Lissencephaly Spectrum Disorders

Mendelian MONDO:0018838 Pathograph 26 Show in embeddings browser congenital nervous system disorder disorder of development or morphogenesis hereditary neurological disease

Lissencephaly spectrum disorders are a genetically heterogeneous group of malformations of cortical development characterized by abnormal cortical folding (reduced gyrification) due chiefly to impaired neuronal migration and disordered cortical lamination during embryonic development. The spectrum ranges from agyria (near-absent gyri) and pachygyria (broad, reduced gyri) to subcortical band heterotopia (SBH, "double cortex"). Most affected individuals present congenitally with a structural brain malformation and develop early intellectual disability, hypotonia, and drug-resistant seizures. Causal genes include PAFAH1B1 (LIS1), DCX, TUBA1A, ARX, RELN, DYNC1H1 and TUBG1, among others, with classic, X-linked, tubulinopathy, ARX-related, RELN-related and cobblestone (glycosylation-pathway) forms.

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Subtypes

Classic lissencephaly (PAFAH1B1/LIS1-related) MONDO:0015146 MONDO:0011830

PAFAH1B1 hgnc:8574 MONDO MONDO:0011830

The most common classic lissencephaly, caused by heterozygous PAFAH1B1 (LIS1) variants or 17p13.3 deletions, usually de novo. Imaging typically shows posterior-predominant agyria/pachygyria. Seizures occur in >90% of individuals and developmental delay ranges from mild to severe.

Show evidence (1 reference)

PMID:29671837 SUPPORT Human Clinical

"LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%)."

In a cohort of 811 patients, LIS1/PAFAH1B1 was the single most common cause of lissencephaly, defining the classic subtype.

X-linked lissencephaly / SBH (DCX-related) MONDO:0010239

DCX hgnc:2714 X-linked inheritance

X-linked DCX-related disorder: males typically have classic thick lissencephaly (more severe anteriorly) while heterozygous females present with subcortical band heterotopia (double cortex). Phenotype severity correlates with the degree of malformation on imaging.

Show evidence (1 reference)

PMID:20301364 SUPPORT Human Clinical

"DCX-related disorders include the following neuronal migration disorders: classic thick lissencephaly (more severe anteriorly), usually in males, and subcortical band heterotopia (SBH), primarily in females."

GeneReviews defines the X-linked DCX subtype with classic lissencephaly in males and SBH in females.

Tubulinopathy-associated lissencephaly (TUBA1A and related tubulins)

TUBA1A hgnc:20766 TUBG1 hgnc:12417

Lissencephaly arising from mutations in tubulin genes (notably TUBA1A, also TUBG1, TUBB2B, TUBB3), typically de novo autosomal dominant. The malformation pattern often combines lissencephaly/pachygyria with cerebellar, brainstem and basal ganglia abnormalities (corpus callosum and internal capsule dysmorphism).

Show evidence (1 reference)

PMID:29671837 SUPPORT Human Clinical

"LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%)."

TUBA1A is the most frequent tubulin-gene cause of lissencephaly in a large cohort, defining the tubulinopathy subtype.

Cobblestone lissencephaly (dystroglycanopathy) MONDO:0018869

POMGNT1 hgnc:19139 POMT1 hgnc:9202 POMT2 hgnc:19743

A distinct "type II"/cobblestone form in which neurons overmigrate through a disrupted pial basement membrane, associated with glycosylation-pathway genes such as POMGNT1, POMT1 and POMT2 (alpha-dystroglycanopathies), typically with eye and muscle involvement. Neuropathology differs from the classic (migration-arrest) forms.

Lissencephaly 10 (CEP85L-related posterior predominant lissencephaly) MONDO:0030031

CEP85L hgnc:21638 Autosomal dominant inheritance

Posterior-predominant lissencephaly caused by rare heterozygous CEP85L variants, occurring sporadically or segregating as an autosomal dominant trait. CEP85L is a pericentriolar-material protein, so this subtype enters the same nucleokinesis machinery as PAFAH1B1 (LIS1) from the centrosome rather than from the dynein regulator itself, which is consistent with the shared posterior-predominant imaging pattern.

Show evidence (2 references)

PMID:32097630 SUPPORT Human Clinical

"We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance."

Establishes CEP85L as a lissencephaly gene, gives the posterior-predominant imaging pattern that defines the subtype, and records the autosomal dominant families.

CGGV:assertion_30a3191e-5ee3-467c-afa1-27fada71f9ea-2024-09-24T170000.000Z SUPPORT Other

The ClinGen Brain Malformations expert panel classifies the CEP85L-lissencephaly 10 relationship as Definitive under autosomal dominant inheritance, and curated it against the same MONDO term this subtype binds.

Lissencephaly 6 with microcephaly (KATNB1-related microlissencephaly) MONDO:0014534

KATNB1 hgnc:6217 Autosomal recessive inheritance

Autosomal recessive microlissencephaly caused by biallelic KATNB1 variants. KATNB1 encodes the regulatory subunit of the microtubule-severing enzyme katanin, and the reported patients carry homozygous or compound heterozygous alleles. Microcephaly is named in the disease label rather than being an added feature, and loss of the KATNB1 orthologs in zebrafish and flies reproduces it.

Show evidence (2 references)

PMID:25521378 SUPPORT Human Clinical

"Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin."

Establishes biallelic KATNB1 variants as a cause of complex cortical malformation and names the gene product, supporting the recessive inheritance recorded here.

PMID:25521378 SUPPORT Model Organism

"Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype."

Supports the microcephaly that this subtype's label names, shown by loss of the gene in two model organisms.

Lissencephaly 7 with cerebellar hypoplasia (CDK5-related) MONDO:0014596

CDK5 hgnc:1774 Autosomal recessive inheritance

Autosomal recessive lissencephaly with cerebellar hypoplasia caused by biallelic loss of function of CDK5. CDK5 sits in a complex with LIS1 and the dynein heavy chain that is required for cortical neuronal migration, so this subtype reaches the same nucleokinesis machinery as the classic forms through loss of the kinase rather than loss of the scaffold. The founding report describes a lethal presentation in one consanguineous family.

Show evidence (2 references)

PMID:25560765 SUPPORT Human Clinical

"We studied a highly consanguineous Israeli Moslem family with a lethal form of autosomal recessive lissencephaly with cerebellar hypoplasia (LCH)."

Gives the clinical setting and the recessive, lethal presentation of the CDK5-related subtype.

CGGV:assertion_2f6ba2ff-6567-493e-bf39-f05c03013e20-2024-04-29T160000.000Z SUPPORT Other

ClinGen classifies CDK5 as Moderate for autosomal recessive lissencephaly with cerebellar hypoplasia. Note the panel curated it against the broader LCH term (MONDO:0019450) that this entry already uses for the RELN subtype, not against the numbered LIS7 term bound here.

Lissencephaly 8 (TMTC3-related cobblestone malformation) MONDO:0014992

TMTC3 hgnc:26899 Autosomal recessive inheritance

Autosomal recessive cobblestone lissencephaly caused by biallelic TMTC3 variants, with brainstem and cerebellar hypoplasia and ventriculomegaly. This is a cobblestone (overmigration) malformation and not one of the migration-arrest forms, but it is reached without an alpha-dystroglycan defect: TMTC3 has no established functional connection to alpha-dystroglycan, and most affected individuals lack the eye involvement and raised creatine kinase of the dystroglycanopathies. It is therefore curated separately from the Cobblestone subtype above, which collects the glycosylation-pathway genes.

Show evidence (2 references)

PMID:27773428 SUPPORT Human Clinical

"Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan."

Establishes biallelic TMTC3 variants as a recessive cause of cobblestone lissencephaly and states that the gene has no obvious functional link to alpha-dystroglycan, which is the reason this subtype is kept separate from the dystroglycanopathy cobblestone group.

PMID:27773428 SUPPORT Human Clinical

"Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement."

Records the clinical separation from typical congenital muscular dystrophy that distinguishes this subtype.

Lissencephaly 9 with complex brainstem malformation (MACF1-related) MONDO:0032677

MACF1 hgnc:13664 Autosomal dominant inheritance

Posterior-predominant lissencephaly with absent anterior commissure and a W-shaped brainstem malformation from small or absent pontine crossing fibres, caused by de novo variants affecting conserved zinc-binding residues of the MACF1 GAR domain. The founding report calls the combination of cortical and midline crossing defects a distinctive and most likely pathognomonic brain malformation.

Show evidence (3 references)

PMID:30471716 SUPPORT Human Clinical

"The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers."

Defines the imaging phenotype of this subtype, including the brainstem malformation that the MONDO label names.

PMID:30471716 SUPPORT Human Clinical

"We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects."

Records the heterozygous de novo variant class and the domain involved, supporting the dominant inheritance recorded here.

CGGV:assertion_67d61f95-4ea3-41a7-ab90-e642c2c65c2a-2023-07-25T160000.000Z SUPPORT Other

ClinGen classifies MACF1 as Moderate under autosomal dominant inheritance. The panel curated it against MONDO:0100472, a second MONDO class with almost the same label as the OMIM-anchored term bound here; see the entry notes.

Complex cortical dysplasia with other brain malformations 9 (CTNNA2-related pachygyria) MONDO:0032578

CTNNA2 hgnc:2510 Autosomal recessive inheritance

Autosomal recessive pachygyria caused by biallelic truncating CTNNA2 variants. CTNNA2 encodes αN-catenin, which represses ARP2/3-driven actin branching; its loss therefore places this subtype on the actin side of the cytoskeletal mechanism rather than the microtubule side that the tubulin, LIS1 and DCX subtypes share. MONDO records the concept under complex cortical dysplasia rather than under lissencephaly spectrum disorders, but carries "CTNNA2-related lissencephaly spectrum disorder" as a synonym, which is why it is curated here.

Show evidence (1 reference)

PMID:30013181 SUPPORT Human Clinical

"Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria."

Establishes biallelic truncating CTNNA2 variants as the cause of a recessive pachygyria, supporting both the gene assignment and the inheritance recorded here.

Discussions and Knowledge Gaps

What explains the opposite anterior-posterior severity gradients and cellular emphasis between PAFAH1B1/LIS1 and DCX disease when both converge on microtubule-dependent neuronal migration failure?

KNOWLEDGE GAP OPEN gap_pafah1b1_dcx_gradient_and_cellular_emphasis

Attached to

pathophysiology#LIS1-NUDEL-Dynein Nucleokinesis Failure pathophysiology#DCX Microtubule Stabilization Failure pathophysiology#LIS1 Progenitor Spindle Orientation Defect

PAFAH1B1/LIS1 and DCX share a migration-failure endpoint, but the human radiographic gradients and cellular branches differ: PAFAH1B1 has a LIS1/NUDEL/dynein motor branch plus a progenitor-spindle component, whereas DCX disease is typically anterior-predominant in males and SBH in heterozygous females. The unresolved issue is whether regional expression, different microtubule-motor versus lattice functions, X-inactivation mosaicism, or human-specific progenitor context best explains these genotype-specific patterns.

Proposed experiments

PAFAH1B1/DCX isogenic cortical-organoid gradient comparison

isogenic cerebral organoid migration and progenitor assay

exp_lis1_dcx_isogenic_organoid_gradient_comparison

Generate matched human iPSC-derived dorsal forebrain organoids with PAFAH1B1 haploinsufficiency, DCX loss, and isogenic correction or knock-in rescue. Compare regional patterning markers, radial-glial spindle orientation, nucleokinesis, migration speed, microtubule lattice stability, and mosaic DCX expression effects to distinguish regional-expression, progenitor-spindle, and X-inactivation models.

Model systems

Human iPSC-derived dorsal forebrain organoid LIS/SBH model

Isogenic human cortical organoids carrying PAFAH1B1 haploinsufficiency or DCX loss/knock-in variants, with corrected and non-disease donor controls.

ORGANOID namo:Organoid link

human NCBITaxon:9606

cerebral cortex UBERON:0000956

radial glial cell CL:0000681 neuron CL:0000540

Perturbations

PAFAH1B1 haploinsufficiency and DCX loss or mosaic knock-in

pathophysiology#DCX Microtubule Stabilization Failure

CRISPR or patient-variant knock-in perturbations with isogenic repair, including mixed DCX-positive and DCX-negative neuronal populations to model female SBH mosaicism.

Readouts

Regional gradient and migration metrics

pathophysiology#Impaired Neuronal Migration

Quantify anterior/posterior patterning markers, radial-glial cleavage orientation, centrosome-nucleus coupling, nuclear translocation speed, tubulin polymerization/stability markers, and ectopic neuronal bands.

Controls

Isogenic corrected controls

Corrected PAFAH1B1 or DCX lines and non-disease donor organoids cultured in parallel.

Decision criterion

A disease-specific gradient mechanism is supported if PAFAH1B1 and DCX perturbations diverge in regional patterning, progenitor-spindle, or mosaic migration readouts despite shared downstream dyslamination.

Would support

pathophysiology#LIS1-NUDEL-Dynein Nucleokinesis Failure pathophysiology#DCX Microtubule Stabilization Failure pathophysiology#LIS1 Progenitor Spindle Orientation Defect

Show evidence (3 references)

PMID:11163259 SUPPORT In Vitro

"These results suggest that LIS1 and NUDEL regulate CDHC activity during neuronal migration and axonal retrograde transport in a Cdk5/p35-dependent fashion."

Supports the LIS1/NUDEL/dynein branch as a distinct molecular mechanism within the shared migration-failure endpoint.

PMID:18267077 SUPPORT Model Organism

"Lis1 is essential for precise control of mitotic spindle orientation in both neuroepithelial stem cells and radial glial progenitor cells."

Supports a PAFAH1B1/LIS1 progenitor branch not captured by a purely postmitotic migration model.

PMID:20301364 SUPPORT Human Clinical

"classic thick lissencephaly (more severe anteriorly), usually in males, and subcortical band heterotopia (SBH), primarily in females."

Establishes the DCX anterior-predominant and sex-biased SBH pattern.

Does the germline Dcx-knockout mouse — the founding animal model of DCX disease — faithfully recapitulate the defining human DCX neocortical malformation (X-linked lissencephaly in hemizygous males, subcortical band heterotopia in heterozygous females), given that germline Dcx-null mice have a near-normal neocortex, that only acute in utero RNAi knockdown reproduces a radial-migration/heterotopia phenotype, and that even this RNAi phenotype forms in rat but not in mouse — so that the severity and very existence of the human neocortical lesion is systematically underdetermined by the standard mouse knockout and its faithful modeling may require an acute-knockdown, a redundancy-free (Dcx/Dclk compound), a rat, or a human-specific progenitor context?

