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:10973257 SUPPORT Human Clinical

"An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN)."

The founding RELN report identifies the Reelin-pathway lissencephaly phenotype as autosomal recessive.

◆

Subtypes

2

RELN-related lissencephaly with cerebellar hypoplasia

Biallelic loss-of-function RELN variants reduce or eliminate the secreted Reelin ligand produced by Cajal-Retzius cells, producing the more severe end of the spectrum: lissencephaly/pachygyria with severe cerebellar hypoplasia, hippocampal malformation, and brainstem (pontine) hypoplasia. Corresponds historically to lissencephaly with cerebellar hypoplasia type B (LCHB).

VLDLR-associated cerebellar hypoplasia with gyral simplification

Homozygous VLDLR loss (classically a 199-kb deletion in the Hutterite "cerebellar hypoplasia and dysequilibrium" / CAMRQ1 syndrome) removes one of the Reelin receptors, producing a generally milder phenotype: nonprogressive cerebellar ataxia and intellectual disability with inferior cerebellar hypoplasia and mild cerebral gyral simplification rather than frank lissencephaly.

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Discussions and Knowledge Gaps

1

Does the reeler (Reln-null) mouse — the principal animal model of Reelin-pathway disruption — faithfully recapitulate the human RELN/VLDLR lissencephaly-with-cerebellar-hypoplasia (LCH) phenotype, or does the fact that the mouse is a natively lissencephalic (agyric) species, lacking the expanded outer subventricular zone (OSVZ) and outer radial glia (oRG) that drive gyrencephalic cortical expansion in humans, mean that the model captures the inside-out lamination and cerebellar defects but cannot reproduce the human gyral-simplification/pachygyria component of the malformation?

HUMAN MODEL MISMATCH OPEN gap_reelin_reeler_mouse_gyrencephaly_mismatch

Attached to

pathophysiology#Cajal-Retzius Reelin Ligand Deficiency pathophysiology#Cortical Lamination and Gyral Simplification

The reeler mouse establishes the molecular logic of this entry: loss of Reelin causes inverted (outside-in) cortical lamination, cerebellar hypoplasia, and abnormal axonal connectivity, paralleling the human LCH syndrome that defines RELN-related disease. However, the human RELN/VLDLR phenotype additionally includes lissencephaly with markedly simplified gyration (pachygyria), a feature that a baseline-agyric rodent cortex cannot phenocopy because mouse cortical development lacks the human-enriched OSVZ/oRG amplification tier responsible for gyrencephalic surface expansion. Mouse data therefore robustly validate the Reelin-DAB1 signaling lesion and the lamination/terminal-translocation defect, but they systematically underdetermine the severity and gyral pattern of the human cortical malformation. Resolving whether the human gyral-simplification arm is a distinct, human-specific consequence of Reelin loss (versus a quantitative extension of the same lamination defect) is mechanistically meaningful for interpreting model-derived evidence and for module conformance.

Proposed experiments

RELN- or VLDLR-null human cortical organoid lamination and oRG analysis

iPSC organoid perturbation assay

exp_reelin_human_cortical_organoid

Generate isogenic RELN-null or VLDLR-null human iPSC-derived cortical organoids and quantify radial-glia/oRG composition, terminal somal translocation, and inside-out laminar positioning relative to controls, testing whether human-specific outer radial glia behave differently from the apical-progenitor-dominated reeler mouse cortex and whether gyrencephalic surface-area phenotypes emerge only in the human model.

Model systems

Human iPSC-derived cortical organoid

Cortical organoid differentiated from gene-edited human iPSCs, preserving human-specific outer radial glia and OSVZ biology absent from the mouse.

ORGANOID

Reelin-pathway perturbation in a gyrencephalic ferret cortex

in vivo gyrencephalic model study

exp_reelin_gyrencephalic_ferret

Disrupt Reelin signaling (RELN or VLDLR) in the developing ferret cortex, a gyrencephalic carnivore model possessing an OSVZ with oRG-like cells, to test whether Reelin loss produces gyral simplification closer to the human LCH phenotype than is seen in the lissencephalic reeler mouse.

Model systems

Gyrencephalic ferret cortex

Ferret (Mustela putorius furo) developing cortex, containing a prominent OSVZ with oRG-like progenitors, used as a bridge between the lissencephalic mouse and the gyrencephalic human cortex.

OTHER

Show evidence (2 references)

PMID:10973257 SUPPORT Model Organism

"LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity."

Establishes the reeler mouse as the parallel model for human RELN disease, recapitulating cerebellar hypoplasia and disordered cortical migration — the shared arm of the mismatch — while leaving the human gyral phenotype as the divergent feature.

PMID:28951247 SUPPORT Other

"We finish by describing the advantages of human in vitro cell culture models, to examine human-specific cells and transcripts"

The Romero et al. review highlights human in vitro models as the route to examine human-specific cortical cells and transcripts that animal models do not reproduce, motivating the proposed organoid resolution of this gap.

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Pathophysiology

5

Cajal-Retzius Reelin Ligand Deficiency

Pathogenic biallelic RELN variants reduce or abolish the secreted Reelin cue normally produced by Cajal-Retzius cells in the developing cortical marginal zone. Loss of this ligand deprives postmitotic neurons of the extracellular positioning signal required for terminal somal translocation and inside-out lamination, the proximal trigger of the RELN subtype branch.

Cajal-Retzius cell CL:0000695

RELN hgnc:9957

reelin-mediated signaling pathway GO:0038026 ↓ DECREASED

cerebral cortex marginal layer UBERON:0014935

Downstream

VLDLR-ApoER2-DAB1 Signal Transduction Failure

Show evidence (2 references)

PMID:10973257 SUPPORT Human Clinical

"An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN)."

Human genetics links biallelic RELN mutation to the cortical, hippocampal, cerebellar, and brainstem malformation pattern, establishing the RELN ligand lesion as the proximal trigger.

PMID:10973257 SUPPORT Human Clinical

"The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein."

Confirms that the disease mechanism is a deficiency of the secreted Reelin ligand, not merely an altered protein.

VLDLR-ApoER2-DAB1 Signal Transduction Failure

Reelin normally binds VLDLR and ApoER2/LRP8 on migrating neurons, activating DAB1 through Src-family kinase signaling. In Reelin-pathway lissencephaly the signal is lost either upstream (RELN ligand deficiency) or at the receptor itself: in the VLDLR subtype a homozygous VLDLR deletion removes the receptor, uncoupling the extracellular Reelin cue from neuron-intrinsic migration and lamination effectors.

migrating cerebral cortex neuron CL:0010012

RELN hgnc:9957 VLDLR hgnc:12698 LRP8 hgnc:6700 DAB1 hgnc:2661

reelin-mediated signaling pathway GO:0038026 ↓ DECREASED

Downstream

Terminal Somal Translocation Failure

Hippocampal and Cerebellar Organization Defect

Show evidence (2 references)

PMID:16080122 SUPPORT Human Clinical

"A 199-kb homozygous deletion encompassing the entire very low density lipoprotein receptor (VLDLR) gene was present in all affected individuals."

Human VLDLR deletion supports receptor loss as the upstream Reelin-pathway lesion in the VLDLR subtype branch.

PMID:16080122 SUPPORT Human Clinical

"VLDLR is part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum."

Places VLDLR within Reelin-guided migration of the cortex and cerebellum, the central effector of this entry.

Terminal Somal Translocation Failure

With Reelin signaling lost, developing cortical neurons fail to complete the glia-independent terminal somal translocation step, retracting or destabilizing leading processes after contact with the marginal zone. This is the central cellular mechanism distinguishing Reelin-pathway lissencephaly from earlier locomotion or microtubule-based migration arrest.

migrating cerebral cortex neuron CL:0010012

neuron migration GO:0001764 ↓ DECREASED

cerebral cortex marginal layer UBERON:0014935

Downstream

Cortical Lamination and Gyral Simplification

Show evidence (2 references)

PMID:21315259 SUPPORT Model Organism

"Dab1, an essential component of the reelin pathway, is required in radially migrating neurons for glia-independent somal translocation, but not for glia-guided locomotion."

Directly separates Reelin/Dab1-dependent terminal somal translocation from glia-guided locomotion, defining the cellular lesion of this entry.

PMID:21315259 SUPPORT Model Organism

"Furthermore, cell-autonomous neuronal deficits in somal translocation are sufficient to cause severe neocortical lamination defects."

Shows the translocation defect is sufficient to drive the lamination endpoint, linking this node to its downstream consequence.

Cortical Lamination and Gyral Simplification

Failed terminal translocation produces disrupted inside-out lamination with the imaging endpoint that defines the subtypes: moderate lissencephaly/pachygyria in RELN-related disease, and milder simplification or thickening of cortical gyration in VLDLR-related disease.

layer formation in cerebral cortex GO:0021819 ↓ DECREASED cerebral cortex development GO:0021987 ↕ DYSREGULATED

cerebral cortex UBERON:0000956

Downstream

Lissencephaly Severe Reelin-pathway cortical lamination failure produces the RELN-related lissencephaly endpoint.

Cerebral gyral simplification Milder receptor-branch lamination disruption produces simplified or thickened cortical gyration.

Intellectual disability Cortical and cerebellar developmental malformations impair neurodevelopmental function, producing intellectual disability.

Show evidence (2 references)

PMID:27000652 SUPPORT Human Clinical

"Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation."

Human RELN-associated disease includes a lissencephaly cortical endpoint.

PMID:27000652 SUPPORT Human Clinical

"These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations."