HUMAN MODEL MISMATCH OPEN gap_dcx_knockout_mouse_neocortex_model_mismatch

Attached to

pathophysiology#DCX Microtubule Stabilization Failure pathophysiology#Impaired Neuronal Migration

DCX is one of the most striking human/model discordances in the cortical malformation literature, and it bears directly on how strongly the mouse can validate the DCX branch of this entry. In humans, X-linked DCX mutations cause classic thick lissencephaly in males and subcortical band heterotopia in females — a severe, defining neocortical migration defect. Yet the germline Dcx-knockout mouse has neocortical lamination largely indistinguishable from wild type, with the migration/lamination phenotype restricted to the hippocampus; the neocortical malformation only appears when Dcx is acutely silenced by in utero RNAi rather than deleted in the germline. Two overlapping explanations are documented: (1) developmental compensation / genetic redundancy, whereby the paralog doublecortin-like kinase (Dclk) substitutes for Dcx in the germline knockout but not under acute knockdown, so that only Dcx/Dclk compound loss reproduces the migration defect; and (2) a genuine species difference, since the same in utero RNAi against Dcx induces band heterotopia in rat but fails to induce heterotopia in mouse. This is a concrete instance of two knowledge gaps flagged by the Romero, Bahi-Buisson & Francis 2018 cortical-malformation review that seeds this epic: that mouse models often fail to reproduce human MCD features, and that acute in utero knockdown can be more severe than germline knockout because of off-target effects, developmental compensation, or redundancy revealed only by double knockouts. Mechanistically it leaves open whether the human neocortical lesion reflects reduced Dcx/Dclk-family redundancy in human migrating neurons, a rat-like rather than mouse-like species requirement for Dcx in neocortical radial migration, or a human-specific progenitor/outer-radial-glia context — meaning the mouse germline knockout, taken alone, validates the DCX microtubule-stabilization mechanism only weakly for the human neocortical phenotype.

Proposed experiments

Dcx germline-KO versus acute-knockdown and Dcx/Dclk compound loss, compared across rat and mouse

in vivo rodent neuronal-migration perturbation study

exp_dcx_dclk_compound_perturbation_rat_vs_mouse

Systematically dissociate the redundancy and species-difference hypotheses by comparing germline Dcx knockout, acute in utero RNAi knockdown, and Dcx/Dclk compound loss for their ability to produce neocortical band heterotopia and laminar displacement, run in parallel in rat and mouse embryos with rescue-by-Dcx-overexpression specificity controls. This tests whether faithful modeling of the human neocortical phenotype requires removing paralog compensation, using acute rather than germline perturbation, and/or a rat rather than mouse substrate.

Model systems

Rat and mouse embryonic neocortex (in utero electroporation)

Developing rat and mouse cortex perturbed by in utero electroporation of RNAi or gene-edited alleles, the paired system that first revealed the rat-versus-mouse discrepancy in Dcx-knockdown heterotopia formation.

OTHER

Human iPSC-derived cortical model of DCX loss and female SBH mosaicism

iPSC cortical organoid migration assay

exp_dcx_human_ipsc_mosaic_migration_assay

Generate isogenic DCX-null and DCX-variant human iPSC-derived cortical organoids/assembloids, including mixed DCX-positive and DCX-negative neuronal populations to model heterozygous-female mosaicism, and quantify radial migration, laminar positioning, and heterotopic-band formation to test whether a human progenitor/neuronal context reproduces the severe neocortical phenotype that the mouse germline knockout does not.

Model systems

Human iPSC-derived cortical organoid/assembloid DCX model

Isogenic human cortical organoids or assembloids carrying DCX loss or patient variants with mosaic DCX expression, preserving human-specific cortical progenitor biology absent from the mouse.

ORGANOID

Show evidence (4 references)

PMID:12196578 SUPPORT Model Organism

"Dcx mutant mice show neocortical lamination that is largely indistinguishable from wild type and show normal patterns of neocortical neurogenesis and neuronal migration."

The founding germline Dcx-knockout mouse report establishes the core mismatch: the mouse neocortex is essentially normal despite DCX loss, whereas the human neocortical phenotype (lissencephaly/SBH) is severe.

PMID:14625554 SUPPORT Model Organism

"Paradoxically, genetic deletion of Dcx in mice does not cause neocortical malformation."

Documents the acute-knockdown-versus-germline-knockout discrepancy: acute in utero RNAi of DCX reproduces the migration defect that germline deletion does not, one of the Romero review's flagged model caveats.

PMID:16292002 SUPPORT Model Organism

"In utero RNAi in the rat consistently leads to both the formation of SBH and laminar displacement of transfected cells in normotopic cortex, whereas the same treatment in mouse fails to induce SBH but does create laminar displacement."

Demonstrates a genuine rat-versus-mouse species difference in the Dcx-loss neocortical phenotype, so even acute knockdown does not model the severe human heterotopia in mouse.

+ 1 more reference

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Pathophysiology

Impaired Neuronal Migration

Pathogenic variants in genes governing cytoskeletal dynamics and neuronal migration disrupt the long-range radial migration of postmitotic cortical neurons from the proliferative ventricular zone to their final laminar position. The resulting failure or delay of migration produces a thickened, smooth (agyric/pachygyric) cortex with disordered six-layered lamination.

migrating cortical neuron CL:0000540 radial glial progenitor CL:0000681

radial neuronal migration in cerebral cortex GO:0021799 ↓ DECREASED neuron migration GO:0001764 ↓ DECREASED

Show evidence (2 references)

PMID:10973257 SUPPORT Human Clinical

"Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth."

Establishes impaired neuronal migration as the core mechanism producing the thickened, smooth cortex that defines the lissencephaly spectrum.

PMID:23495356 SUPPORT Human Clinical

"Failure or delay in neuronal migration causes severe abnormalities in cortical layering, which consequently results in human lissencephaly ('smooth brain'), a neuronal migration disorder."

Directly links failure/delay of neuronal migration to the abnormal cortical lamination that characterizes lissencephaly.

Cytoskeletal and Microtubule Dysfunction

Neuronal migration depends on microtubule and actin cytoskeletal dynamics and on the dynein motor and its regulators. Mutations in microtubule subunits (tubulins) and in microtubule/dynein-associated proteins such as PAFAH1B1 (LIS1) and DCX impair microtubule organization, transport and nucleokinesis, the coupling of the nucleus to the centrosome that drives forward movement of migrating neurons.

migrating cortical neuron CL:0000540

TUBA1A hgnc:20766 TUBG1 hgnc:12417 MACF1 hgnc:13664 DYNC1H1 hgnc:2961

microtubule-based movement GO:0007018 ⚠ ABNORMAL nucleokinesis during radial migration GO:0021817 ⚠ ABNORMAL

Downstream

Impaired Neuronal Migration Disruption of the LIS1/DCX/tubulin microtubule machinery impairs the nucleokinesis and somal translocation that radially migrating cortical neurons require, producing the migration arrest underlying lissencephaly.

Show evidence (4 references)

PMID:23495356 SUPPORT Human Clinical

"Since microtubule (MT) and actin-associated proteins play important functions in regulating the dynamics of MT and actin cytoskeletons during neuronal migration, genetic mutations or deletions of crucial genes involved in cytoskeletal processes lead to lissencephaly in human and neuronal..."

Supports cytoskeletal/microtubule dysfunction as the molecular basis for the migration defect underlying lissencephaly.

PMID:23495356 SUPPORT Human Clinical

"During neuronal migration, MT organization and transport are controlled by platelet-activating factor acetylhydrolase isoform 1b regulatory subunit 1 (PAFAH1B1, formerly known as LIS1, Lissencephaly-1), doublecortin (DCX), YWHAE, and tubulin."

Names the key microtubule-regulating proteins (LIS1/PAFAH1B1, DCX, tubulin) whose mutations cause classic lissencephaly.

PMID:30471716 SUPPORT Human Clinical

"Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation."

Supports binding MACF1 to this node: the causal variants sit in the gene's microtubule-binding domain, which is the function this node asserts is perturbed.

+ 1 more reference

LIS1-NUDEL-Dynein Nucleokinesis Failure

PAFAH1B1/LIS1 dosage loss disrupts a LIS1-NUDEL-cytoplasmic dynein heavy chain complex that normally regulates dynein on microtubules during neuronal migration. The resulting defect impairs centrosome-nucleus coupling and nucleokinesis in migrating cortical neurons, producing the classical type I lissencephaly/SBH migration-arrest branch. Mouse allelic series show that lower Pafah1b1 activity causes progressively more severe neuronal migration and brain-organization defects, matching the clinical severity gradient from pachygyria/SBH toward more severe lissencephaly.

migrating cortical neuron CL:0000540

PAFAH1B1 hgnc:8574 NDEL1 hgnc:17620

nucleokinesis during radial migration GO:0021817 ⚠ ABNORMAL microtubule-based movement GO:0007018 ↕ DYSREGULATED

Downstream

Impaired Neuronal Migration Disruption of the LIS1-NUDEL-dynein motor pathway impairs nucleokinesis and radial migration, converging on the lissencephaly cortical-lamination defect.

Show evidence (3 references)

PMID:11163259 SUPPORT In Vitro

"we demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL"

Demonstrates the core LIS1-NUDEL-dynein molecular complex underlying the neuronal migration branch.

PMID:16481446 SUPPORT In Vitro

"recombinant Lis1 binds to native brain dynein and significantly increases the microtubule-stimulated enzymatic activity of dynein in vitro."

Shows that LIS1 directly modulates dynein enzymatic activity, connecting PAFAH1B1 loss to microtubule motor dysfunction.

PMID:9697693 SUPPORT Model Organism

"Mice with one inactive allele display cortical, hippocampal and olfactory bulb disorganization resulting from delayed neuronal migration by a cell-autonomous neuronal pathway."

Supports dosage-sensitive LIS1 neuronal migration failure in vivo.

DCX Microtubule Stabilization Failure

DCX encodes a neuronal microtubule-associated protein required for normal migration of cortical neurons. Pathogenic DCX variants impair the microtubule-stabilizing and tubulin-polymerizing function of doublecortin, slowing or arresting migration. Hemizygous males usually develop anterior-predominant classic lissencephaly, whereas heterozygous females often develop subcortical band heterotopia through X-linked mosaicism.

migrating cortical neuron CL:0000540

DCX hgnc:2714

microtubule cytoskeleton organization GO:0000226 ↕ DYSREGULATED cytoplasmic microtubule organization GO:0031122 ↓ DECREASED

Downstream

Impaired Neuronal Migration Loss of DCX microtubule stabilization disrupts migration of cortical neurons, producing lissencephaly or subcortical band heterotopia depending on sex, mosaicism, and variant context.

Show evidence (3 references)

PMID:9489700 SUPPORT Human Clinical

"X-linked lissencephaly and "double cortex" are allelic human disorders mapping to Xq22.3-Xq23 associated with arrest of migrating cerebral cortical neurons."

Establishes DCX-related lissencephaly and double-cortex/SBH as allelic human neuronal-migration arrest disorders.

PMID:10399933 SUPPORT In Vitro

"DCX coassembles with brain microtubules, and recombinant DCX stimulates the polymerization of purified tubulin."

Supports the microtubule-stabilization and tubulin-polymerization branch of DCX disease biology.

PMID:10399933 SUPPORT In Vitro

"DCX likely directs neuronal migration by regulating the organization and stability of microtubules."

Links DCX microtubule organization and stability to neuronal migration.

LIS1 Progenitor Spindle Orientation Defect

In addition to the postmitotic neuronal migration branch, PAFAH1B1/LIS1 loss perturbs neuroepithelial and radial-glial progenitor mitotic spindle orientation through LIS1/NDEL1/dynein-mediated cortical microtubule capture. This progenitor branch affects symmetric division, progenitor expansion and cortical neuron output, explaining why PAFAH1B1 disease can include cortical thickness, simplified gyration and severity features not captured by a migration-only model.

neuroepithelial stem cell CL:0011020 radial glial progenitor CL:0000681

PAFAH1B1 hgnc:8574 NDEL1 hgnc:17620

mitotic spindle organization GO:0007052 ↕ DYSREGULATED cell division GO:0051301 ↕ DYSREGULATED

Downstream

Impaired Neuronal Migration The progenitor-spindle branch changes cortical neuron output and cortical organization, worsening the same abnormal cortical lamination endpoint as the neuronal migration branch.

Show evidence (2 references)

PMID:18267077 SUPPORT Model Organism

"Lis1 is essential for precise control of mitotic spindle orientation in both neuroepithelial stem cells and radial glial progenitor cells."

Supports a LIS1 progenitor-spindle branch in neuroepithelial and radial glial progenitors.

PMID:18267077 SUPPORT Model Organism

"control of symmetric division, essential for neuroepithelial stem cell proliferation, is mediated through spindle orientation determined via LIS1/NDEL1/dynein-mediated cortical microtubule capture."

Links the progenitor division phenotype to the LIS1/NDEL1/dynein microtubule-capture mechanism.

Reelin Signaling Deficiency

RELN encodes the large secreted glycoprotein reelin, which acts on migrating cortical neurons by binding lipoprotein receptors (VLDLR and ApoER2). Loss-of-function RELN mutations cause an autosomal recessive lissencephaly with cerebellar hypoplasia, reflecting reelin's role in directing cortical neuronal migration and laminar positioning.

migrating cortical neuron CL:0000540

RELN hgnc:9957

neuron migration GO:0001764 ↓ DECREASED

Downstream

Impaired Neuronal Migration Loss of reelin signaling to migrating cortical neurons disrupts the orderly inside-out cortical lamination, producing the migration defect underlying RELN-related lissencephaly with cerebellar hypoplasia.

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)."

Establishes RELN loss of function as a recessive cause of lissencephaly with cerebellar hypoplasia.

PMID:10973257 SUPPORT Human Clinical

"RELN encodes a large (388 kD) secreted protein that acts on migrating cortical neurons by binding to the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 9-11 ), alpha3beta1 integrin and protocadherins."

Describes the molecular mechanism by which reelin signaling guides migrating cortical neurons, lost in RELN-related lissencephaly.

Pericentriolar CEP85L Deficiency

CEP85L localizes to the pericentriolar material of the maternal centriole and is required cell-autonomously for cortical neuronal migration; knockdown of the mouse orthologue produces a neuronal migration defect. The malformation heterozygous CEP85L variants cause is posterior-predominant, matching the topography of PAFAH1B1 disease, which places the lesion at the centrosome rather than on the dynein regulator itself.

migrating cortical neuron CL:0000540

CEP85L hgnc:21638

pericentriolar material GO:0000242

Downstream

CDK5 Activation Failure at the Centrosome Loss of CEP85L disrupts the localization and activation of CDK5 at the centrosome, so the pericentriolar defect is transmitted to the kinase that the nucleokinesis module depends on.

Show evidence (2 references)

PMID:32097630 SUPPORT Model Organism

"We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice."

Supports both the pericentriolar localization bound on this node and the requirement for CEP85L in neuronal migration, the latter shown by mouse knockdown.

PMID:32097629 SUPPORT In Vitro

"We show that CEP85L is required cell autonomously in vivo and in vitro for migration, that it localizes to the maternal centriole"

Independently supports the cell-autonomous migration requirement and the centriolar localization asserted by this node.

CDK5 Activation Failure at the Centrosome

CDK5 is a cyclin-dependent kinase that forms a complex with LIS1, NDE1, KIF2A and the dynein heavy chain, all of which are required for neuronal migration. Its activity is reduced either by biallelic loss-of-function CDK5 alleles or by loss of CEP85L, which is needed for CDK5 to be correctly localized and activated at the centrosome. Human biallelic CDK5 null alleles cause lissencephaly with cerebellar hypoplasia, so the kinase is required for cortical migration in humans and not only in model systems.

migrating cortical neuron CL:0000540

CDK5 hgnc:1774

cyclin-dependent protein serine/threonine kinase activity GO:0004693 ↓ DECREASED

Downstream

LIS1-NUDEL-Dynein Nucleokinesis Failure Reduced CDK5 activity disorganizes the centrosome and the microtubule cytoskeleton, so nucleokinesis fails by the same route as in PAFAH1B1 disease even though the scaffold protein itself is intact.

Show evidence (2 references)

PMID:25560765 SUPPORT Human Clinical

"Functional analysis of the p.V162SfsX19 mutation, using a yeast complementation assay, showed loss-of-function of the mutant CDK5 gene product, thereby implicating its role in the pathogenesis of autosomal recessive LCH in the studied family."

Supports the loss of CDK5 kinase function bound on this node and ties it to the human recessive lissencephaly phenotype.

PMID:32097629 SUPPORT In Vitro

"it forms a complex with many other proteins required for migration, including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1"

Places CDK5 in a physical complex with LIS1 and the dynein heavy chain, which is the basis for the downstream edge to the nucleokinesis node.

Katanin p80 Deficiency in Dividing Neural Progenitors

KATNB1 encodes the regulatory p80 subunit of the microtubule-severing enzyme katanin. Biallelic deleterious KATNB1 alleles disrupt its interaction with the catalytic subunit KATNA1 and with other microtubule-associated proteins, and patient-derived fibroblasts show defective mitotic spindle formation. The lesion is therefore in the dividing progenitor rather than in the locomotion of an already postmitotic neuron, which is consistent with microcephaly being what loss of the orthologs reproduces in zebrafish and flies.

neuroepithelial stem cell CL:0002259 radial glial progenitor CL:0000681

KATNB1 hgnc:6217

microtubule severing GO:0051013 ↓ DECREASED mitotic spindle organization GO:0007052 ⚠ ABNORMAL

Downstream

Impaired Neuronal Migration Spindle and centrosome abnormalities in dividing neural progenitors reduce and mis-time the output of migrating neurons, producing the cortical malformation seen in KATNB1 disease.

Show evidence (2 references)

PMID:25521378 SUPPORT In Vitro

"Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins."

Supports the abnormal mitotic spindle organization bound on this node, measured in cells from affected individuals, and names katanin as the severing enzyme whose regulation is lost.

PMID:25521378 SUPPORT Model Organism

"kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis"

Supports locating the defect in the dividing progenitor compartment that this node binds, shown in the Drosophila ortholog.

ARP2/3 De-repression from αN-Catenin Loss

CTNNA2 encodes αN-catenin, which binds actin and represses ARP2/3-driven actin branching. Biallelic truncating CTNNA2 alleles remove that repression, and the neuronal phenotype is rescued either by the actin-binding domain of αN-catenin or by ARP2/3 inhibitors. This is an actin-side mechanism and is distinct from the microtubule and dynein lesions that the tubulin, PAFAH1B1 and DCX subtypes share.

cerebral cortex neuron CL:0010012

CTNNA2 hgnc:2510

Arp2/3 complex-mediated actin nucleation GO:0034314 ↑ INCREASED actin filament branching GO:0090135 ↑ INCREASED

Downstream

Impaired Neuronal Migration Unrestrained ARP2/3 activity destabilizes neurites and impairs cortical neuronal migration, producing the recessive pachygyria of the CTNNA2 subtype.

Show evidence (2 references)

PMID:30013181 SUPPORT In Vitro

"recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity"

Establishes that αN-catenin represses ARP2/3 actin branching, so its loss increases the two actin processes bound on this node.

PMID:30013181 SUPPORT In Vitro

"The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism."

The rescue by ARP2/3 inhibition is what makes de-repression the mechanism this node asserts rather than a correlated observation.

Neuronal Overmigration Across the Pial Boundary

In the cobblestone forms the cortical pial boundary fails rather than locomotion, and neurons and glia migrate past the cortical surface into the arachnoid space, forming an extracortical layer. This is the opposite direction of error from the migration-arrest nodes above and is why cobblestone malformation is kept separate from classic lissencephaly in this entry. TMTC3 reaches this node without an alpha-dystroglycan defect, while the glycosylation-pathway genes on the Cobblestone subtype reach it through alpha-dystroglycan.

cerebral cortex neuron CL:0010012

TMTC3 hgnc:26899 POMT1 hgnc:9202 POMT2 hgnc:19743 POMGNT1 hgnc:19139

neuron migration GO:0001764 ↑ INCREASED cerebral cortex radial glia-guided migration GO:0021801 ↕ DYSREGULATED

cerebral cortex UBERON:0000956

Downstream

Cobblestone lissencephaly Neuroglial overmigration past the pial boundary produces the extracortical layer and nodular brain surface that define cobblestone (type II) lissencephaly.

Show evidence (4 references)

PMID:22323514 SUPPORT Human Clinical

"Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain."

A fetal neuropathological series states the overmigration direction and the boundary lesion that this node asserts, distinguishing it from migration arrest.

PMID:22323514 SUPPORT Human Clinical

"The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%)."

Attaches POMT1, POMT2 and POMGNT1 to the human cobblestone phenotype in a genotyped fetal cohort, which is what justifies binding those three genes to this node.

PMID:27773428 SUPPORT Human Clinical

"Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement."

Attaches TMTC3 to the same cobblestone endpoint while separating it clinically from the dystroglycanopathies, which is why both routes are bound to one node here.

+ 1 more reference

ARX-Dependent Interneuron Tangential Migration Failure

In the ARX-related subtype the lesion is a transcription factor, not the dynein, microtubule or reelin machinery behind the other migration nodes in this entry. Loss of ARX impairs the production and tangential migration of GABAergic interneurons from the ganglionic eminences into the neocortex, so the cortical plate is left almost without interneurons. This interneuron deficit is the well-supported ARX-specific branch and the established route to the neonatal-onset epilepsy. How ARX loss produces the gyral malformation itself is unresolved and is not asserted here; the subtype's full mechanism, including a candidate neocortical radial-migration route, is curated in the ARX-Related_Lissencephaly_and_Interneuronopathy entry.

GABAergic interneuron CL:0011005

ARX hgnc:18060

neuron migration GO:0001764 ↓ DECREASED

DNA-binding transcriptional repressor activity GO:0001227 ↓ DECREASED

cerebral cortex UBERON:0000956

Downstream

Seizures Depletion of cortical inhibitory interneurons is considered the cause of the intractable, first-day-of-life seizures in XLAG. The intervening loss of cortical inhibition is inferred and has not been measured in human XLAG cortex.

Show evidence (5 references)

PMID:12379852 SUPPORT Human Clinical

"We found multiple loss-of-function mutations in ARX in individuals affected with XLAG and in some female relatives, and conclude that mutation of ARX causes XLAG."

Establishes ARX loss of function as the cause of the XLAG subtype, which is what places ARX on this node.

PMID:17460091 SUPPORT Model Organism

"Both tangential migration toward the cortex and striatum and radial migration to the globus pallidus and striatum were greatly reduced in the mutants, causing a periventricular accumulation of NPY+ or calretinin+ neurons in the MGE."

Arx-mutant mice show the reduced tangential migration from the ganglionic eminence that this node asserts.

PMID:20461390 SUPPORT Human Clinical

"In the ARX-mutated brain, the cortical plate contained almost exclusively pyramidal cells and was devoid of interneurons. The ganglionic eminences and basal ganglia were poorly cellular, suggesting an interneuron production and/or differentiation defect."

Human neuropathology of an ARX-mutated lissencephalic brain shows the interneuron-depleted cortex and hypocellular ganglionic eminences, and distinguishes the ARX defect from the LIS1 and DCX ones studied alongside it.

+ 2 more references

⬡

Pathograph

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

●

Phenotypes

Digestive 1

Feeding Difficulties HP:0011968

Show evidence (1 reference)

PMID:20301752 SUPPORT Human Clinical

"Other findings in PAFAH1B1-related lissencephaly/SBH include feeding issues and aspiration (which may result in need for gastrostomy tube placement), progressive microcephaly, and occasional developmental regression."

GeneReviews documents feeding issues and aspiration requiring gastrostomy as common complications.

Eye 1

Visual Impairment HP:0000505

Show evidence (1 reference)

PMID:20301752 SUPPORT Human Clinical

"visual tracking and response to sounds"

PAFAH1B1 GeneReviews documents poor visual tracking among the early neurologic findings of classic lissencephaly.

Head and Neck 1

Progressive Microcephaly HP:0000252

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301752 SUPPORT Human Clinical

"feeding issues and aspiration (which may result in need for gastrostomy tube placement), progressive microcephaly, and occasional developmental regression."

GeneReviews documents progressive microcephaly among the findings of PAFAH1B1-related lissencephaly.

Musculoskeletal 2

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:20301752 SUPPORT Human Clinical

"Affected newborns typically have mild-to-moderate hypotonia, feeding difficulties, and poor head control."

GeneReviews documents early hypotonia as a characteristic feature of PAFAH1B1-related lissencephaly.

Spasticity HP:0001257

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301752 SUPPORT Human Clinical

"axial hypotonia, and mild distal spasticity that can transition over time to more severe spasticity."

GeneReviews documents distal spasticity that progresses over time in PAFAH1B1-related lissencephaly.

Nervous System 8

Lissencephaly HP:0001339

Show evidence (1 reference)

PMID:23495356 SUPPORT Human Clinical

"The brains of lissencephaly patients have less-convoluted gyri in the cerebral cortex with impaired cortical lamination of neurons."

Directly describes the defining lissencephaly imaging/pathology phenotype of reduced gyration and impaired lamination.

Pachygyria HP:0001302

Show evidence (1 reference)

PMID:29671837 SUPPORT Human Clinical

"The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria."

Documents pachygyria (posterior and frontal) as a recognized pattern within the lissencephaly spectrum cohort.

Subcortical Band Heterotopia HP:0032409

Show evidence (1 reference)

PMID:20301364 SUPPORT Human Clinical

GeneReviews documents subcortical band heterotopia as a core DCX-related lissencephaly-spectrum phenotype, predominantly in females.

Seizures VERY_FREQUENT HP:0001250

Show evidence (1 reference)

PMID:20301752 SUPPORT Human Clinical

"Seizures occur in more than 90% of individuals with lissencephaly and often include infantile spasms."

GeneReviews documents seizures in >90% of individuals with lissencephaly, supporting both the association and a VERY_FREQUENT frequency band.

Infantile Spasms HP:0012469

Show evidence (1 reference)

PMID:20301752 SUPPORT Human Clinical

"Seizures occur in more than 90% of individuals with lissencephaly and often include infantile spasms."

GeneReviews explicitly notes that lissencephaly-associated seizures often include infantile spasms.

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:20301752 SUPPORT Human Clinical

"In individuals with PAFAH1B1-related lissencephaly/SBH, developmental delay ranges from mild to severe."

GeneReviews documents developmental delay/intellectual disability of variable severity as a core feature.

Cerebellar Hypoplasia HP:0001321

Show evidence (1 reference)

PMID:10973257 SUPPORT Human Clinical

Documents severe cerebellar (and hippocampal/brainstem) abnormalities as the hallmark distinguishing RELN-related recessive lissencephaly.

Cobblestone lissencephaly Type II lissencephaly HP:0007260

Show evidence (1 reference)

PMID:27773428 SUPPORT BACKGROUND Human Clinical

"Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia."

Defines the phenotype bound here. Recorded as BACKGROUND because the sentence is the cited report's framing of an established definition rather than its own finding, which is the TMTC3 gene discovery.

🧬

Genetic Associations

PAFAH1B1 (Loss of function)

Gene: PAFAH1B1 hgnc:8574 gene page

Show evidence (2 references)

PMID:29671837 SUPPORT Human Clinical

"LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%)."

LIS1/PAFAH1B1 is the most common genetic cause of lissencephaly in an 811-patient cohort.

PMID:20301752 SUPPORT Human Clinical

"The diagnosis of PAFAH1B1-related lissencephaly/SBH is established in a proband with a heterozygous pathogenic variant in PAFAH1B1 identified by molecular genetic testing."

GeneReviews confirms heterozygous PAFAH1B1 pathogenic variants as causal for classic lissencephaly/SBH.

DCX (Loss of function)

Gene: DCX hgnc:2714

Show evidence (2 references)

PMID:20301364 SUPPORT Human Clinical

"The diagnosis of a DCX-related disorder is established in a proband with a DCX pathogenic variant identified by molecular genetic testing."

GeneReviews confirms DCX pathogenic variants as causal for X-linked lissencephaly/SBH.

PMID:29671837 SUPPORT Human Clinical

"LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%)."

DCX is the second most common lissencephaly gene in a large cohort.

TUBA1A (Pathogenic variant)

Gene: TUBA1A hgnc:20766 gene page

Show evidence (1 reference)

PMID:29671837 SUPPORT Human Clinical

"LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%)."

TUBA1A is an established lissencephaly gene and the most common tubulin-gene cause in this cohort.

DYNC1H1 (Pathogenic variant)

Gene: DYNC1H1 hgnc:2961

Show evidence (1 reference)

PMID:29671837 SUPPORT Human Clinical

"LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%)."

DYNC1H1, encoding the dynein heavy chain, is a recognized lissencephaly gene consistent with the dynein/migration mechanism.

RELN (Loss of function)

Gene: RELN hgnc:9957 gene page

Show evidence (1 reference)

PMID:10973257 SUPPORT Human Clinical

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

Documents RELN loss-of-function (splicing-disrupting) variants causing recessive lissencephaly with cerebellar hypoplasia.

ARX (Pathogenic variant)

Gene: ARX hgnc:18060 gene page

Show evidence (1 reference)

PMID:29671837 SUPPORT Human Clinical

"Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes."

ARX is an established X-linked lissencephaly gene included in standard diagnostic testing.

CEP85L (Loss of function)

Gene: CEP85L hgnc:21638

Show evidence (2 references)

PMID:32097630 SUPPORT Human Clinical

Establishes heterozygous CEP85L variants as causal for posterior-predominant lissencephaly in 13 individuals.

CGGV:assertion_30a3191e-5ee3-467c-afa1-27fada71f9ea-2024-09-24T170000.000Z SUPPORT Other

ClinGen classifies the CEP85L gene-disease relationship as Definitive.