Human VLDLR-associated disease shows the milder simplified/thickened gyration endpoint of the receptor-branch.

Hippocampal and Cerebellar Organization Defect

Reelin-pathway disruption affects laminated structures beyond neocortex, especially the hippocampal formation, cerebellum, and brainstem. Human RELN and VLDLR disease both show cerebellar hypoplasia, with hippocampal and pontine involvement most pronounced in the RELN branch.

hippocampus development GO:0021766 ↕ DYSREGULATED cerebellum development GO:0021549 ↕ DYSREGULATED

hippocampal formation UBERON:0002421 cerebellum UBERON:0002037

Downstream

Abnormal hippocampus morphology Reelin-pathway disruption of hippocampal organization produces hippocampal malformation in the RELN branch.

Cerebellar hypoplasia Disrupted Reelin signaling in cerebellar development produces profound cerebellar hypoplasia.

Hypoplasia of the pons Brainstem involvement in the same organization-defect branch produces pontine flattening or hypoplasia.

Nonprogressive cerebellar ataxia Cerebellar hypoplasia in the VLDLR branch produces a nonprogressive cerebellar ataxia phenotype.

Show evidence (2 references)

PMID:10973257 SUPPORT Human Clinical

"LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity."

Links human RELN disease with the reeler mouse phenotype and the cerebellar hypoplasia/cortical migration branch.

PMID:27000652 SUPPORT Human Clinical

"All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities."

Human cohort evidence supports combined cerebellar, pontine, and neocortical involvement in Reelin-pathway disorders.

⬡

Pathograph

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

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Phenotypes

7

Nervous System 3

Nonprogressive cerebellar ataxia Ataxia HP:0001251

Course: STABLE

Show evidence (1 reference)

PMID:16080122 SUPPORT Human Clinical

"An autosomal recessive syndrome of nonprogressive cerebellar ataxia and mental retardation is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population."

Establishes nonprogressive cerebellar ataxia as a defining clinical feature of the VLDLR-related subtype.

Cerebellar hypoplasia Cerebellar hypoplasia HP:0001321

Show evidence (1 reference)

PMID:27000652 SUPPORT Human Clinical

"All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities."

Cerebellar hypoplasia is the hallmark imaging feature across the Reelin pathway spectrum.

Intellectual disability Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:27000652 SUPPORT Human Clinical

"Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation."

Intellectual disability is a consistent neurodevelopmental outcome across the Reelin pathway spectrum.

Other 4

Lissencephaly Lissencephaly HP:0001339

Show evidence (1 reference)

PMID:27000652 SUPPORT Human Clinical

"Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation."

Documents lissencephaly in a genetically confirmed RELN patient.

Cerebral gyral simplification Pachygyria HP:0001302

Show evidence (1 reference)

PMID:16080122 SUPPORT Human Clinical

"An autosomal recessive syndrome of nonprogressive cerebellar ataxia and mental retardation is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population."

Documents the milder cerebral gyral simplification of the VLDLR subtype.

Hypoplasia of the pons Hypoplasia of the pons HP:0012110

Show evidence (1 reference)

PMID:27000652 SUPPORT Human Clinical

"All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities."

Flattened/hypoplastic pons accompanies the cerebellar phenotype in the Reelin pathway disorders.

Abnormal hippocampus morphology Abnormal hippocampus morphology HP:0025100

Show evidence (1 reference)

PMID:10973257 SUPPORT Human Clinical

"An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN)."

Hippocampal abnormality is part of the RELN-related malformation pattern.

💊

Medical Actions

4

Antiseizure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: anticonvulsant agent NCIT:C264

Symptomatic management of epilepsy/seizures with anticonvulsant agents. There is no disease-modifying therapy for the underlying cortical malformation; antiseizure medication targets the downstream epileptogenic consequence.

Physical and Developmental Therapy

Action: physical therapy MAXO:0000011

Physiotherapy, occupational therapy, and developmental support for hypotonia, motor delay, and ataxia, which are prominent particularly in VLDLR-related disease.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling for the autosomal recessive inheritance of RELN and VLDLR disease, including recurrence-risk and carrier-testing discussion for at-risk families.

Supportive and Multidisciplinary Care

Action: supportive care MAXO:0000950

Coordinated supportive care for the multisystem neurodevelopmental burden (feeding, respiratory, orthopedic, and rehabilitative needs).