CDK5 (Loss of function)

Gene: CDK5 hgnc:1774

Show evidence (2 references)

PMID:25560765 SUPPORT Human Clinical

"we identified a homozygous splice site mutation g.IVS8+1G>A in cyclin-dependent kinase 5 (CDK5), causing complete skipping of exon 8, and leading to a frame shift and premature stop codon (p.V162SfsX19)."

Records the specific homozygous null allele that establishes CDK5 as a recessive lissencephaly gene.

PMID:25560765 SUPPORT Human Clinical

Supports the loss-of-function association recorded on this record rather than a gain or altered function.

KATNB1 (Loss of function)

Gene: KATNB1 hgnc:6217 gene page

Show evidence (2 references)

PMID:25521378 SUPPORT Human Clinical

Establishes biallelic deleterious KATNB1 alleles as a cause of complex cortical malformation.

PMID:25521378 SUPPORT In Vitro

Patient-derived fibroblasts localize the defect to mitotic spindle formation, supporting the loss-of-function association recorded here.

MACF1 (Pathogenic variant)

Gene: MACF1 hgnc:13664

Show evidence (2 references)

PMID:30471716 SUPPORT Human Clinical

"We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects."

Establishes the variant class and domain, supporting the dominant de novo mechanism recorded here.

CGGV:assertion_67d61f95-4ea3-41a7-ab90-e642c2c65c2a-2023-07-25T160000.000Z SUPPORT Other

ClinGen classifies MACF1 as Moderate for this malformation under autosomal dominant inheritance.

TMTC3 (Loss of function)

Gene: TMTC3 hgnc:26899

Show evidence (1 reference)

PMID:27773428 SUPPORT Human Clinical

Establishes biallelic TMTC3 variants in six families as a recessive cause of cobblestone lissencephaly.

CTNNA2 (Loss of function)

Gene: CTNNA2 hgnc:2510

Show evidence (1 reference)

PMID:30013181 SUPPORT Human Clinical

"Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria."

Establishes biallelic truncating CTNNA2 variants as causal for a recessive pachygyria, supporting the loss-of-function association recorded here.

💊

Medical Actions

Anti-Seizure Medication

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: valproic acid CHEBI:39867 lamotrigine CHEBI:6367

Standard anti-seizure medication selected by seizure type; in PAFAH1B1-related lissencephaly, polytherapy with valproic acid and lamotrigine appears most effective for drug-resistant seizures. Seizures are often refractory.

Show evidence (1 reference)

PMID:20301752 SUPPORT Human Clinical

"polytherapy with valproic acid and lamotrigine appears most effective in reducing drug-resistant seizures"

GeneReviews recommends valproic acid plus lamotrigine polytherapy for drug-resistant seizures in PAFAH1B1-related lissencephaly.

Gastrostomy and Feeding Support

Action: gastrostomy Ontology label: Gastrostomy NCIT:C52006

Placement of a gastrostomy tube for individuals with failure to thrive, dysphagia, and/or recurrent aspiration pneumonia, with feeding strategies for newborns with poor suck and swallow.

Show evidence (1 reference)

PMID:20301752 SUPPORT Human Clinical

"placement of a gastrostomy tube for those with failure to thrive, dysphagia, and/or recurrent aspiration pneumonia"

GeneReviews recommends gastrostomy for feeding failure and aspiration risk in lissencephaly.

Physical Therapy

Action: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Physical therapy to promote mobility and prevent contractures; in patient cohorts physiotherapy is reported among the most effective supportive therapies.

Show evidence (1 reference)

PMID:20301364 SUPPORT Human Clinical

"physical therapy to promote mobility and prevent contractures"

GeneReviews recommends physical therapy to support mobility and prevent contractures in DCX-related disorders.

Occupational Therapy

Action: occupational therapy Ontology label: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

Occupational therapy to improve fine motor skills and oral motor control, as part of multidisciplinary supportive management of lissencephaly.

Show evidence (1 reference)

PMID:20301364 SUPPORT Human Clinical

"occupational therapy to improve fine motor skills"

GeneReviews recommends occupational therapy to improve fine and oral motor skills in DCX-related lissencephaly.

Speech Therapy

Action: speech therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech therapy to support communication and oral-motor function as part of multidisciplinary supportive management.

Show evidence (1 reference)

PMID:20301364 SUPPORT Human Clinical

"participation in speech therapy"

GeneReviews includes speech therapy in the supportive management of DCX-related lissencephaly.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling and reproductive options (prenatal and preimplantation genetic testing) once a familial pathogenic variant is identified; important given the high de novo rate and variable inheritance across the spectrum.

Show evidence (1 reference)

PMID:20301364 SUPPORT Human Clinical

"Once the DCX pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews supports genetic counseling with prenatal/preimplantation testing once the familial variant is known.

{ }

Source YAML

click to show

name: Lissencephaly Spectrum Disorders
creation_date: "2026-06-03T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: lissencephaly spectrum disorders
  term:
    id: MONDO:0018838
    label: lissencephaly spectrum disorders
description: >-
  Lissencephaly spectrum disorders are a genetically heterogeneous group of
  malformations of cortical development characterized by abnormal cortical
  folding (reduced gyrification) due chiefly to impaired neuronal migration and
  disordered cortical lamination during embryonic development. The spectrum
  ranges from agyria (near-absent gyri) and pachygyria (broad, reduced gyri) to
  subcortical band heterotopia (SBH, "double cortex"). Most affected individuals
  present congenitally with a structural brain malformation and develop early
  intellectual disability, hypotonia, and drug-resistant seizures. Causal genes
  include PAFAH1B1 (LIS1), DCX, TUBA1A, ARX, RELN, DYNC1H1 and TUBG1, among
  others, with classic, X-linked, tubulinopathy, ARX-related, RELN-related and
  cobblestone (glycosylation-pathway) forms.
notes: >-
  Issue 4080 narrows this enrichment to the PAFAH1B1/LIS1 and DCX classical
  LIS/SBH microtubule-dynein core. Miller-Dieker syndrome is handled as a
  separate contiguous 17p13.3 deletion entry because YWHAE co-deletion and the
  broader deletion phenotype are not equivalent to isolated PAFAH1B1 disease.

  Three gene-defined concepts that MONDO files within or beside the lissencephaly
  spectrum are curated elsewhere rather than as subtypes here. Neu-Laxova
  syndrome 2 (MONDO:0014466, PSAT1) is a serine-biosynthesis disorder and is
  covered by 3-Phosphoglycerate_Dehydrogenase_Deficiency; lissencephaly due to
  TUBA1A mutation (MONDO:0012703) has its own entry,
  TUBA1A-related_Tubulinopathy, and the Tubulinopathy/TUBA1A subtype here is the
  spectrum-level view of it; cobblestone lissencephaly without muscular or
  ocular involvement (MONDO:0014077, LAMB1) has its own entry,
  LAMB1-Related_Cobblestone_Lissencephaly.

  Norman-Roberts syndrome (MONDO:0009760) carries MONDO's RELN gene edge, but the
  RELN association was established in autosomal recessive lissencephaly with
  cerebellar hypoplasia (PMID:10973257), which is the concept the RELN-related
  subtype binds and the one ClinGen curated RELN against (MONDO:0019450,
  Definitive). The one publication reporting molecular work under the
  Norman-Roberts clinical label, PMID:8368261, reports only the exclusion of a
  17p Miller-Dieker / isolated lissencephaly deletion by in situ hybridization
  and DNA probe analysis, and predates the RELN finding. No separate
  Norman-Roberts subtype is created, because the gene is already curated and the
  clinical label adds no distinct molecular claim.

  Two MONDO observations from this pass, recorded for a maintainer rather than
  acted on. MONDO:0032677 (lissencephaly 9 with complex brainstem malformation,
  xrefs including OMIM:618325) and MONDO:0100472 (lissencephaly spectrum disorder
  with complex brainstem malformation, whose only xref is GARD:0026233) denote the
  same MACF1 malformation; MONDO carries the MACF1 gene edge on the first, while
  ClinGen curated MACF1 against the second. And MONDO:0032578 (CTNNA2) sits under
  complex cortical dysplasia with other brain malformations rather than under
  lissencephaly spectrum disorders, although it carries "CTNNA2-related
  lissencephaly spectrum disorder" as a synonym, which is why it is curated here.
parents:
- congenital nervous system disorder
- disorder of development or morphogenesis
- hereditary neurological disease
references:
- reference: PMID:20301752
  title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
  tags:
  - GeneReviews
- reference: PMID:20301364
  title: "DCX-Related Disorders."
  tags:
  - GeneReviews
- reference: PMID:27010057
  title: "Tubulinopathies Overview."
  tags:
  - GeneReviews
pathophysiology:
- name: Impaired Neuronal Migration
  description: >-
    Pathogenic variants in genes governing cytoskeletal dynamics and neuronal
    migration disrupt the long-range radial migration of postmitotic cortical
    neurons from the proliferative ventricular zone to their final laminar
    position. The resulting failure or delay of migration produces a thickened,
    smooth (agyric/pachygyric) cortex with disordered six-layered lamination.
  cell_types:
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: radial glial progenitor
    term:
      id: CL:0000681
      label: radial glial cell
  biological_processes:
  - preferred_term: radial neuronal migration in cerebral cortex
    term:
      id: GO:0021799
      label: cerebral cortex radially oriented cell migration
    modifier: DECREASED
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  evidence:
  - reference: PMID:10973257
    reference_title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lissencephaly ("smooth brain," from "lissos," meaning smooth, and
      "encephalos," meaning brain) is a severe developmental disorder in
      which neuronal migration is impaired, leading to a thickened cerebral
      cortex whose normally folded contour is simplified and smooth.
    explanation: >-
      Establishes impaired neuronal migration as the core mechanism
      producing the thickened, smooth cortex that defines the lissencephaly
      spectrum.
  - reference: PMID:23495356
    reference_title: 'Cytoskeleton in action: lissencephaly, a neuronal migration disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Failure or delay in neuronal migration causes severe abnormalities in
      cortical layering, which consequently results in human lissencephaly
      ('smooth brain'), a neuronal migration disorder.
    explanation: >-
      Directly links failure/delay of neuronal migration to the abnormal
      cortical lamination that characterizes lissencephaly.
- name: Cytoskeletal and Microtubule Dysfunction
  genes:
  - preferred_term: TUBA1A
    term:
      id: hgnc:20766
      label: TUBA1A
  - preferred_term: TUBG1
    term:
      id: hgnc:12417
      label: TUBG1
  - preferred_term: MACF1
    term:
      id: hgnc:13664
      label: MACF1
  - preferred_term: DYNC1H1
    term:
      id: hgnc:2961
      label: DYNC1H1
  conforms_to: "microtubule_dependent_neuronal_migration_failure#Microtubule Apparatus Perturbation"
  description: >-
    Neuronal migration depends on microtubule and actin cytoskeletal dynamics
    and on the dynein motor and its regulators. Mutations in microtubule
    subunits (tubulins) and in microtubule/dynein-associated proteins such as
    PAFAH1B1 (LIS1) and DCX impair microtubule organization, transport and
    nucleokinesis, the coupling of the nucleus to the centrosome that drives
    forward movement of migrating neurons.
  cell_types:
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: microtubule-based movement
    term:
      id: GO:0007018
      label: microtubule-based movement
    modifier: ABNORMAL
  - preferred_term: nucleokinesis during radial migration
    term:
      id: GO:0021817
      label: nucleokinesis involved in cell motility in cerebral cortex radial glia guided migration
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23495356
    reference_title: 'Cytoskeleton in action: lissencephaly, a neuronal migration disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since microtubule (MT) and actin-associated proteins play important
      functions in regulating the dynamics of MT and actin cytoskeletons
      during neuronal migration, genetic mutations or deletions of crucial
      genes involved in cytoskeletal processes lead to lissencephaly in
      human and neuronal migration defects in mouse.
    explanation: >-
      Supports cytoskeletal/microtubule dysfunction as the molecular basis
      for the migration defect underlying lissencephaly.
  - reference: PMID:23495356
    reference_title: 'Cytoskeleton in action: lissencephaly, a neuronal migration disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During neuronal migration, MT organization and transport are
      controlled by platelet-activating factor acetylhydrolase isoform 1b
      regulatory subunit 1 (PAFAH1B1, formerly known as LIS1,
      Lissencephaly-1), doublecortin (DCX), YWHAE, and tubulin.
    explanation: >-
      Names the key microtubule-regulating proteins (LIS1/PAFAH1B1, DCX,
      tubulin) whose mutations cause classic lissencephaly.
  - reference: PMID:30471716
    reference_title: MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, we report variants of the microtubule-binding GAR domain of MACF1 as
      the cause of a distinctive and most likely pathognomonic brain
      malformation.
    explanation: >-
      Supports binding MACF1 to this node: the causal variants sit in the gene's
      microtubule-binding domain, which is the function this node asserts is perturbed.
  - reference: PMID:32097629
    reference_title: Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      it forms a complex with many other proteins required for migration,
      including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1
    explanation: >-
      Supports binding DYNC1H1 to this node by placing the dynein heavy chain in the same
      migration-required complex as LIS1, which this node already models.
  downstream:
  - target: Impaired Neuronal Migration
    description: >-
      Disruption of the LIS1/DCX/tubulin microtubule machinery impairs the
      nucleokinesis and somal translocation that radially migrating cortical
      neurons require, producing the migration arrest underlying lissencephaly.
- name: LIS1-NUDEL-Dynein Nucleokinesis Failure
  conforms_to: "microtubule_dependent_neuronal_migration_failure#Microtubule-Based Neuronal Motility Failure"
  description: >-
    PAFAH1B1/LIS1 dosage loss disrupts a LIS1-NUDEL-cytoplasmic dynein heavy
    chain complex that normally regulates dynein on microtubules during
    neuronal migration. The resulting defect impairs centrosome-nucleus coupling
    and nucleokinesis in migrating cortical neurons, producing the classical
    type I lissencephaly/SBH migration-arrest branch. Mouse allelic series show
    that lower Pafah1b1 activity causes progressively more severe neuronal
    migration and brain-organization defects, matching the clinical severity
    gradient from pachygyria/SBH toward more severe lissencephaly.
  genes:
  - preferred_term: PAFAH1B1
    term:
      id: hgnc:8574
      label: PAFAH1B1
  - preferred_term: NDEL1
    term:
      id: hgnc:17620
      label: NDEL1
  cell_types:
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: nucleokinesis during radial migration
    term:
      id: GO:0021817
      label: nucleokinesis involved in cell motility in cerebral cortex radial glia guided migration
    modifier: ABNORMAL
  - preferred_term: microtubule-based movement
    term:
      id: GO:0007018
      label: microtubule-based movement
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:11163259
    reference_title: "A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrate that LIS1 directly interacts with the cytoplasmic dynein
      heavy chain (CDHC) and NUDEL
    explanation: >-
      Demonstrates the core LIS1-NUDEL-dynein molecular complex underlying the
      neuronal migration branch.
  - reference: PMID:16481446
    reference_title: "Regulation of cytoplasmic dynein ATPase by Lis1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      recombinant Lis1 binds to native brain dynein and significantly increases
      the microtubule-stimulated enzymatic activity of dynein in vitro.
    explanation: >-
      Shows that LIS1 directly modulates dynein enzymatic activity, connecting
      PAFAH1B1 loss to microtubule motor dysfunction.
  - reference: PMID:9697693
    reference_title: "Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice with one inactive allele display cortical, hippocampal and olfactory
      bulb disorganization resulting from delayed neuronal migration by a
      cell-autonomous neuronal pathway.
    explanation: >-
      Supports dosage-sensitive LIS1 neuronal migration failure in vivo.
  downstream:
  - target: Impaired Neuronal Migration
    description: >-
      Disruption of the LIS1-NUDEL-dynein motor pathway impairs nucleokinesis
      and radial migration, converging on the lissencephaly cortical-lamination
      defect.
- name: DCX Microtubule Stabilization Failure
  conforms_to: "microtubule_dependent_neuronal_migration_failure#Microtubule Apparatus Perturbation"
  description: >-
    DCX encodes a neuronal microtubule-associated protein required for normal
    migration of cortical neurons. Pathogenic DCX variants impair the
    microtubule-stabilizing and tubulin-polymerizing function of doublecortin,
    slowing or arresting migration. Hemizygous males usually develop
    anterior-predominant classic lissencephaly, whereas heterozygous females
    often develop subcortical band heterotopia through X-linked mosaicism.
  genes:
  - preferred_term: DCX
    term:
      id: hgnc:2714
      label: DCX
  cell_types:
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: microtubule cytoskeleton organization
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
    modifier: DYSREGULATED
  - preferred_term: cytoplasmic microtubule organization
    term:
      id: GO:0031122
      label: cytoplasmic microtubule organization
    modifier: DECREASED
  evidence:
  - reference: PMID:9489700
    reference_title: "Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked lissencephaly and "double cortex" are allelic human disorders
      mapping to Xq22.3-Xq23 associated with arrest of migrating cerebral
      cortical neurons.
    explanation: >-
      Establishes DCX-related lissencephaly and double-cortex/SBH as allelic
      human neuronal-migration arrest disorders.
  - reference: PMID:10399933
    reference_title: "Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      DCX coassembles with brain microtubules, and recombinant DCX stimulates
      the polymerization of purified tubulin.
    explanation: >-
      Supports the microtubule-stabilization and tubulin-polymerization branch
      of DCX disease biology.
  - reference: PMID:10399933
    reference_title: "Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      DCX likely directs neuronal migration by regulating the organization and
      stability of microtubules.
    explanation: >-
      Links DCX microtubule organization and stability to neuronal migration.
  downstream:
  - target: Impaired Neuronal Migration
    description: >-
      Loss of DCX microtubule stabilization disrupts migration of cortical
      neurons, producing lissencephaly or subcortical band heterotopia depending
      on sex, mosaicism, and variant context.
- name: LIS1 Progenitor Spindle Orientation Defect
  conforms_to: "neural_progenitor_centrosome_spindle_dysfunction#Centrosome and Mitotic Spindle Perturbation"
  description: >-
    In addition to the postmitotic neuronal migration branch, PAFAH1B1/LIS1 loss
    perturbs neuroepithelial and radial-glial progenitor mitotic spindle
    orientation through LIS1/NDEL1/dynein-mediated cortical microtubule capture.
    This progenitor branch affects symmetric division, progenitor expansion and
    cortical neuron output, explaining why PAFAH1B1 disease can include cortical
    thickness, simplified gyration and severity features not captured by a
    migration-only model.
  genes:
  - preferred_term: PAFAH1B1
    term:
      id: hgnc:8574
      label: PAFAH1B1
  - preferred_term: NDEL1
    term:
      id: hgnc:17620
      label: NDEL1
  cell_types:
  - preferred_term: neuroepithelial stem cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: radial glial progenitor
    term:
      id: CL:0000681
      label: radial glial cell
  biological_processes:
  - preferred_term: mitotic spindle organization
    term:
      id: GO:0007052
      label: mitotic spindle organization
    modifier: DYSREGULATED
  - preferred_term: cell division
    term:
      id: GO:0051301
      label: cell division
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:18267077
    reference_title: "Neuroepithelial stem cell proliferation requires LIS1 for precise spindle orientation and symmetric division."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lis1 is essential for precise control of mitotic spindle orientation in
      both neuroepithelial stem cells and radial glial progenitor cells.
    explanation: >-
      Supports a LIS1 progenitor-spindle branch in neuroepithelial and radial
      glial progenitors.
  - reference: PMID:18267077
    reference_title: "Neuroepithelial stem cell proliferation requires LIS1 for precise spindle orientation and symmetric division."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      control of symmetric division, essential for neuroepithelial stem cell
      proliferation, is mediated through spindle orientation determined via
      LIS1/NDEL1/dynein-mediated cortical microtubule capture.
    explanation: >-
      Links the progenitor division phenotype to the LIS1/NDEL1/dynein
      microtubule-capture mechanism.
  downstream:
  - target: Impaired Neuronal Migration
    description: >-
      The progenitor-spindle branch changes cortical neuron output and cortical
      organization, worsening the same abnormal cortical lamination endpoint as
      the neuronal migration branch.
- name: Reelin Signaling Deficiency
  description: >-
    RELN encodes the large secreted glycoprotein reelin, which acts on
    migrating cortical neurons by binding lipoprotein receptors (VLDLR and
    ApoER2). Loss-of-function RELN mutations cause an autosomal recessive
    lissencephaly with cerebellar hypoplasia, reflecting reelin's role in
    directing cortical neuronal migration and laminar positioning.
  genes:
  - preferred_term: RELN
    term:
      id: hgnc:9957
      label: RELN
  cell_types:
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  evidence:
  - reference: PMID:10973257
    reference_title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.
    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: >-
      Establishes RELN loss of function as a recessive cause of
      lissencephaly with cerebellar hypoplasia.
  - reference: PMID:10973257
    reference_title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RELN encodes a large (388 kD) secreted protein that acts on migrating
      cortical neurons by binding to the very low density lipoprotein
      receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 9-11
      ), alpha3beta1 integrin and protocadherins.
    explanation: >-
      Describes the molecular mechanism by which reelin signaling guides
      migrating cortical neurons, lost in RELN-related lissencephaly.
  downstream:
  - target: Impaired Neuronal Migration
    description: >-
      Loss of reelin signaling to migrating cortical neurons disrupts the
      orderly inside-out cortical lamination, producing the migration defect
      underlying RELN-related lissencephaly with cerebellar hypoplasia.
- name: Pericentriolar CEP85L Deficiency
  description: >-
    CEP85L localizes to the pericentriolar material of the maternal centriole and
    is required cell-autonomously for cortical neuronal migration; knockdown of
    the mouse orthologue produces a neuronal migration defect. The malformation
    heterozygous CEP85L variants cause is posterior-predominant, matching the
    topography of PAFAH1B1 disease, which places the lesion at the centrosome
    rather than on the dynein regulator itself.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CEP85L
    term:
      id: hgnc:21638
      label: CEP85L
  cell_types:
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0000540
      label: neuron
  cellular_components:
  - preferred_term: pericentriolar material
    term:
      id: GO:0000242
      label: pericentriolar material
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32097630
    reference_title: Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that CEP85L is a centrosome protein localizing to the
      pericentriolar material, and knockdown of Cep85l causes a neuronal
      migration defect in mice.
    explanation: >-
      Supports both the pericentriolar localization bound on this node and the
      requirement for CEP85L in neuronal migration, the latter shown by mouse
      knockdown.
  - reference: PMID:32097629
    reference_title: Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that CEP85L is required cell autonomously in vivo and in vitro for
      migration, that it localizes to the maternal centriole
    explanation: >-
      Independently supports the cell-autonomous migration requirement and the
      centriolar localization asserted by this node.
  downstream:
  - target: CDK5 Activation Failure at the Centrosome
    description: >-
      Loss of CEP85L disrupts the localization and activation of CDK5 at the
      centrosome, so the pericentriolar defect is transmitted to the kinase that
      the nucleokinesis module depends on.
    evidence:
    - reference: PMID:32097629
      reference_title: Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Loss of CEP85L disrupts CDK5 localization and activation, leading to
        centrosome disorganization and disrupted microtubule cytoskeleton
        organization.
      explanation: >-
        States the causal step from CEP85L loss to failed CDK5 activation that this
        edge asserts.
- name: CDK5 Activation Failure at the Centrosome
  description: >-
    CDK5 is a cyclin-dependent kinase that forms a complex with LIS1, NDE1, KIF2A
    and the dynein heavy chain, all of which are required for neuronal migration.
    Its activity is reduced either by biallelic loss-of-function CDK5 alleles or
    by loss of CEP85L, which is needed for CDK5 to be correctly localized and
    activated at the centrosome. Human biallelic CDK5 null alleles cause
    lissencephaly with cerebellar hypoplasia, so the kinase is required for
    cortical migration in humans and not only in model systems.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CDK5
    term:
      id: hgnc:1774
      label: CDK5
  cell_types:
  - preferred_term: migrating cortical neuron
    term:
      id: CL:0000540
      label: neuron
  molecular_functions:
  - preferred_term: cyclin-dependent protein serine/threonine kinase activity
    term:
      id: GO:0004693
      label: cyclin-dependent protein serine/threonine kinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:25560765
    reference_title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional analysis of the p.V162SfsX19 mutation, using a yeast
      complementation assay, showed loss-of-function of the mutant CDK5 gene
      product, thereby implicating its role in the pathogenesis of autosomal
      recessive LCH in the studied family.
    explanation: >-
      Supports the loss of CDK5 kinase function bound on this node and ties it to the
      human recessive lissencephaly phenotype.
  - reference: PMID:32097629
    reference_title: Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      it forms a complex with many other proteins required for migration,
      including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1
    explanation: >-
      Places CDK5 in a physical complex with LIS1 and the dynein heavy chain, which is
      the basis for the downstream edge to the nucleokinesis node.
  downstream:
  - target: LIS1-NUDEL-Dynein Nucleokinesis Failure
    description: >-
      Reduced CDK5 activity disorganizes the centrosome and the microtubule
      cytoskeleton, so nucleokinesis fails by the same route as in PAFAH1B1
      disease even though the scaffold protein itself is intact.
    evidence:
    - reference: PMID:32097629
      reference_title: Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Loss of CEP85L disrupts CDK5 localization and activation, leading to
        centrosome disorganization and disrupted microtubule cytoskeleton
        organization.
      explanation: >-
        Supports the step from failed CDK5 activation to disorganized centrosome and
        microtubule cytoskeleton, which is what the nucleokinesis node models.
- name: Katanin p80 Deficiency in Dividing Neural Progenitors
  description: >-
    KATNB1 encodes the regulatory p80 subunit of the microtubule-severing enzyme
    katanin. Biallelic deleterious KATNB1 alleles disrupt its interaction with
    the catalytic subunit KATNA1 and with other microtubule-associated proteins,
    and patient-derived fibroblasts show defective mitotic spindle formation. The
    lesion is therefore in the dividing progenitor rather than in the locomotion
    of an already postmitotic neuron, which is consistent with microcephaly being
    what loss of the orthologs reproduces in zebrafish and flies.
  biological_scale: CELLULAR
  genes:
  - preferred_term: KATNB1
    term:
      id: hgnc:6217
      label: KATNB1
  cell_types:
  - preferred_term: neuroepithelial stem cell
    term:
      id: CL:0002259
      label: neuroepithelial stem cell
  - preferred_term: radial glial progenitor
    term:
      id: CL:0000681
      label: radial glial cell
  biological_processes:
  - preferred_term: microtubule severing
    term:
      id: GO:0051013
      label: microtubule severing
    modifier: DECREASED
  - preferred_term: mitotic spindle organization
    term:
      id: GO:0007052
      label: mitotic spindle organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25521378
    reference_title: Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mitotic spindle formation is defective in patient-derived fibroblasts, a
      consequence of disrupted interactions of mutant KATNB1 with KATNA1, the
      catalytic subunit of Katanin, and other microtubule-associated proteins.
    explanation: >-
      Supports the abnormal mitotic spindle organization bound on this node, measured in
      cells from affected individuals, and names katanin as the severing enzyme whose
      regulation is lost.
  - reference: PMID:25521378
    reference_title: Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      kat80 loss specifically affects the asymmetrically dividing neuroblasts,
      which display supernumerary centrosomes and spindle abnormalities during
      mitosis
    explanation: >-
      Supports locating the defect in the dividing progenitor compartment that this node
      binds, shown in the Drosophila ortholog.
  downstream:
  - target: Impaired Neuronal Migration
    description: >-
      Spindle and centrosome abnormalities in dividing neural progenitors reduce
      and mis-time the output of migrating neurons, producing the cortical
      malformation seen in KATNB1 disease.
    evidence:
    - reference: PMID:25521378
      reference_title: Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Exome sequencing analysis of over 2,000 children with complex
        malformations of cortical development identified five independent (four
        homozygous and one compound heterozygous) deleterious mutations in
        KATNB1, encoding the regulatory subunit of the microtubule-severing
        enzyme Katanin.
      explanation: >-
        Links biallelic KATNB1 loss to complex malformations of cortical development in
        humans, which is the consequence this edge asserts.
- name: ARP2/3 De-repression from αN-Catenin Loss
  description: >-
    CTNNA2 encodes αN-catenin, which binds actin and represses ARP2/3-driven
    actin branching. Biallelic truncating CTNNA2 alleles remove that repression,
    and the neuronal phenotype is rescued either by the actin-binding domain of
    αN-catenin or by ARP2/3 inhibitors. This is an actin-side mechanism and is
    distinct from the microtubule and dynein lesions that the tubulin, PAFAH1B1
    and DCX subtypes share.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CTNNA2
    term:
      id: hgnc:2510
      label: CTNNA2
  cell_types:
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: Arp2/3 complex-mediated actin nucleation
    term:
      id: GO:0034314
      label: Arp2/3 complex-mediated actin nucleation
    modifier: INCREASED
  - preferred_term: actin filament branching
    term:
      id: GO:0090135
      label: actin filament branching
    modifier: INCREASED
  evidence:
  - reference: PMID:30013181
    reference_title: "Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      recombinant αN-catenin interacted with purified actin and repressed ARP2/3
      actin-branching activity
    explanation: >-
      Establishes that αN-catenin represses ARP2/3 actin branching, so its loss
      increases the two actin processes bound on this node.
  - reference: PMID:30013181
    reference_title: "Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the
      neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3
      de-repression as a potential disease mechanism.
    explanation: >-
      The rescue by ARP2/3 inhibition is what makes de-repression the mechanism this
      node asserts rather than a correlated observation.
  downstream:
  - target: Impaired Neuronal Migration
    description: >-
      Unrestrained ARP2/3 activity destabilizes neurites and impairs cortical
      neuronal migration, producing the recessive pachygyria of the CTNNA2
      subtype.
    evidence:
    - reference: PMID:30013181
      reference_title: "Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        CTNNA2 was expressed in human cerebral cortex, and its loss in neurons
        led to defects in neurite stability and migration.
      explanation: >-
        States the migration defect that follows CTNNA2 loss, which is the consequence
        this edge asserts.
- name: Neuronal Overmigration Across the Pial Boundary
  conforms_to: "pial_basement_membrane_radial_glial_endfoot_failure#Neuronal Overmigration Across the Pial Boundary"
  description: >-
    In the cobblestone forms the cortical pial boundary fails rather than
    locomotion, and neurons and glia migrate past the cortical surface into the
    arachnoid space, forming an extracortical layer. This is the opposite
    direction of error from the migration-arrest nodes above and is why
    cobblestone malformation is kept separate from classic lissencephaly in this
    entry. TMTC3 reaches this node without an alpha-dystroglycan defect, while
    the glycosylation-pathway genes on the Cobblestone subtype reach it through
    alpha-dystroglycan.
  biological_scale: TISSUE
  genes:
  - preferred_term: TMTC3
    term:
      id: hgnc:26899
      label: TMTC3
  - preferred_term: POMT1
    term:
      id: hgnc:9202
      label: POMT1
  - preferred_term: POMT2
    term:
      id: hgnc:19743
      label: POMT2
  - preferred_term: POMGNT1
    term:
      id: hgnc:19139
      label: POMGNT1
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  cell_types:
  - preferred_term: 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: INCREASED
  - preferred_term: cerebral cortex radial glia-guided migration
    term:
      id: GO:0021801
      label: cerebral cortex radial glia-guided migration
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:22323514
    reference_title: "Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cortical dysplasia results from neuroglial overmigration into the
      arachnoid space, forming an extracortical layer, responsible for agyria
      and/or 'cobblestone' brain surface and ventricular enlargement. The
      underlying mechanism is a disruption of the glia limitans, the outermost
      layer of the brain.
    explanation: >-
      A fetal neuropathological series states the overmigration direction and the
      boundary lesion that this node asserts, distinguishing it from migration arrest.
  - reference: PMID:22323514
    reference_title: "Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most severe, which we called cobblestone lissencephaly A, was linked
      to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe,
      cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%).
    explanation: >-
      Attaches POMT1, POMT2 and POMGNT1 to the human cobblestone phenotype in a
      genotyped fetal cohort, which is what justifies binding those three genes to this
      node.
  - reference: PMID:27773428
    reference_title: "Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement."
    explanation: >-
      Attaches TMTC3 to the same cobblestone endpoint while separating it clinically from
      the dystroglycanopathies, which is why both routes are bound to one node here.
  - reference: PMID:22323514
    reference_title: "Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed
      these diseases to alpha-dystroglycanopathies.
    explanation: >-
      Supports the claim in this node's description that POMT1, POMT2 and POMGNT1 reach the
      cobblestone endpoint through alpha-dystroglycan, where TMTC3 does not. Recorded as
      BACKGROUND because it is the cited study's summary of prior gene discoveries rather
      than its own result.
  downstream:
  - target: Cobblestone lissencephaly
    description: >-
      Neuroglial overmigration past the pial boundary produces the extracortical
      layer and nodular brain surface that define cobblestone (type II)
      lissencephaly.
    evidence:
    - reference: PMID:22323514
      reference_title: "Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cortical dysplasia results from neuroglial overmigration into the
        arachnoid space, forming an extracortical layer, responsible for agyria
        and/or 'cobblestone' brain surface and ventricular enlargement. The
        underlying mechanism is a disruption of the glia limitans, the outermost
        layer of the brain.
      explanation: >-
        States the step from overmigration to the cobblestone brain surface that this
        edge asserts.
- name: ARX-Dependent Interneuron Tangential Migration Failure
  conforms_to: "interneuron_specification_tangential_migration_failure#Tangential Migration Failure from Ganglionic Eminences"
  description: >-
    In the ARX-related subtype the lesion is a transcription factor, not the
    dynein, microtubule or reelin machinery behind the other migration nodes in
    this entry. Loss of ARX impairs the production and tangential migration of
    GABAergic interneurons from the ganglionic eminences into the neocortex, so
    the cortical plate is left almost without interneurons. This interneuron
    deficit is the well-supported ARX-specific branch and the established route
    to the neonatal-onset epilepsy. How ARX loss produces the gyral malformation
    itself is unresolved and is not asserted here; the subtype's full mechanism,
    including a candidate neocortical radial-migration route, is curated in the
    ARX-Related_Lissencephaly_and_Interneuronopathy entry.
  biological_scale: CELLULAR
  genes:
  - preferred_term: ARX
    term:
      id: hgnc:18060
      label: ARX
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  cell_types:
  - preferred_term: GABAergic interneuron
    term:
      id: CL:0011005
      label: GABAergic interneuron
  molecular_functions:
  - preferred_term: DNA-binding transcriptional repressor activity
    modifier: DECREASED
    term:
      id: GO:0001227
      label: DNA-binding transcription repressor activity, RNA polymerase II-specific
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  evidence:
  - reference: PMID:12379852
    reference_title: "Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found multiple loss-of-function mutations in ARX in individuals
      affected with XLAG and in some female relatives, and conclude that mutation
      of ARX causes XLAG.
    explanation: >-
      Establishes ARX loss of function as the cause of the XLAG subtype, which is
      what places ARX on this node.
  - reference: PMID:17460091
    reference_title: "Inactivation of Arx, the murine ortholog of the X-linked lissencephaly with ambiguous genitalia gene, leads to severe disorganization of the ventral telencephalon with impaired neuronal migration and differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Both tangential migration toward the cortex and striatum and radial
      migration to the globus pallidus and striatum were greatly reduced in the
      mutants, causing a periventricular accumulation of NPY+ or calretinin+
      neurons in the MGE.
    explanation: >-
      Arx-mutant mice show the reduced tangential migration from the ganglionic
      eminence that this node asserts.
  - reference: PMID:20461390
    reference_title: "Evidence for tangential migration disturbances in human lissencephaly resulting from a defect in LIS1, DCX and ARX genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the ARX-mutated brain, the cortical plate contained almost exclusively
      pyramidal cells and was devoid of interneurons. The ganglionic eminences
      and basal ganglia were poorly cellular, suggesting an interneuron
      production and/or differentiation defect.
    explanation: >-
      Human neuropathology of an ARX-mutated lissencephalic brain shows the
      interneuron-depleted cortex and hypocellular ganglionic eminences, and
      distinguishes the ARX defect from the LIS1 and DCX ones studied alongside it.
  - reference: PMID:15921244
    reference_title: 'X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, "interneuronopathy".'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      X-linked lissencephaly with abnormal genitalia is the first human disorder
      in which deficient tangential migration in the brain has been demonstrated.
    explanation: >-
      A clinical review frames XLAG as the human prototype of a tangential
      migration disorder.
  - reference: PMID:18835247
    reference_title: The function of the Aristaless-related homeobox (Arx) gene product as a transcriptional repressor
      is diminished by mutations associated with X-linked mental retardation (XLMR).
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: Here, we show that two disease-associated mutations disrupt the function of Arx as a transcriptional
      repressor.
    explanation: Grounds the molecular function bound on this node. ARX acts as a transcriptional repressor and
      disease mutations reduce that activity. Indirect for this node because the assayed mutations are XLMR
      alleles; the XLAG alleles behind this subtype are loss-of-function and remove the activity outright.
  downstream:
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Depletion of cortical inhibitory interneurons is considered the cause of
      the intractable, first-day-of-life seizures in XLAG. The intervening loss of
      cortical inhibition is inferred and has not been measured in human XLAG
      cortex.
    evidence:
    - reference: PMID:15921244
      reference_title: 'X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, "interneuronopathy".'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The striking epileptogenicity of X-linked lissencephaly with abnormal
        genitalia and West's syndrome associated with ARX mutations i s
        considered to be caused by a disorder of interneurons involving a
        tangentialmigration disorder.
      explanation: >-
        States the interneuron-migration route to epilepsy in ARX-related
        lissencephaly. The source's own typography ("i s", "tangentialmigration")
        is kept because the snippet must quote it exactly.
phenotypes:
- name: Lissencephaly
  description: >-
    A smooth cerebral surface with absent or reduced gyration (agyria or
    pachygyria) due to arrest of neuronal migration and cortical
    dyslamination.
  phenotype_term:
    preferred_term: Lissencephaly
    term:
      id: HP:0001339
      label: Lissencephaly
  evidence:
  - reference: PMID:23495356
    reference_title: 'Cytoskeleton in action: lissencephaly, a neuronal migration disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The brains of lissencephaly patients have less-convoluted gyri in the
      cerebral cortex with impaired cortical lamination of neurons.
    explanation: >-
      Directly describes the defining lissencephaly imaging/pathology
      phenotype of reduced gyration and impaired lamination.
- name: Pachygyria
  description: >-
    Broad, abnormally thick gyri with reduced sulcation, a milder pattern
    within the lissencephaly spectrum, often posterior-predominant in
    LIS1/PAFAH1B1 disease.
  phenotype_term:
    preferred_term: Pachygyria
    term:
      id: HP:0001302
      label: Pachygyria
  evidence:
  - reference: PMID:29671837
    reference_title: Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of unsolved patients had posterior pachygyria,
      subcortical band heterotopia, or mild frontal pachygyria.
    explanation: >-
      Documents pachygyria (posterior and frontal) as a recognized pattern
      within the lissencephaly spectrum cohort.
- name: Subcortical Band Heterotopia
  description: >-
    A band of arrested, heterotopic neurons in the white matter beneath the
    cortex ("double cortex"), characteristically seen in females with
    DCX-related disorders.
  phenotype_term:
    preferred_term: Subcortical band heterotopia
    term:
      id: HP:0032409
      label: Subcortical band heterotopia
  evidence:
  - reference: PMID:20301364
    reference_title: DCX-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DCX-related disorders include the following neuronal migration
      disorders: classic thick lissencephaly (more severe anteriorly),
      usually in males, and subcortical band heterotopia (SBH), primarily in
      females.
    explanation: >-
      GeneReviews documents subcortical band heterotopia as a core
      DCX-related lissencephaly-spectrum phenotype, predominantly in females.
- name: Seizures
  description: >-
    Epilepsy occurs in the great majority of individuals with classic