{ }

Source YAML

click to show

name: Reelin Pathway Lissencephaly
creation_date: "2026-06-11T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Reelin-pathway lissencephaly with cerebellar hypoplasia
  term:
    id: MONDO:0019450
    label: lissencephaly with cerebellar hypoplasia
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:10973257
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An autosomal recessive form of lissencephaly (LCH) associated with severe
      abnormalities of the cerebellum, hippocampus and brainstem maps to
      chromosome 7q22, and is associated with two independent mutations in the
      human gene encoding reelin (RELN).
    explanation: >-
      The founding RELN report identifies the Reelin-pathway lissencephaly
      phenotype as autosomal recessive.
parents:
- Lissencephaly Spectrum Disorders
synonyms:
- Lissencephaly with cerebellar hypoplasia (LCH)
- RELN-related lissencephaly
- VLDLR-associated cerebellar hypoplasia with gyral simplification
- Reelin signaling pathway cortical malformation
description: >-
  Reelin-pathway lissencephaly is an autosomal recessive malformation of cortical
  development whose coherent pathomechanism skeleton is failure of extracellular
  Reelin signaling rather than the microtubule/dynein-based neuronal-migration arrest
  of classical lissencephaly. Reelin is a large glycoprotein secreted by Cajal-Retzius
  cells in the cortical marginal zone; it binds the lipoprotein receptors VLDLR and
  ApoER2/LRP8 on migrating postmitotic neurons, activating the intracellular adaptor
  DAB1 and downstream adhesion/cytoskeletal effectors that drive glia-independent
  terminal somal translocation and inside-out cortical lamination. Biallelic loss of
  the ligand (RELN) or the receptor (VLDLR) collapses this signal, producing a
  cortex with simplified/thickened gyration together with the hallmark cerebellar
  hypoplasia, and—because the same pathway organizes the hippocampus, cerebellum, and
  brainstem—recurring hippocampal disorganization and pontine/brainstem hypoplasia.
  The two principal human lesions define the disease's subtype branches: RELN
  mutations (Hong et al. 2000) cause a more severe lissencephaly-with-cerebellar-
  hypoplasia phenotype with hippocampal and brainstem involvement, whereas VLDLR
  deletion (Boycott et al. 2005; the "dysequilibrium syndrome"/CAMRQ1 spectrum)
  causes nonprogressive cerebellar ataxia with milder cerebral gyral simplification.
  This is the exemplar Reelin-signaling cortical malformation and conforms to the
  reelin terminal-translocation lamination-failure module rather than to the
  tubulinopathy or generic migration-arrest modules.
has_subtypes:
- name: RELN-related
  display_name: RELN-related lissencephaly with cerebellar hypoplasia
  description: >-
    Biallelic loss-of-function RELN variants reduce or eliminate the secreted Reelin
    ligand produced by Cajal-Retzius cells, producing the more severe end of the
    spectrum: lissencephaly/pachygyria with severe cerebellar hypoplasia, hippocampal
    malformation, and brainstem (pontine) hypoplasia. Corresponds historically to
    lissencephaly with cerebellar hypoplasia type B (LCHB).
- name: VLDLR-related
  display_name: VLDLR-associated cerebellar hypoplasia with gyral simplification
  description: >-
    Homozygous VLDLR loss (classically a 199-kb deletion in the Hutterite "cerebellar
    hypoplasia and dysequilibrium" / CAMRQ1 syndrome) removes one of the Reelin
    receptors, producing a generally milder phenotype: nonprogressive cerebellar
    ataxia and intellectual disability with inferior cerebellar hypoplasia and mild
    cerebral gyral simplification rather than frank lissencephaly.
pathophysiology:
- name: Cajal-Retzius Reelin Ligand Deficiency
  conforms_to: "reelin_terminal_translocation_lamination_failure#Cajal-Retzius Reelin Ligand Deficiency"
  description: >-
    Pathogenic biallelic RELN variants reduce or abolish the secreted Reelin cue
    normally produced by Cajal-Retzius cells in the developing cortical marginal zone.
    Loss of this ligand deprives postmitotic neurons of the extracellular positioning
    signal required for terminal somal translocation and inside-out lamination, the
    proximal trigger of the RELN subtype branch.
  role: trigger
  genes:
  - preferred_term: RELN
    term:
      id: hgnc:9957
      label: RELN
  locations:
  - preferred_term: cerebral cortex marginal layer
    term:
      id: UBERON:0014935
      label: cerebral cortex marginal layer
  cell_types:
  - preferred_term: Cajal-Retzius cell
    term:
      id: CL:0000695
      label: Cajal-Retzius cell
  biological_processes:
  - preferred_term: reelin-mediated signaling pathway
    term:
      id: GO:0038026
      label: reelin-mediated signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:10973257
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An autosomal recessive form of lissencephaly (LCH) associated with severe
      abnormalities of the cerebellum, hippocampus and brainstem maps to
      chromosome 7q22, and is associated with two independent mutations in the
      human gene encoding reelin (RELN).
    explanation: >-
      Human genetics links biallelic RELN mutation to the cortical, hippocampal,
      cerebellar, and brainstem malformation pattern, establishing the RELN ligand
      lesion as the proximal trigger.
  - reference: PMID:10973257
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutations disrupt splicing of RELN cDNA, resulting in low or
      undetectable amounts of reelin protein.
    explanation: >-
      Confirms that the disease mechanism is a deficiency of the secreted Reelin
      ligand, not merely an altered protein.
  downstream:
  - target: VLDLR-ApoER2-DAB1 Signal Transduction Failure
- name: VLDLR-ApoER2-DAB1 Signal Transduction Failure
  conforms_to: "reelin_terminal_translocation_lamination_failure#VLDLR-ApoER2-DAB1 Signal Transduction Failure"
  description: >-
    Reelin normally binds VLDLR and ApoER2/LRP8 on migrating neurons, activating DAB1
    through Src-family kinase signaling. In Reelin-pathway lissencephaly the signal is
    lost either upstream (RELN ligand deficiency) or at the receptor itself: in the
    VLDLR subtype a homozygous VLDLR deletion removes the receptor, uncoupling the
    extracellular Reelin cue from neuron-intrinsic migration and lamination effectors.
  role: central_effector
  genes:
  - preferred_term: RELN
    term:
      id: hgnc:9957
      label: RELN
  - preferred_term: VLDLR
    term:
      id: hgnc:12698
      label: VLDLR
  - preferred_term: LRP8
    term:
      id: hgnc:6700
      label: LRP8
  - preferred_term: DAB1
    term:
      id: hgnc:2661
      label: DAB1
  cell_types:
  - preferred_term: migrating cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: reelin-mediated signaling pathway
    term:
      id: GO:0038026
      label: reelin-mediated signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:16080122
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 199-kb homozygous deletion encompassing the entire very low density
      lipoprotein receptor (VLDLR) gene was present in all affected individuals.
    explanation: >-
      Human VLDLR deletion supports receptor loss as the upstream Reelin-pathway
      lesion in the VLDLR subtype branch.
  - reference: PMID:16080122
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VLDLR is part of the reelin signaling pathway, which guides neuroblast
      migration in the cerebral cortex and cerebellum.
    explanation: >-
      Places VLDLR within Reelin-guided migration of the cortex and cerebellum,
      the central effector of this entry.
  downstream:
  - target: Terminal Somal Translocation Failure
  - target: Hippocampal and Cerebellar Organization Defect
- name: Terminal Somal Translocation Failure
  conforms_to: "reelin_terminal_translocation_lamination_failure#Terminal Somal Translocation Failure"
  description: >-
    With Reelin signaling lost, developing cortical neurons fail to complete the
    glia-independent terminal somal translocation step, retracting or destabilizing
    leading processes after contact with the marginal zone. This is the central
    cellular mechanism distinguishing Reelin-pathway lissencephaly from earlier
    locomotion or microtubule-based migration arrest.
  role: central_effector
  locations:
  - preferred_term: cerebral cortex marginal layer
    term:
      id: UBERON:0014935
      label: cerebral cortex marginal layer
  cell_types:
  - preferred_term: migrating cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  evidence:
  - reference: PMID:21315259
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Dab1, an essential component of the reelin pathway, is required in
      radially migrating neurons for glia-independent somal translocation, but
      not for glia-guided locomotion.
    explanation: >-
      Directly separates Reelin/Dab1-dependent terminal somal translocation from
      glia-guided locomotion, defining the cellular lesion of this entry.
  - reference: PMID:21315259
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, cell-autonomous neuronal deficits in somal translocation are
      sufficient to cause severe neocortical lamination defects.
    explanation: >-
      Shows the translocation defect is sufficient to drive the lamination
      endpoint, linking this node to its downstream consequence.
  downstream:
  - target: Cortical Lamination and Gyral Simplification
- name: Cortical Lamination and Gyral Simplification
  conforms_to: "reelin_terminal_translocation_lamination_failure#Cortical Lamination and Gyral Simplification"
  description: >-
    Failed terminal translocation produces disrupted inside-out lamination with the
    imaging endpoint that defines the subtypes: moderate lissencephaly/pachygyria in
    RELN-related disease, and milder simplification or thickening of cortical gyration
    in VLDLR-related disease.
  role: consequence
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  biological_processes:
  - preferred_term: layer formation in cerebral cortex
    term:
      id: GO:0021819
      label: layer formation in cerebral cortex
    modifier: DECREASED
  - preferred_term: cerebral cortex development
    term:
      id: GO:0021987
      label: cerebral cortex development
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:27000652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 had profound motor and intellectual disability with moderate
      lissencephaly suggestive of RELN mutations and was shown to harbor a
      splicing homozygous RELN mutation.
    explanation: >-
      Human RELN-associated disease includes a lissencephaly cortical endpoint.
  - reference: PMID:27000652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients showed mild simplification or thickening of cortical
      gyration and had VLDLR mutations.
    explanation: >-
      Human VLDLR-associated disease shows the milder simplified/thickened gyration
      endpoint of the receptor-branch.
  downstream:
  - target: Lissencephaly
    causal_link_type: DIRECT
    description: >-
      Severe Reelin-pathway cortical lamination failure produces the RELN-related
      lissencephaly endpoint.
    evidence:
    - reference: PMID:27000652
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patient 1 had profound motor and intellectual disability with moderate
        lissencephaly suggestive of RELN mutations and was shown to harbor a
        splicing homozygous RELN mutation.
      explanation: >-
        Genetically confirmed RELN disease directly supports lissencephaly as
        the severe cortical endpoint.
  - target: Cerebral gyral simplification
    causal_link_type: DIRECT
    description: >-
      Milder receptor-branch lamination disruption produces simplified or
      thickened cortical gyration.
    evidence:
    - reference: PMID:27000652
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These patients showed mild simplification or thickening of cortical
        gyration and had VLDLR mutations.
      explanation: >-
        VLDLR-associated Reelin-pathway disease directly supports the simplified
        gyral endpoint.
  - target: Intellectual disability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cortical malformation
    - cerebellar malformation
    description: >-
      Cortical and cerebellar developmental malformations impair
      neurodevelopmental function, producing intellectual disability.
    evidence:
    - reference: PMID:27000652
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patient 1 had profound motor and intellectual disability with moderate
        lissencephaly suggestive of RELN mutations and was shown to harbor a
        splicing homozygous RELN mutation.
      explanation: >-
        This genetically confirmed RELN patient links the cortical malformation
        phenotype with intellectual disability.
- name: Hippocampal and Cerebellar Organization Defect
  conforms_to: "reelin_terminal_translocation_lamination_failure#Hippocampal and Cerebellar Organization Defect"
  description: >-
    Reelin-pathway disruption affects laminated structures beyond neocortex,
    especially the hippocampal formation, cerebellum, and brainstem. Human RELN and
    VLDLR disease both show cerebellar hypoplasia, with hippocampal and pontine
    involvement most pronounced in the RELN branch.
  role: consequence
  locations:
  - preferred_term: hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  biological_processes:
  - preferred_term: hippocampus development
    term:
      id: GO:0021766
      label: hippocampus development
    modifier: DYSREGULATED
  - preferred_term: cerebellum development
    term:
      id: GO:0021549
      label: cerebellum development
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:10973257
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations
      cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration
      and abnormal axonal connectivity.
    explanation: >-
      Links human RELN disease with the reeler mouse phenotype and the cerebellar
      hypoplasia/cortical migration branch.
  - reference: PMID:27000652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had profound cerebellar hypoplasia on MRI with peculiar
      cerebellar morphology, associated with flattened pons and neocortical
      abnormalities.
    explanation: >-
      Human cohort evidence supports combined cerebellar, pontine, and neocortical
      involvement in Reelin-pathway disorders.
  downstream:
  - target: Abnormal hippocampus morphology
    causal_link_type: DIRECT
    description: >-
      Reelin-pathway disruption of hippocampal organization produces