    lissencephaly, frequently includes infantile spasms, and is often
    drug-resistant.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures occur in more than 90% of individuals with lissencephaly and
      often include infantile spasms.
    explanation: >-
      GeneReviews documents seizures in >90% of individuals with
      lissencephaly, supporting both the association and a VERY_FREQUENT
      frequency band.
- name: Infantile Spasms
  description: >-
    An early-onset epileptic encephalopathy commonly seen in lissencephaly,
    often refractory to anti-seizure medication.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures occur in more than 90% of individuals with lissencephaly and
      often include infantile spasms.
    explanation: >-
      GeneReviews explicitly notes that lissencephaly-associated seizures
      often include infantile spasms.
- name: Hypotonia
  description: >-
    Affected newborns typically have mild-to-moderate axial hypotonia and poor
    head control, which may transition over time to spasticity.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected newborns typically have mild-to-moderate hypotonia, feeding
      difficulties, and poor head control.
    explanation: >-
      GeneReviews documents early hypotonia as a characteristic feature of
      PAFAH1B1-related lissencephaly.
- name: Spasticity
  description: >-
    Mild distal spasticity emerging in the first years that can progress to
    more severe spasticity, following early hypotonia.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      axial hypotonia, and mild distal spasticity that can transition over
      time to more severe spasticity.
    explanation: >-
      GeneReviews documents distal spasticity that progresses over time in
      PAFAH1B1-related lissencephaly.
- name: Intellectual Disability
  description: >-
    Developmental delay and intellectual disability are near-universal,
    ranging from mild to severe; the best developmental level achieved in
    classic lissencephaly is often only that of a 3-5 month-old infant.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In individuals with PAFAH1B1-related lissencephaly/SBH, developmental
      delay ranges from mild to severe.
    explanation: >-
      GeneReviews documents developmental delay/intellectual disability of
      variable severity as a core feature.
- name: Feeding Difficulties
  description: >-
    Feeding issues and aspiration are common and may require gastrostomy tube
    placement; dysphagia contributes to failure to thrive and aspiration
    pneumonia.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings in PAFAH1B1-related lissencephaly/SBH include feeding
      issues and aspiration (which may result in need for gastrostomy tube
      placement), progressive microcephaly, and occasional developmental
      regression.
    explanation: >-
      GeneReviews documents feeding issues and aspiration requiring
      gastrostomy as common complications.
- name: Progressive Microcephaly
  description: >-
    Head growth deceleration leading to progressive (acquired/postnatal)
    microcephaly is a recognized feature of PAFAH1B1-related lissencephaly.
  phenotype_term:
    preferred_term: Progressive microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      feeding issues and aspiration (which may result in need for
      gastrostomy tube placement), progressive microcephaly, and occasional
      developmental regression.
    explanation: >-
      GeneReviews documents progressive microcephaly among the findings of
      PAFAH1B1-related lissencephaly.
- name: Cerebellar Hypoplasia
  description: >-
    RELN-related autosomal recessive lissencephaly is distinguished by severe
    cerebellar hypoplasia together with hippocampal and brainstem
    abnormalities.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  subtype: RELN-related
  evidence:
  - reference: PMID:10973257
    reference_title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.
    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: >-
      Documents severe cerebellar (and hippocampal/brainstem) abnormalities
      as the hallmark distinguishing RELN-related recessive lissencephaly.
- name: Visual Impairment
  description: >-
    Infants with classic (PAFAH1B1-related) lissencephaly typically show poor
    visual tracking and reduced response to sounds during the first years of
    life.
  phenotype_term:
    preferred_term: Poor visual tracking
    term:
      id: HP:0000505
      label: Visual impairment
  subtype: Classic/LIS1
  evidence:
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      visual tracking and response to sounds
    explanation: >-
      PAFAH1B1 GeneReviews documents poor visual tracking among the early
      neurologic findings of classic lissencephaly.
- name: Cobblestone lissencephaly
  category: Neurological
  description: >-
    Cobblestone (type II) lissencephaly, in which neurons and glia overmigrate
    past the pial boundary into the arachnoid space and form an extracortical
    layer with a nodular brain surface. Present in the TMTC3 and
    glycosylation-pathway subtypes and absent from the migration-arrest forms.
  phenotype_term:
    preferred_term: Type II lissencephaly
    term:
      id: HP:0007260
      label: Type II lissencephaly
  evidence:
  - reference: PMID:27773428
    reference_title: "Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Cobblestone lissencephaly (COB) is a severe brain malformation in which
      overmigration of neurons and glial cells into the arachnoid space results
      in the formation of cortical dysplasia.
    explanation: >-
      Defines the phenotype bound here. Recorded as BACKGROUND because the sentence is
      the cited report's framing of an established definition rather than its own
      finding, which is the TMTC3 gene discovery.
has_subtypes:
- name: Classic/LIS1
  display_name: Classic lissencephaly (PAFAH1B1/LIS1-related)
  subtype_term:
    preferred_term: classic lissencephaly
    term:
      id: MONDO:0015146
      label: classic lissencephaly
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0011830
        label: lissencephaly due to LIS1 mutation
      mapping_predicate: skos:narrowMatch
      mapping_source: MONDO
      mapping_justification: >-
        MONDO:0011830 names the PAFAH1B1/LIS1-specific disease and carries MONDO's
        PAFAH1B1 gene edge. It is narrower than the subtype_term bound above, which
        denotes classic lissencephaly as a radiological class and also covers the
        DCX-related form curated as a separate subtype here.
  description: >-
    The most common classic lissencephaly, caused by heterozygous PAFAH1B1
    (LIS1) variants or 17p13.3 deletions, usually de novo. Imaging typically
    shows posterior-predominant agyria/pachygyria. Seizures occur in >90% of
    individuals and developmental delay ranges from mild to severe.
  genes:
  - preferred_term: PAFAH1B1
    term:
      id: hgnc:8574
      label: PAFAH1B1
  evidence:
  - reference: PMID:29671837
    reference_title: Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A
      (5%), and DYNC1H1 (3%).
    explanation: >-
      In a cohort of 811 patients, LIS1/PAFAH1B1 was the single most common
      cause of lissencephaly, defining the classic subtype.
- name: X-linked/DCX
  display_name: X-linked lissencephaly / SBH (DCX-related)
  subtype_term:
    preferred_term: lissencephaly type 1 due to doublecortin gene mutation
    term:
      id: MONDO:0010239
      label: lissencephaly type 1 due to doublecortin gene mutation
  description: >-
    X-linked DCX-related disorder: males typically have classic thick
    lissencephaly (more severe anteriorly) while heterozygous females present
    with subcortical band heterotopia (double cortex). Phenotype severity
    correlates with the degree of malformation on imaging.
  genes:
  - preferred_term: DCX
    term:
      id: hgnc:2714
      label: DCX
  inheritance:
  - name: X-linked
    inheritance_term:
      preferred_term: X-linked inheritance
      term:
        id: HP:0001417
        label: X-linked inheritance
    evidence:
    - reference: PMID:20301364
      reference_title: DCX-Related Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "DCX-related disorders are inherited in an X-linked manner."
      explanation: >-
        GeneReviews establishes X-linked inheritance for DCX-related
        lissencephaly/SBH.
  evidence:
  - reference: PMID:20301364
    reference_title: DCX-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DCX-related disorders include the following neuronal migration
      disorders: classic thick lissencephaly (more severe anteriorly),
      usually in males, and subcortical band heterotopia (SBH), primarily in
      females.
    explanation: >-
      GeneReviews defines the X-linked DCX subtype with classic
      lissencephaly in males and SBH in females.
- name: Tubulinopathy/TUBA1A
  display_name: Tubulinopathy-associated lissencephaly (TUBA1A and related tubulins)
  description: >-
    Lissencephaly arising from mutations in tubulin genes (notably TUBA1A,
    also TUBG1, TUBB2B, TUBB3), typically de novo autosomal dominant. The
    malformation pattern often combines lissencephaly/pachygyria with
    cerebellar, brainstem and basal ganglia abnormalities (corpus callosum
    and internal capsule dysmorphism).
  genes:
  - preferred_term: TUBA1A
    term:
      id: hgnc:20766
      label: TUBA1A
  - preferred_term: TUBG1
    term:
      id: hgnc:12417
      label: TUBG1
  evidence:
  - reference: PMID:29671837
    reference_title: Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A
      (5%), and DYNC1H1 (3%).
    explanation: >-
      TUBA1A is the most frequent tubulin-gene cause of lissencephaly in a
      large cohort, defining the tubulinopathy subtype.
- name: ARX-related
  display_name: ARX-related lissencephaly (XLAG spectrum)
  subtype_term:
    preferred_term: X-linked lissencephaly with abnormal genitalia
    term:
      id: MONDO:0010268
      label: X-linked lissencephaly with abnormal genitalia
  description: >-
    X-linked lissencephaly associated with ARX variants, classically X-linked
    lissencephaly with abnormal genitalia (XLAG) in males, a distinct
    anterior-predominant form within the spectrum.
  genes:
  - preferred_term: ARX
    term:
      id: hgnc:18060
      label: ARX
  evidence:
  - reference: PMID:29671837
    reference_title: Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and
      ARX, but few other genes.
    explanation: >-
      ARX is one of the established lissencephaly-associated genes routinely
      tested in the diagnostic workup.
- name: RELN-related
  display_name: RELN-related lissencephaly with cerebellar hypoplasia
  subtype_term:
    preferred_term: lissencephaly with cerebellar hypoplasia
    term:
      id: MONDO:0019450
      label: lissencephaly with cerebellar hypoplasia
  description: >-
    Autosomal recessive lissencephaly with cerebellar hypoplasia (LCH) caused
    by biallelic RELN loss-of-function mutations, with severe cerebellar,
    hippocampal and brainstem abnormalities reflecting deficient reelin
    signaling.
  genes:
  - preferred_term: RELN
    term:
      id: hgnc:9957
      label: RELN
  evidence:
  - reference: PMID:10973257
    reference_title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.
    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: >-
      Defines the RELN-related recessive subtype with cerebellar hypoplasia.
- name: Cobblestone
  display_name: Cobblestone lissencephaly (dystroglycanopathy)
  subtype_term:
    preferred_term: cobblestone lissencephaly
    term:
      id: MONDO:0018869
      label: cobblestone lissencephaly
  description: >-
    A distinct "type II"/cobblestone form in which neurons overmigrate through
    a disrupted pial basement membrane, associated with glycosylation-pathway
    genes such as POMGNT1, POMT1 and POMT2 (alpha-dystroglycanopathies),
    typically with eye and muscle involvement. Neuropathology differs from the
    classic (migration-arrest) forms.
  genes:
  - preferred_term: POMGNT1
    term:
      id: hgnc:19139
      label: POMGNT1
  - preferred_term: POMT1
    term:
      id: hgnc:9202
      label: POMT1
  - preferred_term: POMT2
    term:
      id: hgnc:19743
      label: POMT2
- name: LIS10/CEP85L
  display_name: Lissencephaly 10 (CEP85L-related posterior predominant lissencephaly)
  subtype_term:
    preferred_term: lissencephaly 10
    term:
      id: MONDO:0030031
      label: lissencephaly 10
  description: >-
    Posterior-predominant lissencephaly caused by rare heterozygous CEP85L
    variants, occurring sporadically or segregating as an autosomal dominant
    trait. CEP85L is a pericentriolar-material protein, so
    this subtype enters the same nucleokinesis machinery as PAFAH1B1 (LIS1) from
    the centrosome rather than from the dynein regulator itself, which is
    consistent with the shared posterior-predominant imaging pattern.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  genes:
  - preferred_term: CEP85L
    term:
      id: hgnc:21638
      label: CEP85L
  evidence:
  - reference: PMID:32097630
    reference_title: Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now implicate CEP85L as an important cause of posterior predominant
      LIS, identifying 13 individuals with rare, heterozygous CEP85L variants,
      including 2 families with autosomal dominant inheritance.
    explanation: >-
      Establishes CEP85L as a lissencephaly gene, gives the posterior-predominant
      imaging pattern that defines the subtype, and records the autosomal dominant
      families.
  - reference: CGGV:assertion_30a3191e-5ee3-467c-afa1-27fada71f9ea-2024-09-24T170000.000Z
    reference_title: "CEP85L / lissencephaly 10 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CEP85L | HGNC:21638 | lissencephaly 10 | MONDO:0030031 | AD | Definitive | SOP11 | Brain Malformations Gene Curation Expert Panel"
    explanation: >-
      The ClinGen Brain Malformations expert panel classifies the CEP85L-lissencephaly 10
      relationship as Definitive under autosomal dominant inheritance, and curated it
      against the same MONDO term this subtype binds.
- name: LIS6/KATNB1
  display_name: Lissencephaly 6 with microcephaly (KATNB1-related microlissencephaly)
  subtype_term:
    preferred_term: lissencephaly 6 with microcephaly
    term:
      id: MONDO:0014534
      label: lissencephaly 6 with microcephaly
  description: >-
    Autosomal recessive microlissencephaly caused by biallelic KATNB1 variants.
    KATNB1 encodes the regulatory subunit of the microtubule-severing enzyme
    katanin, and the reported patients carry homozygous or compound
    heterozygous alleles. Microcephaly is named in the disease label rather than
    being an added feature, and loss of the KATNB1 orthologs in zebrafish and
    flies reproduces it.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  genes:
  - preferred_term: KATNB1
    term:
      id: hgnc:6217
      label: KATNB1
  evidence:
  - reference: PMID:25521378
    reference_title: Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing analysis of over 2,000 children with complex
      malformations of cortical development identified five independent (four
      homozygous and one compound heterozygous) deleterious mutations in
      KATNB1, encoding the regulatory subunit of the microtubule-severing
      enzyme Katanin.
    explanation: >-
      Establishes biallelic KATNB1 variants as a cause of complex cortical
      malformation and names the gene product, supporting the recessive
      inheritance recorded here.
  - reference: PMID:25521378
    reference_title: Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in
      microcephaly, recapitulating the human phenotype.
    explanation: >-
      Supports the microcephaly that this subtype's label names, shown by loss of the
      gene in two model organisms.
- name: LIS7/CDK5
  display_name: Lissencephaly 7 with cerebellar hypoplasia (CDK5-related)
  subtype_term:
    preferred_term: lissencephaly 7 with cerebellar hypoplasia
    term:
      id: MONDO:0014596
      label: lissencephaly 7 with cerebellar hypoplasia
  description: >-
    Autosomal recessive lissencephaly with cerebellar hypoplasia caused by
    biallelic loss of function of CDK5. CDK5 sits in a complex with LIS1 and the
    dynein heavy chain that is required for cortical neuronal migration, so this
    subtype reaches the same nucleokinesis machinery as the classic forms through
    loss of the kinase rather than loss of the scaffold. The founding report
    describes a lethal presentation in one consanguineous family.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  genes:
  - preferred_term: CDK5
    term:
      id: hgnc:1774
      label: CDK5
  evidence:
  - reference: PMID:25560765
    reference_title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied a highly consanguineous Israeli Moslem family with a lethal
      form of autosomal recessive lissencephaly with cerebellar hypoplasia
      (LCH).
    explanation: >-
      Gives the clinical setting and the recessive, lethal presentation of the
      CDK5-related subtype.
  - reference: CGGV:assertion_2f6ba2ff-6567-493e-bf39-f05c03013e20-2024-04-29T160000.000Z
    reference_title: "CDK5 / lissencephaly with cerebellar hypoplasia (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CDK5 | HGNC:1774 | lissencephaly with cerebellar hypoplasia | MONDO:0019450 | AR | Moderate | SOP10 | Brain Malformations Gene Curation Expert Panel"
    explanation: >-
      ClinGen classifies CDK5 as Moderate for autosomal recessive lissencephaly with
      cerebellar hypoplasia. Note the panel curated it against the broader LCH term
      (MONDO:0019450) that this entry already uses for the RELN subtype, not against
      the numbered LIS7 term bound here.
- name: LIS8/TMTC3
  display_name: Lissencephaly 8 (TMTC3-related cobblestone malformation)
  subtype_term:
    preferred_term: lissencephaly 8
    term:
      id: MONDO:0014992
      label: lissencephaly 8
  description: >-
    Autosomal recessive cobblestone lissencephaly caused by biallelic TMTC3
    variants, with brainstem and cerebellar hypoplasia and ventriculomegaly.
    This is a cobblestone (overmigration) malformation and not one of the
    migration-arrest forms, but it is reached without an alpha-dystroglycan
    defect: TMTC3 has no established functional connection to
    alpha-dystroglycan, and most affected individuals lack the eye involvement
    and raised creatine kinase of the dystroglycanopathies. It is therefore
    curated separately from the Cobblestone subtype above, which collects the
    glycosylation-pathway genes.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  genes:
  - preferred_term: TMTC3
    term:
      id: hgnc:26899
      label: TMTC3
  evidence:
  - reference: PMID:27773428
    reference_title: "Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our screening of a cohort of 25 families with recessive forms of COB
      identified six families affected by biallelic mutations in TMTC3
      (encoding transmembrane and tetratricopeptide repeat containing 3), a
      gene without obvious functional connections to alpha-dystroglycan.
    explanation: >-
      Establishes biallelic TMTC3 variants as a recessive cause of cobblestone
      lissencephaly and states that the gene has no obvious functional link to
      alpha-dystroglycan, which is the reason this subtype is kept separate from