      hippocampal malformation in the RELN branch.
    evidence:
    - reference: PMID:10973257
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An autosomal recessive form of lissencephaly (LCH) associated with severe
        abnormalities of the cerebellum, hippocampus and brainstem maps to
        chromosome 7q22, and is associated with two independent mutations in the
        human gene encoding reelin (RELN).
      explanation: >-
        The founding RELN report includes hippocampal abnormality in the
        malformation pattern.
  - target: Cerebellar hypoplasia
    causal_link_type: DIRECT
    description: >-
      Disrupted Reelin signaling in cerebellar development produces profound
      cerebellar hypoplasia.
    evidence:
    - reference: PMID:27000652
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients had profound cerebellar hypoplasia on MRI with peculiar
        cerebellar morphology, associated with flattened pons and neocortical
        abnormalities.
      explanation: >-
        Human cohort evidence directly supports cerebellar hypoplasia across
        Reelin-pathway disorders.
  - target: Hypoplasia of the pons
    causal_link_type: DIRECT
    description: >-
      Brainstem involvement in the same organization-defect branch produces
      pontine flattening or hypoplasia.
    evidence:
    - reference: PMID:27000652
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients had profound cerebellar hypoplasia on MRI with peculiar
        cerebellar morphology, associated with flattened pons and neocortical
        abnormalities.
      explanation: >-
        The MRI cohort evidence links flattened pons with the cerebellar and
        neocortical Reelin-pathway phenotype.
  - target: Nonprogressive cerebellar ataxia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - inferior cerebellar hypoplasia
    description: >-
      Cerebellar hypoplasia in the VLDLR branch produces a nonprogressive
      cerebellar ataxia phenotype.
    evidence:
    - reference: PMID:16080122
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An autosomal recessive syndrome of nonprogressive cerebellar ataxia and
        mental retardation is associated with inferior cerebellar hypoplasia and
        mild cerebral gyral simplification in the Hutterite population.
      explanation: >-
        The VLDLR cohort directly connects nonprogressive cerebellar ataxia with
        inferior cerebellar hypoplasia.
phenotypes:
- name: Lissencephaly
  category: Neurologic
  subtype: RELN-related
  description: >-
    RELN-related disease can present with true lissencephaly or pachygyria,
    representing the more severe cortical-lamination end of the Reelin-pathway
    spectrum.
  phenotype_term:
    preferred_term: Lissencephaly
    term:
      id: HP:0001339
      label: Lissencephaly
  evidence:
  - reference: PMID:27000652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 had profound motor and intellectual disability with moderate
      lissencephaly suggestive of RELN mutations and was shown to harbor a
      splicing homozygous RELN mutation.
    explanation: >-
      Documents lissencephaly in a genetically confirmed RELN patient.
- name: Cerebral gyral simplification
  category: Neurologic
  subtype: VLDLR-related
  description: >-
    VLDLR-related disease more often shows simplified cortical gyration or
    pachygyria-like cortical thickening rather than the severe RELN-associated
    lissencephaly pattern.
  phenotype_term:
    preferred_term: Pachygyria / simplified gyral pattern
    term:
      id: HP:0001302
      label: Pachygyria
  evidence:
  - reference: PMID:16080122
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An autosomal recessive syndrome of nonprogressive cerebellar ataxia and
      mental retardation is associated with inferior cerebellar hypoplasia and
      mild cerebral gyral simplification in the Hutterite population.
    explanation: >-
      Documents the milder cerebral gyral simplification of the VLDLR subtype.
- name: Nonprogressive cerebellar ataxia
  category: Neurologic
  subtype: VLDLR-related
  description: >-
    VLDLR-related disease classically includes a nonprogressive cerebellar
    ataxia phenotype, consistent with the inferior cerebellar hypoplasia branch
    of the receptor-loss subtype.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
    clinical_course: STABLE
  evidence:
  - reference: PMID:16080122
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An autosomal recessive syndrome of nonprogressive cerebellar ataxia and
      mental retardation is associated with inferior cerebellar hypoplasia and
      mild cerebral gyral simplification in the Hutterite population.
    explanation: >-
      Establishes nonprogressive cerebellar ataxia as a defining clinical
      feature of the VLDLR-related subtype.
- name: Cerebellar hypoplasia
  category: Neurologic
  description: >-
    Cerebellar hypoplasia is a core shared neuroradiologic feature across the
    RELN and VLDLR branches of the Reelin-pathway disorder spectrum.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:27000652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had profound cerebellar hypoplasia on MRI with peculiar
      cerebellar morphology, associated with flattened pons and neocortical
      abnormalities.
    explanation: >-
      Cerebellar hypoplasia is the hallmark imaging feature across the Reelin
      pathway spectrum.
- name: Hypoplasia of the pons
  category: Neurologic
  description: >-
    Pontine flattening or hypoplasia accompanies the cerebellar phenotype in the
    human Reelin-pathway cohort evidence and should not be restricted to the
    RELN branch.
  phenotype_term:
    preferred_term: Hypoplasia of the pons
    term:
      id: HP:0012110
      label: Hypoplasia of the pons
  evidence:
  - reference: PMID:27000652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had profound cerebellar hypoplasia on MRI with peculiar
      cerebellar morphology, associated with flattened pons and neocortical
      abnormalities.
    explanation: >-
      Flattened/hypoplastic pons accompanies the cerebellar phenotype in the
      Reelin pathway disorders.
- name: Abnormal hippocampus morphology
  category: Neurologic
  subtype: RELN-related
  description: >-
    Hippocampal malformation is especially documented in RELN-related
    lissencephaly with cerebellar hypoplasia, consistent with Reelin's role in
    hippocampal lamination.
  phenotype_term:
    preferred_term: Hippocampal malformation
    term:
      id: HP:0025100
      label: Abnormal hippocampus morphology
  evidence:
  - reference: PMID:10973257
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An autosomal recessive form of lissencephaly (LCH) associated with severe
      abnormalities of the cerebellum, hippocampus and brainstem maps to
      chromosome 7q22, and is associated with two independent mutations in the
      human gene encoding reelin (RELN).
    explanation: >-
      Hippocampal abnormality is part of the RELN-related malformation pattern.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Intellectual disability is a major neurodevelopmental outcome in patients
    with Reelin-pathway cortical and cerebellar malformations.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:27000652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 had profound motor and intellectual disability with moderate
      lissencephaly suggestive of RELN mutations and was shown to harbor a
      splicing homozygous RELN mutation.
    explanation: >-
      Intellectual disability is a consistent neurodevelopmental outcome across
      the Reelin pathway spectrum.
treatments:
- name: Antiseizure Pharmacotherapy
  description: >-
    Symptomatic management of epilepsy/seizures with anticonvulsant agents. There is
    no disease-modifying therapy for the underlying cortical malformation; antiseizure
    medication targets the downstream epileptogenic consequence.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
- name: Physical and Developmental Therapy
  description: >-
    Physiotherapy, occupational therapy, and developmental support for hypotonia,
    motor delay, and ataxia, which are prominent particularly in VLDLR-related disease.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
- name: Genetic Counseling
  description: >-
    Counseling for the autosomal recessive inheritance of RELN and VLDLR disease,
    including recurrence-risk and carrier-testing discussion for at-risk families.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Supportive and Multidisciplinary Care
  description: >-
    Coordinated supportive care for the multisystem neurodevelopmental burden
    (feeding, respiratory, orthopedic, and rehabilitative needs).
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
notes: >-
  Entry boundary follows the cortical-malformation epic 4098 modeling stance:
  a dismech entry should correspond to a coherent shared pathomechanism skeleton,
  here extracellular Reelin signaling / terminal somal translocation failure, rather
  than MONDO/OMIM granularity. RELN and VLDLR are represented as subtype branches of
  the shared skeleton. The entry conforms to the
  reelin_terminal_translocation_lamination_failure module. Created from issue 4081,
  seeded by Romero, Bahi-Buisson & Francis (Semin Cell Dev Biol 2018) but curated
  against verified primary papers (Hong et al. 2000; Boycott et al. 2005; Valence et
  al. 2016; Franco et al. 2011). DAB1/LRP8 mechanistic detail and additional clinical
  features (neonatal seizures, generalized hypotonia, ataxia) are candidates for
  future enrichment with directly quotable primary evidence. PubMed GeneReviews
  searches for Reelin Pathway Lissencephaly and lissencephaly with cerebellar
  hypoplasia found no GeneReviews baseline article.
discussions:
- discussion_id: gap_reelin_reeler_mouse_gyrencephaly_mismatch
  prompt: >-
    Does the reeler (Reln-null) mouse — the principal animal model of
    Reelin-pathway disruption — faithfully recapitulate the human RELN/VLDLR
    lissencephaly-with-cerebellar-hypoplasia (LCH) phenotype, or does the fact
    that the mouse is a natively lissencephalic (agyric) species, lacking the
    expanded outer subventricular zone (OSVZ) and outer radial glia (oRG) that
    drive gyrencephalic cortical expansion in humans, mean that the model
    captures the inside-out lamination and cerebellar defects but cannot
    reproduce the human gyral-simplification/pachygyria component of the
    malformation?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Cajal-Retzius Reelin Ligand Deficiency
  - pathophysiology#Cortical Lamination and Gyral Simplification
  rationale: >-
    The reeler mouse establishes the molecular logic of this entry: loss of
    Reelin causes inverted (outside-in) cortical lamination, cerebellar
    hypoplasia, and abnormal axonal connectivity, paralleling the human LCH
    syndrome that defines RELN-related disease. However, the human RELN/VLDLR
    phenotype additionally includes lissencephaly with markedly simplified gyration
    (pachygyria), a feature that a baseline-agyric rodent cortex cannot
    phenocopy because mouse cortical development lacks the human-enriched
    OSVZ/oRG amplification tier responsible for gyrencephalic surface expansion.
    Mouse data therefore robustly validate the Reelin-DAB1 signaling lesion and
    the lamination/terminal-translocation defect, but they systematically
    underdetermine the severity and gyral pattern of the human cortical
    malformation. Resolving whether the human gyral-simplification arm is a
    distinct, human-specific consequence of Reelin loss (versus a quantitative
    extension of the same lamination defect) is mechanistically meaningful for
    interpreting model-derived evidence and for module conformance.
  proposed_experiments:
  - experiment_id: exp_reelin_human_cortical_organoid
    name: RELN- or VLDLR-null human cortical organoid lamination and oRG analysis
    description: >-
      Generate isogenic RELN-null or VLDLR-null human iPSC-derived cortical
      organoids and quantify radial-glia/oRG composition, terminal somal
      translocation, and inside-out laminar positioning relative to controls,
      testing whether human-specific outer radial glia behave differently from
      the apical-progenitor-dominated reeler mouse cortex and whether
      gyrencephalic surface-area phenotypes emerge only in the human model.
    experiment_type:
      preferred_term: iPSC organoid perturbation assay
    model_systems:
    - name: Human iPSC-derived cortical organoid
      description: >-
        Cortical organoid differentiated from gene-edited human iPSCs, preserving
        human-specific outer radial glia and OSVZ biology absent from the mouse.
      experimental_model_type: ORGANOID
  - experiment_id: exp_reelin_gyrencephalic_ferret
    name: Reelin-pathway perturbation in a gyrencephalic ferret cortex
    description: >-
      Disrupt Reelin signaling (RELN or VLDLR) in the developing ferret cortex,
      a gyrencephalic carnivore model possessing an OSVZ with oRG-like cells, to
      test whether Reelin loss produces gyral simplification closer to the human
      LCH phenotype than is seen in the lissencephalic reeler mouse.
    experiment_type:
      preferred_term: in vivo gyrencephalic model study
    model_systems:
    - name: Gyrencephalic ferret cortex
      description: >-
        Ferret (Mustela putorius furo) developing cortex, containing a prominent
        OSVZ with oRG-like progenitors, used as a bridge between the
        lissencephalic mouse and the gyrencephalic human cortex.
      experimental_model_type: OTHER
  evidence:
  - reference: PMID:10973257
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations
      cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration
      and abnormal axonal connectivity.
    explanation: >-
      Establishes the reeler mouse as the parallel model for human RELN disease,
      recapitulating cerebellar hypoplasia and disordered cortical migration —
      the shared arm of the mismatch — while leaving the human gyral phenotype as
      the divergent feature.
  - reference: PMID:28951247
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We finish by describing the advantages of human in vitro cell culture
      models, to examine human-specific cells and transcripts
    explanation: >-
      The Romero et al. review highlights human in vitro models as the route to
      examine human-specific cortical cells and transcripts that animal models do
      not reproduce, motivating the proposed organoid resolution of this gap.

📚

References & Deep Research

Deep Research

1

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Reelin Pathway Lissencephaly (Reelin-pathway LIS/LCH): Comprehensive Research Report

Edison Scientific Literature 36 citations 2026-06-11T19:25:14.177347

Reelin Pathway Lissencephaly (Reelin-pathway LIS/LCH): Comprehensive Research Report

Executive summary

“Reelin pathway lissencephaly” is best captured clinically as lissencephaly with cerebellar hypoplasia (LCH) / lissencephaly 2 (LIS2; Norman–Roberts syndrome) caused primarily by biallelic loss-of-function variants in RELN, with overlapping/related phenotypes caused by biallelic DAB1 variants (RELN-like mild lissencephaly with cerebellar hypoplasia) and biallelic VLDLR variants (cerebellar hypoplasia with gyral simplification). The core mechanism is disruption of the canonical Reelin→VLDLR/ApoER2→DAB1 phosphorylation pathway required for neuronal migration and cortical/cerebellar lamination. Recent (2024) work demonstrates that de novo monoallelic RELN missense variants can cause dominant neuronal migration disorders via a dominant-negative mechanism, broadening inheritance models beyond classic autosomal recessive disease. (hong2000autosomalrecessivelissencephaly pages 1-2, smits2021biallelicdab1variants pages 4-5, donato2022monoallelicandbiallelic pages 1-3, riva2024denovomonoallelic pages 17-17)

Concept	Evidence-supported details	Key citations (pqac ids)	URL/publication year where available
Core disease label	Reelin-pathway lissencephaly is most directly represented in the evidence as lissencephaly with cerebellar hypoplasia (LCH), a cortical malformation/neurodevelopmental disorder with simplified or smooth gyri plus cerebellar hypoplasia.	(hong2000autosomalrecessivelissencephaly pages 1-2, lossi2019thereelermouse pages 3-6, chang2007theroleof pages 5-6)	Hong et al., Nature Genetics (2000): https://doi.org/10.1038/79246; Lossi et al., J Clin Med (2019): https://doi.org/10.3390/jcm8122088
Alternative disease labels / synonyms	The evidence explicitly states “Lissencephaly 2 (LIS2)” and that LIS2 is also referred to as “lissencephaly syndrome, Norman–Roberts type or Norman–Roberts syndrome.”	(lossi2019thereelermouse pages 3-6)	Lossi et al., J Clin Med (2019): https://doi.org/10.3390/jcm8122088
OMIM identifier explicitly present	OMIM #257320 is explicitly attached in the evidence to Lissencephaly 2 (LIS2) / Norman–Roberts syndrome.	(lossi2019thereelermouse pages 3-6)	Lossi et al., J Clin Med (2019): https://doi.org/10.3390/jcm8122088
Primary causal gene: RELN	Strongest disease-defining gene in the evidence. Autosomal recessive RELN mutations were linked to LCH/LIS2; 2022 evidence further shows biallelic RELN variants cause severe LIS-CBLH, while monoallelic RELN variants can produce milder/intermediate neuronal migration disorders.	(hong2000autosomalrecessivelissencephaly pages 1-2, donato2022monoallelicandbiallelic pages 4-5, donato2022monoallelicandbiallelic pages 1-3, riva2024denovomonoallelic pages 17-17)	Hong et al. (2000): https://doi.org/10.1038/79246; Di Donato et al. (2022): https://doi.org/10.1093/brain/awac164; Riva et al. (2024): https://doi.org/10.1172/jci153097
Reelin-pathway gene: DAB1	Biallelic DAB1 splice variants were reported to cause mild lissencephaly and cerebellar hypoplasia with a RELN-like phenotype, supporting inclusion of DAB1-related disease within the Reelin-pathway lissencephaly spectrum.	(smits2021biallelicdab1variants pages 4-5)	Smits et al., Neurology Genetics (2021): https://doi.org/10.1212/nxg.0000000000000558
Reelin-pathway gene: VLDLR	Biallelic VLDLR loss-of-function variants cause a related recessive Reelin-pathway disorder characterized by cerebellar hypoplasia with cerebral gyral simplification; evidence supports overlap with the broader Reelin-pathway lissencephaly/cerebellar hypoplasia spectrum, although some literature distinguishes VLDLR cerebellar hypoplasia from classic RELN-LIS2.	(ozcelik2008mutationsinthe pages 1-3, holling2024ahomozygousnonsense pages 1-2, donato2018analysisof17 pages 2-4)	Ozcelik et al., PNAS (2008): https://doi.org/10.1073/pnas.0710010105; Holling et al. (2024): https://doi.org/10.1038/s10038-024-01279-w; Di Donato et al. (2018): https://doi.org/10.1038/gim.2018.8
Inheritance pattern	RELN-LIS2/LCH: autosomal recessive in classic disease. DAB1-related RELN-like lissencephaly: recessive in the reported case. VLDLR-related cerebellar hypoplasia/gyral simplification: recessive. Newer evidence shows monoallelic/dominant RELN variants can also cause neuronal migration disorders, but the classic Norman–Roberts/LIS2 phenotype remains recessive.	(hong2000autosomalrecessivelissencephaly pages 1-2, smits2021biallelicdab1variants pages 4-5, donato2022monoallelicandbiallelic pages 4-5, lossi2019thereelermouse pages 3-6, ozcelik2008mutationsinthe pages 1-3, riva2024denovomonoallelic pages 17-17)	Hong et al. (2000): https://doi.org/10.1038/79246; Smits et al. (2021): https://doi.org/10.1212/nxg.0000000000000558; Di Donato et al. (2022): https://doi.org/10.1093/brain/awac164; Riva et al. (2024): https://doi.org/10.1172/jci153097
Hallmark MRI / neuroimaging findings	Across the evidence, hallmark imaging includes moderate lissencephaly/pachygyria, thick cerebral cortex (~5–10 mm), simplified gyral pattern (often frontotemporal/temporal-predominant in RELN-related cases), profound/very hypoplastic cerebellum with reduced or absent folia, hypoplastic inferior vermis and hemispheres, malformed or flattened hippocampus, thin corpus callosum, small pons/brainstem, and enlarged lateral ventricles. VLDLR-related imaging emphasizes inferior cerebellar vermis/hemisphere hypoplasia, simplified cortical gyration, and small brain stem.	(hong2000autosomalrecessivelissencephaly pages 1-2, lossi2019thereelermouse pages 3-6, donato2022monoallelicandbiallelic pages 4-5, holling2024ahomozygousnonsense pages 1-2, ozcelik2008mutationsinthe pages 1-3)	Hong et al. (2000): https://doi.org/10.1038/79246; Lossi et al. (2019): https://doi.org/10.3390/jcm8122088; Di Donato et al. (2022): https://doi.org/10.1093/brain/awac164; Holling et al. (2024): https://doi.org/10.1038/s10038-024-01279-w; Ozcelik et al. (2008): https://doi.org/10.1073/pnas.0710010105
Identifier/diagnostic context in sequencing cohorts	In a large lissencephaly cohort, RELN accounted for ~1% of diagnosed cases and VLDLR for <1%, supporting that Reelin-pathway lissencephaly is genetically rare within the broader lissencephaly spectrum.	(donato2018analysisof17 pages 2-4)	Di Donato et al., Genetics in Medicine (2018): https://doi.org/10.1038/gim.2018.8

Table: This table summarizes the evidence-supported disease names, identifiers, causal genes, inheritance patterns, and hallmark imaging findings for Reelin-pathway lissencephaly. It is useful for mapping the disorder across historical labels such as LIS2 and Norman–Roberts syndrome while distinguishing RELN-, DAB1-, and VLDLR-related forms.

1. Disease information

1.1 Definition and overview

Lissencephaly is a neuronal migration disorder with a “thickened, simplified cortex,” and the Reelin-pathway form is classically lissencephaly with cerebellar hypoplasia (LCH) due to RELN deficiency. (hong2000autosomalrecessivelissencephaly pages 1-2)

A widely used clinical label for the RELN form is Lissencephaly 2 (LIS2), also referred to as “Norman–Roberts type” / “Norman–Roberts syndrome.” (lossi2019thereelermouse pages 3-6)

1.2 Key identifiers (available from retrieved evidence)

OMIM: LIS2 / Norman–Roberts syndrome OMIM #257320 (explicit in reviewed evidence). (lossi2019thereelermouse pages 3-6)
MONDO / Orphanet / ICD-10/ICD-11 / MeSH: Not directly retrievable from the current evidence corpus using the available tools; therefore not reported here.

1.3 Common synonyms and alternative names

Lissencephaly with cerebellar hypoplasia (LCH) (hong2000autosomalrecessivelissencephaly pages 1-2)
Lissencephaly 2 (LIS2) (lossi2019thereelermouse pages 3-6)
Norman–Roberts type lissencephaly syndrome / Norman–Roberts syndrome (lossi2019thereelermouse pages 3-6)

1.4 Evidence source types

Human genetic case series / family studies: e.g., classic RELN-LCH linkage/variant study. (hong2000autosomalrecessivelissencephaly pages 1-2)
Cohort sequencing studies: large lissencephaly cohorts with panel/WES yields including RELN and VLDLR. (donato2018analysisof17 pages 2-4)
Functional and model-organism studies: mechanism and phenotypic recapitulation (mouse). (smits2021biallelicdab1variants pages 4-5, lossi2019thereelermouse pages 1-3)

2. Etiology

2.1 Disease causal factors

Primary causal factor: germline pathogenic variants disrupting Reelin signaling, most often resulting in loss of Reelin function (RELN) or impaired receptor/adaptor signaling (VLDLR, DAB1). (hong2000autosomalrecessivelissencephaly pages 1-2, smits2021biallelicdab1variants pages 4-5, ozcelik2008mutationsinthe pages 1-3)

2.2 Genetic risk factors (causal genes/variants)

RELN (Reelin)

Classic disease: autosomal recessive RELN mutations causing LCH (Norman–Roberts/LIS2). (hong2000autosomalrecessivelissencephaly pages 1-2, lossi2019thereelermouse pages 3-6)
Spectrum expansion (important recent development): dominant neuronal migration disorders from monoallelic RELN missense variants via dominant-negative effects.
Abstract quote (JCI 2024): “The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing WT RELN secretion in culture, animal models, and patients, thereby causing dominant NMDs.” (riva2024denovomonoallelic pages 17-17)

DAB1 (Disabled-1)

Biallelic splice variants affecting the PTB domain are associated with mild lissencephaly and cerebellar hypoplasia, and authors propose considering loss-of-function DAB1 variants in patients with RELN-like cortical malformations. (smits2021biallelicdab1variants pages 4-5)

VLDLR (Very low-density lipoprotein receptor)

Biallelic VLDLR loss-of-function variants cause a recessive neurodevelopmental disorder with cerebellar hypoplasia and gyral simplification; early work mapped families to chromosome 9p24 and identified truncating variants (e.g., R257X). (ozcelik2008mutationsinthe pages 1-3)
2024 isoform-specific insight: a homozygous nonsense variant in alternatively spliced exon 4 was reported in two sisters with ID and microcephaly but normal brain imaging, with authors suggesting that expression of exon-4–lacking neuronal isoforms may protect from the classic cerebellar hypoplasia phenotype. (holling2024ahomozygousnonsense pages 1-2)
Abstract quote (J Hum Genet 2024): “The characteristic MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified cortical gyration, and a small brain stem.” (holling2024ahomozygousnonsense pages 1-2)

2.3 Environmental risk/protective factors and gene–environment interactions

No environmental risk factors, protective factors, or gene–environment interaction evidence specific to Reelin-pathway lissencephaly were identified in the retrieved corpus; the disorder is best supported as a Mendelian neurodevelopmental malformation driven by germline variants. (hong2000autosomalrecessivelissencephaly pages 1-2, donato2022monoallelicandbiallelic pages 1-3)

3. Phenotypes

3.1 Core clinical phenotype (human)

In autosomal recessive RELN-associated LCH, reported clinical features include severe neurodevelopmental disability and epilepsy alongside ocular and tone abnormalities. - Human clinical features summarized in the classic study include hypotonia, severe delay in neurological and cognitive development, myopia and nystagmus, and generalized seizures (noted as medication-controllable in those cases). (hong2000autosomalrecessivelissencephaly pages 1-2)

For VLDLR-related disease, reported neurologic findings include ataxia and severe ID. - Primary report described truncal ataxia, profound intellectual disability, and dysarthric speech. (ozcelik2008mutationsinthe pages 1-3)

3.2 Neuroimaging phenotype

RELN-LCH neuroimaging can include a thickened simplified cortex and marked cerebellar hypoplasia. - Review synopsis of LIS2 MRI: “5–10 mm thick cerebral cortex, a malformed hippocampus and a very hypoplastic cerebellum, almost completely devoid of folia.” (lossi2019thereelermouse pages 3-6) - Classic RELN-LCH MRI description includes moderate lissencephaly plus profound cerebellar hypoplasia and associated brainstem/ventricle abnormalities. (hong2000autosomalrecessivelissencephaly pages 1-2)

3.3 Suggested HPO terms (non-exhaustive; for KB annotation)

(These are ontology suggestions aligned to the evidence-backed clinical/imaging findings; they are not claimed as exhaustive.) - Lissencephaly (HP:0001339) - Pachygyria (HP:0001302) - Cerebellar hypoplasia (HP:0001321) - Abnormal cerebellar vermis morphology (HP:0001320) - Global developmental delay (HP:0001263) - Intellectual disability (HP:0001249) - Hypotonia (HP:0001252) - Seizures (HP:0001250) - Nystagmus (HP:0000639) - Myopia (HP:0000545) - Ventriculomegaly (HP:0002119)

3.4 Onset, severity, progression

The phenotype is congenital/early-onset with structural malformations evident on neuroimaging and severe developmental impairment in classic RELN-LCH. (hong2000autosomalrecessivelissencephaly pages 1-2)

3.5 Frequency and QoL impact

Robust phenotype frequencies and standardized QoL instruments (e.g., EQ-5D/SF-36) were not identified in the retrieved corpus for this rare Mendelian disorder. Available evidence is largely from families/cases and malformation cohorts. (hong2000autosomalrecessivelissencephaly pages 1-2, donato2018analysisof17 pages 2-4)

4. Genetic / molecular information

4.1 Causal genes and pathway positioning

RELN encodes Reelin, a secreted glycoprotein essential for cerebral cortex development; recessive deficiency causes LCH/LIS2. (hong2000autosomalrecessivelissencephaly pages 1-2, riva2024denovomonoallelic pages 17-17)
VLDLR encodes a Reelin receptor (lipoprotein receptor family) required for cortical/cerebellar development. (ozcelik2008mutationsinthe pages 1-3)
DAB1 encodes an intracellular adaptor; Reelin binding to VLDLR/ApoER2 induces DAB1 tyrosine phosphorylation. (smits2021biallelicdab1variants pages 4-5)

4.2 Variant classes and functional consequences

RELN: splice-disrupting variants causing low/undetectable protein in classic autosomal recessive disease; monoallelic missense can be dominant-negative (reduced secretion) in 2024 mechanistic work. (hong2000autosomalrecessivelissencephaly pages 1-2, riva2024denovomonoallelic pages 17-17)
DAB1: biallelic splice variants affecting the PTB domain cause loss of normal transcripts and are proposed pathogenic for RELN-like cortical malformations. (smits2021biallelicdab1variants pages 4-5)
VLDLR: truncating variants; 2024 work highlights alternative splicing (exon 4/16) as potentially modifying phenotype severity. (holling2024ahomozygousnonsense pages 1-2, ozcelik2008mutationsinthe pages 1-3)

4.3 Population allele frequency information

Population frequencies (e.g., gnomAD AF) and carrier frequencies were not extractable from the retrieved full-text excerpts; one study notes monoallelic RELN rare variants “not seen in gnomAD,” but specific allele frequency values were not captured in the available evidence snippets. (donato2022monoallelicandbiallelic pages 4-5)

5. Environmental information

No disease-specific environmental, lifestyle, or infectious contributors were identified in the retrieved evidence; the disorder is primarily genetically determined. (hong2000autosomalrecessivelissencephaly pages 1-2)

6. Mechanism / pathophysiology

6.1 Canonical causal chain (molecular → cellular → anatomical → clinical)

Initiating trigger: germline pathogenic variants in RELN, VLDLR, or DAB1. (hong2000autosomalrecessivelissencephaly pages 1-2, smits2021biallelicdab1variants pages 4-5, ozcelik2008mutationsinthe pages 1-3)
Upstream molecular defect: reduced/absent Reelin secretion or impaired receptor/adaptor engagement.
RELN recessive variants produce low/undetectable Reelin. (hong2000autosomalrecessivelissencephaly pages 1-2)
2024 dominant-negative RELN missense prevent secretion of wild-type RELN. (riva2024denovomonoallelic pages 17-17)
Signal transduction defect: Reelin normally binds VLDLR/ApoER2 and induces DAB1 phosphorylation; loss of this cascade disrupts migration/lamination programs. (smits2021biallelicdab1variants pages 4-5)
Cellular process: defective neuronal migration and impaired laminar organization.
Anatomical phenotype: simplified/thickened cortex (lissencephaly/pachygyria), hippocampal malformation, and cerebellar hypoplasia (often severe in classic RELN-LCH). (hong2000autosomalrecessivelissencephaly pages 1-2, lossi2019thereelermouse pages 3-6)
Clinical manifestations: profound developmental delay/intellectual disability, hypotonia/ataxia, seizures, ocular motor findings, etc. (hong2000autosomalrecessivelissencephaly pages 1-2, ozcelik2008mutationsinthe pages 1-3)

6.2 Recent mechanistic developments (prioritize 2023–2024)

Dominant-negative vs gain-/loss-of-function effects in RELN missense variants (2024):
Abstract quote (JCI 2024): “Polymicrogyria-associated variants behaved as gain-of-function… while those linked to pachygyria behaved as loss-of-function… The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative…” (riva2024denovomonoallelic pages 17-17)
Isoform-level modulation in VLDLR (2024): alternative splicing of exon 4/16 may modulate clinical expressivity (brain isoforms lacking exon 4 potentially protective in one family). (holling2024ahomozygousnonsense pages 1-2)

6.3 Suggested ontology terms for mechanism annotation

GO (biological process) suggestions: - Neuron migration (GO:0001764) - Neuron projection development (GO:0031175) - Cerebral cortex development (GO:0021987) - Cerebellum development (GO:0021549)

Cell Ontology (CL) suggestions: - Cortical pyramidal neuron (e.g., CL:0000540) - Cerebellar Purkinje cell (CL:0000121) - Cerebellar granule cell (CL:0000120)

7. Anatomical structures affected

7.1 Organ/tissue level

Primary: central nervous system—cerebral cortex, cerebellum, hippocampus, and often brainstem/pons and ventricles on imaging. (hong2000autosomalrecessivelissencephaly pages 1-2, lossi2019thereelermouse pages 3-6)

UBERON suggestions: - Cerebral cortex (UBERON:0000956) - Cerebellum (UBERON:0002037) - Hippocampus (UBERON:0001954) - Pons (UBERON:0000988) - Lateral ventricle (UBERON:0002081)

8. Temporal development

The malformation pattern is congenital/early developmental with structural abnormalities detectable on MRI and severe early developmental impact in classic RELN-LCH. (hong2000autosomalrecessivelissencephaly pages 1-2)

9. Inheritance and population

9.1 Inheritance

Classic RELN-LCH / LIS2 (Norman–Roberts): autosomal recessive. (hong2000autosomalrecessivelissencephaly pages 1-2, lossi2019thereelermouse pages 3-6)
DAB1-related RELN-like lissencephaly + cerebellar hypoplasia: autosomal recessive (biallelic splice variants reported). (smits2021biallelicdab1variants pages 4-5)
VLDLR-related cerebellar hypoplasia with gyral simplification: autosomal recessive. (ozcelik2008mutationsinthe pages 1-3)
Important update: dominant neuronal migration disorders due to de novo monoallelic RELN missense variants via dominant-negative mechanism. (riva2024denovomonoallelic pages 17-17)

9.2 Epidemiology and population genetics (what is and is not available)

Direct prevalence/incidence for “Reelin pathway lissencephaly” was not identified in retrieved sources.

However, large sequencing cohorts provide useful rarity estimates within lissencephaly: - In a cohort of 811 patients with lissencephaly/subcortical band heterotopia, overall mutation frequency across 17 genes was 81%, and RELN accounted for ~1% while VLDLR accounted for <1% of subjects. (donato2018analysisof17 pages 2-4)

10. Diagnostics

10.1 Clinical and neuroimaging hallmarks

Hallmark MRI patterns include thickened/simplified cortex (often frontotemporal/temporal-predominant in some RELN-related presentations), hippocampal malformation, and cerebellar hypoplasia (often severe with reduced foliation in classic disease). (hong2000autosomalrecessivelissencephaly pages 1-2, lossi2019thereelermouse pages 3-6, donato2022monoallelicandbiallelic pages 1-3)

10.2 Genetic testing strategies and real-world implementation

Sequencing-based diagnosis is central to clinical implementation: - Large lissencephaly cohort testing supports multi-gene panels and/or WES as effective strategies. - Abstract quote (Genet Med 2018): “The overall mutation frequency in the entire cohort was 81%.” (donato2018analysisof17 pages 2-4) - Exome sequencing for brain malformations in routine practice: - Abstract quote (Brain Communications 2024): “The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up.” (kooshavar2024diagnosticutilityof pages 1-3)

Practical diagnostic workflow (evidence-aligned): 1) Brain MRI phenotype classification (to guide differential and gene prioritization). (donato2018analysisof17 pages 2-4) 2) Chromosomal microarray (often required/used as first-tier in malformation programs), followed by WES or targeted panels when CMA is negative. (kooshavar2024diagnosticutilityof pages 1-3) 3) Variant interpretation with attention to inheritance (biallelic LoF typical for classic LCH; de novo monoallelic missense possible for dominant RELN-related migration disorders). (riva2024denovomonoallelic pages 17-17)

10.3 Differential diagnosis

Not exhaustively derivable from the retrieved evidence corpus. In practice, different lissencephaly genes produce distinct imaging patterns; cohort studies emphasize that “brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways.” (donato2018analysisof17 pages 2-4)

10.4 Screening and prevention

No newborn screening or biochemical screening is supported by retrieved evidence. Prevention in Mendelian disease is primarily via genetic counseling, carrier testing, and prenatal/preimplantation options (not directly evidenced in retrieved excerpts).

11. Outcome / prognosis

Long-term outcome statistics (survival curves, standardized disability scales) were not identified in the retrieved corpus. The classic RELN-LCH description supports a severe neurodevelopmental outcome with profound impairment and seizures (sometimes medication-controlled). (hong2000autosomalrecessivelissencephaly pages 1-2)

12. Treatment

12.1 Current management (real-world implementation)

No disease-modifying therapy is established in the retrieved evidence. Management is supportive and symptom-directed. - In classic autosomal recessive RELN-LCH families, generalized seizures were reported and “could be controlled with medication.” (hong2000autosomalrecessivelissencephaly pages 1-2)

MAXO suggestions (supportive-care aligned): - Antiseizure therapy (e.g., MAXO:0000757 [anticonvulsant therapy] — term suggestion) - Physical therapy / rehabilitation (MAXO term suggestions) - Feeding therapy / management of oral motor difficulty (noted in DAB1 case). (smits2021biallelicdab1variants pages 4-5)

12.2 Experimental therapies and clinical trials

A ClinicalTrials.gov query for “RELN OR reelin AND lissencephaly” did not retrieve lissencephaly-specific interventional trials in the current tool state (retrieved trials were largely unrelated to congenital malformations). Therefore, no disease-specific NCT identifiers can be supported from this search output.

13. Prevention

Evidence in the retrieved corpus does not address primary prevention beyond genetic etiology. For affected families, prevention is typically via reproductive genetic counseling, but such recommendations are not explicitly supported by the retrieved excerpts.

14. Other species / natural disease

Sheep: a RELN deletion causing lissencephaly with cerebellar hypoplasia has been reported (comparative genetics evidence). (ozcelik2008mutationsinthe pages 1-3)

15. Model organisms

Mouse (reeler; Reln−/−): widely used translational model; review summarizes disrupted lamination of cerebral cortex/hippocampus/cerebellum and motor phenotype, and notes that disruption of pathway components (e.g., DAB1, receptors) yields similar phenotypes. (lossi2019thereelermouse pages 1-3)
Mouse receptor/adaptor loss: DAB1 loss or receptor loss produces “Reeler/Disabled-like disruption of neuronal migration” (reviewed). (chang2007theroleof pages 5-6)

Evidence gaps and limitations (explicit)

MONDO/Orphanet/ICD/MeSH identifiers, prevalence/incidence, carrier frequencies, and systematic phenotype frequencies/QoL measures were not retrievable from the current tool-accessible full texts.
Some key recent disease-specific case reports mentioned by search results (e.g., a 2023 Pediatric Neurology “new RELN mutation”) were listed as unobtainable and could not be included.

Key recent sources (2023–2024 prioritized)

Riva M et al. “De novo monoallelic Reelin missense variants cause dominant neuronal migration disorders via a dominant-negative mechanism.” J Clin Invest. 2024-07. https://doi.org/10.1172/jci153097 (riva2024denovomonoallelic pages 17-17)
Holling T et al. “A homozygous nonsense variant in the alternatively spliced VLDLR exon 4…” Journal of Human Genetics. 2024-07. https://doi.org/10.1038/s10038-024-01279-w (holling2024ahomozygousnonsense pages 1-2)
Kooshavar D et al. “Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations.” Brain Communications. 2024-02. https://doi.org/10.1093/braincomms/fcae056 (kooshavar2024diagnosticutilityof pages 1-3)

Foundational primary sources

Hong SE et al. “Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.” Nature Genetics. 2000-09. https://doi.org/10.1038/79246 (hong2000autosomalrecessivelissencephaly pages 1-2)
Smits DJ et al. “Biallelic DAB1 variants are associated with mild lissencephaly and cerebellar hypoplasia.” Neurology Genetics. 2021-04. https://doi.org/10.1212/nxg.0000000000000558 (smits2021biallelicdab1variants pages 4-5)
Di Donato N et al. “Monoallelic and biallelic mutations in RELN underlie a graded series of neurodevelopmental disorders.” Brain. 2022-06. https://doi.org/10.1093/brain/awac164 (donato2022monoallelicandbiallelic pages 1-3)
Di Donato N et al. “Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.” Genetics in Medicine. 2018-11. https://doi.org/10.1038/gim.2018.8 (donato2018analysisof17 pages 2-4)

References

(hong2000autosomalrecessivelissencephaly pages 1-2): Susan E. Hong, Yin Yao Shugart, David T. Huang, Saad Al Shahwan, P. Ellen Grant, Jonathan O'B. Hourihane, Neil D.T. Martin, and Christopher A. Walsh. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human reln mutations. Nature Genetics, 26:93-96, Sep 2000. URL: https://doi.org/10.1038/79246, doi:10.1038/79246. This article has 1067 citations and is from a highest quality peer-reviewed journal.
(smits2021biallelicdab1variants pages 4-5): MD Msc Daphne J. Smits, BSc Rachel Schot, PhD Martina Wilke, PhD Marjon van Slegtenhorst, Marie Claire, MD Y. de Wit, Marjolein H.G. Dremmen PhD, M. W. B. Md, PhD A. James Barkovich, and PhD Grazia M.S. Mancini. Biallelic dab1 variants are associated with mild lissencephaly and cerebellar hypoplasia. Neurology Genetics, Apr 2021. URL: https://doi.org/10.1212/nxg.0000000000000558, doi:10.1212/nxg.0000000000000558. This article has 13 citations.
(donato2022monoallelicandbiallelic pages 1-3): Nataliya Di Donato, Renzo Guerrini, Charles J Billington, A James Barkovich, Philine Dinkel, Elena Freri, Michael Heide, Elliot S Gershon, Tracy S Gertler, Robert J Hopkin, Suma Jacob, Sarah K Keedy, Daniz Kooshavar, Paul J Lockhart, Dietmar R Lohmann, Iman G Mahmoud, Elena Parrini, Evelin Schrock, Giulia Severi, Andrew E Timms, Richard I Webster, Mary J H Willis, Maha S Zaki, Joseph G Gleeson, Richard J Leventer, and William B Dobyns. Monoallelic and biallelic mutations in reln underlie a graded series of neurodevelopmental disorders. Brain : a journal of neurology, 145:3274-3287, Jun 2022. URL: https://doi.org/10.1093/brain/awac164, doi:10.1093/brain/awac164. This article has 26 citations.
(riva2024denovomonoallelic pages 17-17): Martina Riva, Sofia Ferreira, Kotaro Hayashi, Yoann Saillour, Vera P. Medvedeva, Takao Honda, Kanehiro Hayashi, Claire Altersitz, Shahad Albadri, Marion Rosello, Julie Dang, Malo Serafini, Frédéric Causeret, Olivia J. Henry, Charles-Joris Roux, Céline Bellesme, Elena Freri, Dragana Josifova, Elena Parrini, Renzo Guerrini, Filippo Del Bene, Kazunori Nakajima, Nadia Bahi-Buisson, and Alessandra Pierani. De novo monoallelic reelin missense variants cause dominant neuronal migration disorders via a dominant-negative mechanism. The Journal of Clinical Investigation, Jul 2024. URL: https://doi.org/10.1172/jci153097, doi:10.1172/jci153097. This article has 9 citations.
(lossi2019thereelermouse pages 3-6): Laura Lossi, Claudia Castagna, Alberto Granato, and Adalberto Merighi. The reeler mouse: a translational model of human neurological conditions, or simply a good tool for better understanding neurodevelopment? Journal of Clinical Medicine, 8:2088, Dec 2019. URL: https://doi.org/10.3390/jcm8122088, doi:10.3390/jcm8122088. This article has 50 citations.
(chang2007theroleof pages 5-6): Bernard S. Chang, Fusun Duzcan, Seonhee Kim, Mine Cinbis, Abha Aggarwal, Kira A. Apse, Osman Ozdel, Munevver Atmaca, Sevil Zencir, Huseyin Bagci, and Christopher A. Walsh. The role of reln in lissencephaly and neuropsychiatric disease. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 144B:58-63, Jan 2007. URL: https://doi.org/10.1002/ajmg.b.30392, doi:10.1002/ajmg.b.30392. This article has 105 citations.
(donato2022monoallelicandbiallelic pages 4-5): Nataliya Di Donato, Renzo Guerrini, Charles J Billington, A James Barkovich, Philine Dinkel, Elena Freri, Michael Heide, Elliot S Gershon, Tracy S Gertler, Robert J Hopkin, Suma Jacob, Sarah K Keedy, Daniz Kooshavar, Paul J Lockhart, Dietmar R Lohmann, Iman G Mahmoud, Elena Parrini, Evelin Schrock, Giulia Severi, Andrew E Timms, Richard I Webster, Mary J H Willis, Maha S Zaki, Joseph G Gleeson, Richard J Leventer, and William B Dobyns. Monoallelic and biallelic mutations in reln underlie a graded series of neurodevelopmental disorders. Brain : a journal of neurology, 145:3274-3287, Jun 2022. URL: https://doi.org/10.1093/brain/awac164, doi:10.1093/brain/awac164. This article has 26 citations.
(ozcelik2008mutationsinthe pages 1-3): Tayfun Ozcelik, Nurten Akarsu, Elif Uz, Safak Caglayan, Suleyman Gulsuner, Onur Emre Onat, Meliha Tan, and Uner Tan. Mutations in the very low-density lipoprotein receptor vldlr cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proceedings of the National Academy of Sciences, 105:4232-4236, Mar 2008. URL: https://doi.org/10.1073/pnas.0710010105, doi:10.1073/pnas.0710010105. This article has 132 citations and is from a highest quality peer-reviewed journal.
(holling2024ahomozygousnonsense pages 1-2): Tess Holling, Ibrahim M. Abdelrazek, Ghada M. Elhady, Marwa Abd Elmaksoud, Seung Woo Ryu, Ebtesam Abdalla, and Kerstin Kutsche. A homozygous nonsense variant in the alternatively spliced vldlr exon 4 causes a neurodevelopmental disorder without features of vldlr cerebellar hypoplasia. Journal of Human Genetics, 69:623-628, Jul 2024. URL: https://doi.org/10.1038/s10038-024-01279-w, doi:10.1038/s10038-024-01279-w. This article has 4 citations and is from a peer-reviewed journal.
(donato2018analysisof17 pages 2-4): Nataliya Di Donato, Andrew E. Timms, Kimberly A. Aldinger, Ghayda M. Mirzaa, James T. Bennett, Sarah Collins, Carissa Olds, Davide Mei, Sara Chiari, Gemma Carvill, Candace T. Myers, Jean-Baptiste Rivière, Maha S. Zaki, Joseph G. Gleeson, Andreas Rump, Valerio Conti, Elena Parrini, M.Elizabeth Ross, David H. Ledbetter, Renzo Guerrini, and William B. Dobyns. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Genetics in Medicine, 20:1354-1364, Nov 2018. URL: https://doi.org/10.1038/gim.2018.8, doi:10.1038/gim.2018.8. This article has 161 citations and is from a highest quality peer-reviewed journal.
(lossi2019thereelermouse pages 1-3): Laura Lossi, Claudia Castagna, Alberto Granato, and Adalberto Merighi. The reeler mouse: a translational model of human neurological conditions, or simply a good tool for better understanding neurodevelopment? Journal of Clinical Medicine, 8:2088, Dec 2019. URL: https://doi.org/10.3390/jcm8122088, doi:10.3390/jcm8122088. This article has 50 citations.
(kooshavar2024diagnosticutilityof pages 1-3): Daniz Kooshavar, David J Amor, Kirsten Boggs, Naomi Baker, Christopher Barnett, Michelle G de Silva, Samantha Edwards, Michael C Fahey, Justine E Marum, Penny Snell, Kiymet Bozaoglu, Kate Pope, Shekeeb S Mohammad, Kate Riney, Rani Sachdev, Ingrid E Scheffer, Sarah Schenscher, John Silberstein, Nicholas Smith, Melanie Tom, Tyson L Ware, Paul J Lockhart, and Richard J Leventer. Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations. Brain Communications, Feb 2024. URL: https://doi.org/10.1093/braincomms/fcae056, doi:10.1093/braincomms/fcae056. This article has 6 citations and is from a peer-reviewed journal.

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Reelin Pathway Lissencephaly (Reelin-pathway LIS/LCH): Comprehensive Research Report

Executive summary

1. Disease information

1.1 Definition and overview

1.2 Key identifiers (available from retrieved evidence)

1.3 Common synonyms and alternative names

1.4 Evidence source types

2. Etiology

2.1 Disease causal factors

2.2 Genetic risk factors (causal genes/variants)

RELN (Reelin)

DAB1 (Disabled-1)

VLDLR (Very low-density lipoprotein receptor)

2.3 Environmental risk/protective factors and gene–environment interactions

3. Phenotypes

3.1 Core clinical phenotype (human)

3.2 Neuroimaging phenotype

3.3 Suggested HPO terms (non-exhaustive; for KB annotation)

3.4 Onset, severity, progression

3.5 Frequency and QoL impact

4. Genetic / molecular information

4.1 Causal genes and pathway positioning

4.2 Variant classes and functional consequences

4.3 Population allele frequency information

5. Environmental information

6. Mechanism / pathophysiology

6.1 Canonical causal chain (molecular → cellular → anatomical → clinical)

6.2 Recent mechanistic developments (prioritize 2023–2024)

6.3 Suggested ontology terms for mechanism annotation

7. Anatomical structures affected

7.1 Organ/tissue level

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology and population genetics (what is and is not available)

10. Diagnostics

10.1 Clinical and neuroimaging hallmarks

10.2 Genetic testing strategies and real-world implementation

10.3 Differential diagnosis

10.4 Screening and prevention

11. Outcome / prognosis

12. Treatment

12.1 Current management (real-world implementation)

12.2 Experimental therapies and clinical trials

13. Prevention

14. Other species / natural disease

15. Model organisms

Evidence gaps and limitations (explicit)

Key recent sources (2023–2024 prioritized)

Foundational primary sources

Artifacts