      the dystroglycanopathy cobblestone group.
  - reference: PMID:27773428
    reference_title: "Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement."
    explanation: >-
      Records the clinical separation from typical congenital muscular dystrophy that
      distinguishes this subtype.
- name: LIS9/MACF1
  display_name: Lissencephaly 9 with complex brainstem malformation (MACF1-related)
  subtype_term:
    preferred_term: lissencephaly 9 with complex brainstem malformation
    term:
      id: MONDO:0032677
      label: lissencephaly 9 with complex brainstem malformation
  description: >-
    Posterior-predominant lissencephaly with absent anterior commissure and a
    W-shaped brainstem malformation from small or absent pontine crossing
    fibres, caused by de novo variants affecting conserved zinc-binding
    residues of the MACF1 GAR domain. The founding report calls the combination
    of cortical and midline crossing defects a distinctive and most likely
    pathognomonic brain malformation.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  genes:
  - preferred_term: MACF1
    term:
      id: hgnc:13664
      label: MACF1
  evidence:
  - reference: PMID:30471716
    reference_title: MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The brain malformation comprised posterior predominant lissencephaly and
      midline crossing defects consisting of absent anterior commissure and a
      striking W-shaped brainstem malformation caused by small or absent
      pontine crossing fibers.
    explanation: >-
      Defines the imaging phenotype of this subtype, including the brainstem
      malformation that the MONDO label names.
  - reference: PMID:30471716
    reference_title: MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discovered heterozygous de novo missense variants or an in-frame
      deletion involving highly conserved zinc-binding residues within the GAR
      domain of MACF1 in the first eight subjects.
    explanation: >-
      Records the heterozygous de novo variant class and the domain involved,
      supporting the dominant inheritance recorded here.
  - reference: CGGV:assertion_67d61f95-4ea3-41a7-ab90-e642c2c65c2a-2023-07-25T160000.000Z
    reference_title: "MACF1 / lissencephaly spectrum disorder with complex brainstem malformation (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MACF1 | HGNC:13664 | lissencephaly spectrum disorder with complex brainstem malformation | MONDO:0100472 | AD | Moderate | SOP9 | Brain Malformations Gene Curation Expert Panel"
    explanation: >-
      ClinGen classifies MACF1 as Moderate under autosomal dominant inheritance. The
      panel curated it against MONDO:0100472, a second MONDO class with almost the
      same label as the OMIM-anchored term bound here; see the entry notes.
- name: CDCBM9/CTNNA2
  display_name: Complex cortical dysplasia with other brain malformations 9 (CTNNA2-related pachygyria)
  subtype_term:
    preferred_term: cortical dysplasia, complex, with other brain malformations 9
    term:
      id: MONDO:0032578
      label: cortical dysplasia, complex, with other brain malformations 9
  description: >-
    Autosomal recessive pachygyria caused by biallelic truncating CTNNA2
    variants. CTNNA2 encodes αN-catenin, which represses ARP2/3-driven actin
    branching; its loss therefore places this subtype on the actin side of the
    cytoskeletal mechanism rather than the microtubule side that the tubulin,
    LIS1 and DCX subtypes share. MONDO records the concept under complex
    cortical dysplasia rather than under lissencephaly spectrum disorders, but
    carries "CTNNA2-related lissencephaly spectrum disorder" as a synonym, which
    is why it is curated here.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  genes:
  - preferred_term: CTNNA2
    term:
      id: hgnc:2510
      label: CTNNA2
  evidence:
  - reference: PMID:30013181
    reference_title: "Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we identify biallelic truncating mutations in CTNNA2, encoding
      αN-catenin, in patients with a distinct recessive form of pachygyria.
    explanation: >-
      Establishes biallelic truncating CTNNA2 variants as the cause of a recessive
      pachygyria, supporting both the gene assignment and the inheritance recorded here.
genetic:
- name: PAFAH1B1
  association: Loss of function
  subtype: Classic/LIS1
  gene_term:
    preferred_term: PAFAH1B1
    term:
      id: hgnc:8574
      label: PAFAH1B1
  evidence:
  - reference: PMID:29671837
    reference_title: Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A
      (5%), and DYNC1H1 (3%).
    explanation: >-
      LIS1/PAFAH1B1 is the most common genetic cause of lissencephaly in an
      811-patient cohort.
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of PAFAH1B1-related lissencephaly/SBH is established in a
      proband with a heterozygous pathogenic variant in PAFAH1B1 identified
      by molecular genetic testing.
    explanation: >-
      GeneReviews confirms heterozygous PAFAH1B1 pathogenic variants as
      causal for classic lissencephaly/SBH.
- name: DCX
  association: Loss of function
  subtype: X-linked/DCX
  gene_term:
    preferred_term: DCX
    term:
      id: hgnc:2714
      label: DCX
  evidence:
  - reference: PMID:20301364
    reference_title: DCX-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of a DCX-related disorder is established in a proband
      with a DCX pathogenic variant identified by molecular genetic testing.
    explanation: >-
      GeneReviews confirms DCX pathogenic variants as causal for X-linked
      lissencephaly/SBH.
  - reference: PMID:29671837
    reference_title: Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A
      (5%), and DYNC1H1 (3%).
    explanation: >-
      DCX is the second most common lissencephaly gene in a large cohort.
- name: TUBA1A
  association: Pathogenic variant
  subtype: Tubulinopathy/TUBA1A
  gene_term:
    preferred_term: TUBA1A
    term:
      id: hgnc:20766
      label: TUBA1A
  evidence:
  - reference: PMID:29671837
    reference_title: Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A
      (5%), and DYNC1H1 (3%).
    explanation: >-
      TUBA1A is an established lissencephaly gene and the most common
      tubulin-gene cause in this cohort.
- name: DYNC1H1
  association: Pathogenic variant
  gene_term:
    preferred_term: DYNC1H1
    term:
      id: hgnc:2961
      label: DYNC1H1
  evidence:
  - reference: PMID:29671837
    reference_title: Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A
      (5%), and DYNC1H1 (3%).
    explanation: >-
      DYNC1H1, encoding the dynein heavy chain, is a recognized
      lissencephaly gene consistent with the dynein/migration mechanism.
- name: RELN
  association: Loss of function
  subtype: RELN-related
  gene_term:
    preferred_term: RELN
    term:
      id: hgnc:9957
      label: RELN
  evidence:
  - reference: PMID:10973257
    reference_title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutations disrupt splicing of RELN cDNA, resulting in low or
      undetectable amounts of reelin protein.
    explanation: >-
      Documents RELN loss-of-function (splicing-disrupting) variants causing
      recessive lissencephaly with cerebellar hypoplasia.
- name: ARX
  association: Pathogenic variant
  subtype: ARX-related
  gene_term:
    preferred_term: ARX
    term:
      id: hgnc:18060
      label: ARX
  evidence:
  - reference: PMID:29671837
    reference_title: Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and
      ARX, but few other genes.
    explanation: >-
      ARX is an established X-linked lissencephaly gene included in standard
      diagnostic testing.
- name: CEP85L
  association: Loss of function
  subtype: LIS10/CEP85L
  gene_term:
    preferred_term: CEP85L
    term:
      id: hgnc:21638
      label: CEP85L
  notes: >-
    CEP85L is a pericentriolar-material protein. Its loss disrupts the
    localization and activation of CDK5 at the centrosome, which places it
    upstream of the same LIS1-NDEL1-dynein nucleokinesis machinery that the
    classic subtype depends on.
  evidence:
  - reference: PMID:32097630
    reference_title: Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now implicate CEP85L as an important cause of posterior predominant
      LIS, identifying 13 individuals with rare, heterozygous CEP85L variants,
      including 2 families with autosomal dominant inheritance.
    explanation: >-
      Establishes heterozygous CEP85L variants as causal for posterior-predominant
      lissencephaly in 13 individuals.
  - reference: CGGV:assertion_30a3191e-5ee3-467c-afa1-27fada71f9ea-2024-09-24T170000.000Z
    reference_title: "CEP85L / lissencephaly 10 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CEP85L | HGNC:21638 | lissencephaly 10 | MONDO:0030031 | AD | Definitive | SOP11 | Brain Malformations Gene Curation Expert Panel"
    explanation: >-
      ClinGen classifies the CEP85L gene-disease relationship as Definitive.
- name: CDK5
  association: Loss of function
  subtype: LIS7/CDK5
  gene_term:
    preferred_term: CDK5
    term:
      id: hgnc:1774
      label: CDK5
  notes: >-
    CDK5 is a member of the migration complex that also contains LIS1, NDE1,
    KIF2A and the dynein heavy chain, so a biallelic null allele removes a kinase
    the classic PAFAH1B1 machinery depends on rather than the scaffold itself.
  evidence:
  - reference: PMID:25560765
    reference_title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a homozygous splice site mutation g.IVS8+1G>A in
      cyclin-dependent kinase 5 (CDK5), causing complete skipping of exon 8, and
      leading to a frame shift and premature stop codon (p.V162SfsX19).
    explanation: >-
      Records the specific homozygous null allele that establishes CDK5 as a
      recessive lissencephaly gene.
  - reference: PMID:25560765
    reference_title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional analysis of the p.V162SfsX19 mutation, using a yeast
      complementation assay, showed loss-of-function of the mutant CDK5 gene
      product, thereby implicating its role in the pathogenesis of autosomal
      recessive LCH in the studied family.
    explanation: >-
      Supports the loss-of-function association recorded on this record rather than a
      gain or altered function.
- name: KATNB1
  association: Loss of function
  subtype: LIS6/KATNB1
  gene_term:
    preferred_term: KATNB1
    term:
      id: hgnc:6217
      label: KATNB1
  notes: >-
    KATNB1 is the regulatory subunit of katanin. Patient fibroblasts show
    defective mitotic spindle formation, which places this gene with the
    progenitor-division mechanism rather than with locomotion of an already
    postmitotic neuron.
  evidence:
  - reference: PMID:25521378
    reference_title: Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing analysis of over 2,000 children with complex
      malformations of cortical development identified five independent (four
      homozygous and one compound heterozygous) deleterious mutations in
      KATNB1, encoding the regulatory subunit of the microtubule-severing
      enzyme Katanin.
    explanation: >-
      Establishes biallelic deleterious KATNB1 alleles as a cause of complex cortical
      malformation.
  - reference: PMID:25521378
    reference_title: Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mitotic spindle formation is defective in patient-derived fibroblasts, a
      consequence of disrupted interactions of mutant KATNB1 with KATNA1, the
      catalytic subunit of Katanin, and other microtubule-associated proteins.
    explanation: >-
      Patient-derived fibroblasts localize the defect to mitotic spindle formation,
      supporting the loss-of-function association recorded here.
- name: MACF1
  association: Pathogenic variant
  subtype: LIS9/MACF1
  gene_term:
    preferred_term: MACF1
    term:
      id: hgnc:13664
      label: MACF1
  notes: >-
    The reported variants are heterozygous, de novo, and concentrated in
    conserved zinc-binding residues of the microtubule-binding GAR domain. The
    founding report proposes a gain-of-function or dominant-negative mechanism
    rather than haploinsufficiency, on the grounds that truncating MACF1 alleles
    are present in population sequencing data, so this record is left as
    "Pathogenic variant" rather than asserting loss of function.
  evidence:
  - reference: PMID:30471716
    reference_title: MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discovered heterozygous de novo missense variants or an in-frame
      deletion involving highly conserved zinc-binding residues within the GAR
      domain of MACF1 in the first eight subjects.
    explanation: >-
      Establishes the variant class and domain, supporting the dominant de novo
      mechanism recorded here.
  - reference: CGGV:assertion_67d61f95-4ea3-41a7-ab90-e642c2c65c2a-2023-07-25T160000.000Z
    reference_title: "MACF1 / lissencephaly spectrum disorder with complex brainstem malformation (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MACF1 | HGNC:13664 | lissencephaly spectrum disorder with complex brainstem malformation | MONDO:0100472 | AD | Moderate | SOP9 | Brain Malformations Gene Curation Expert Panel"
    explanation: >-
      ClinGen classifies MACF1 as Moderate for this malformation under autosomal
      dominant inheritance.
- name: TMTC3
  association: Loss of function
  subtype: LIS8/TMTC3
  gene_term:
    preferred_term: TMTC3
    term:
      id: hgnc:26899
      label: TMTC3
  notes: >-
    TMTC3 loss produces a cobblestone malformation, so this gene acts on the
    overmigration route rather than the migration-arrest route that PAFAH1B1,
    DCX and the tubulins share. The founding report states it has no obvious
    functional connection to alpha-dystroglycan, which separates it from the
    glycosylation-pathway genes on the Cobblestone subtype.
  evidence:
  - reference: PMID:27773428
    reference_title: "Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our screening of a cohort of 25 families with recessive forms of COB
      identified six families affected by biallelic mutations in TMTC3
      (encoding transmembrane and tetratricopeptide repeat containing 3), a
      gene without obvious functional connections to alpha-dystroglycan.
    explanation: >-
      Establishes biallelic TMTC3 variants in six families as a recessive cause of
      cobblestone lissencephaly.
- name: CTNNA2
  association: Loss of function
  subtype: CDCBM9/CTNNA2
  gene_term:
    preferred_term: CTNNA2
    term:
      id: hgnc:2510
      label: CTNNA2
  notes: >-
    CTNNA2 encodes αN-catenin. The reported alleles are biallelic and
    truncating, and the mechanism proposed is de-repression of ARP2/3-driven
    actin branching rather than a microtubule defect.
  evidence:
  - reference: PMID:30013181
    reference_title: "Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we identify biallelic truncating mutations in CTNNA2, encoding
      αN-catenin, in patients with a distinct recessive form of pachygyria.
    explanation: >-
      Establishes biallelic truncating CTNNA2 variants as causal for a recessive
      pachygyria, supporting the loss-of-function association recorded here.
treatments:
- name: Anti-Seizure Medication
  description: >-
    Standard anti-seizure medication selected by seizure type; in
    PAFAH1B1-related lissencephaly, polytherapy with valproic acid and
    lamotrigine appears most effective for drug-resistant seizures. Seizures
    are often refractory.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
    - preferred_term: lamotrigine
      term:
        id: CHEBI:6367
        label: lamotrigine
  evidence:
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      polytherapy with valproic acid and lamotrigine appears most effective
      in reducing drug-resistant seizures
    explanation: >-
      GeneReviews recommends valproic acid plus lamotrigine polytherapy for
      drug-resistant seizures in PAFAH1B1-related lissencephaly.
- name: Gastrostomy and Feeding Support
  description: >-
    Placement of a gastrostomy tube for individuals with failure to thrive,
    dysphagia, and/or recurrent aspiration pneumonia, with feeding strategies
    for newborns with poor suck and swallow.
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  evidence:
  - reference: PMID:20301752
    reference_title: PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      placement of a gastrostomy tube for those with failure to thrive,
      dysphagia, and/or recurrent aspiration pneumonia
    explanation: >-
      GeneReviews recommends gastrostomy for feeding failure and aspiration
      risk in lissencephaly.
- name: Physical Therapy
  description: >-
    Physical therapy to promote mobility and prevent contractures; in patient
    cohorts physiotherapy is reported among the most effective supportive
    therapies.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301364
    reference_title: DCX-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      physical therapy to promote mobility and prevent contractures
    explanation: >-
      GeneReviews recommends physical therapy to support mobility and
      prevent contractures in DCX-related disorders.
- name: Occupational Therapy
  description: >-
    Occupational therapy to improve fine motor skills and oral motor control,
    as part of multidisciplinary supportive management of lissencephaly.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - reference: PMID:20301364
    reference_title: DCX-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      occupational therapy to improve fine motor skills
    explanation: >-
      GeneReviews recommends occupational therapy to improve fine and oral
      motor skills in DCX-related lissencephaly.
- name: Speech Therapy
  description: >-
    Speech therapy to support communication and oral-motor function as part of
    multidisciplinary supportive management.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: PMID:20301364
    reference_title: DCX-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      participation in speech therapy
    explanation: >-
      GeneReviews includes speech therapy in the supportive management of
      DCX-related lissencephaly.
- name: Genetic Counseling
  description: >-
    Genetic counseling and reproductive options (prenatal and preimplantation
    genetic testing) once a familial pathogenic variant is identified;
    important given the high de novo rate and variable inheritance across the
    spectrum.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301364
    reference_title: DCX-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the DCX pathogenic variant has been identified in an affected
      family member, prenatal and preimplantation genetic testing are
      possible.
    explanation: >-
      GeneReviews supports genetic counseling with prenatal/preimplantation
      testing once the familial variant is known.
discussions:
- discussion_id: gap_pafah1b1_dcx_gradient_and_cellular_emphasis
  prompt: >-
    What explains the opposite anterior-posterior severity gradients and
    cellular emphasis between PAFAH1B1/LIS1 and DCX disease when both converge
    on microtubule-dependent neuronal migration failure?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#LIS1-NUDEL-Dynein Nucleokinesis Failure
  - pathophysiology#DCX Microtubule Stabilization Failure
  - pathophysiology#LIS1 Progenitor Spindle Orientation Defect
  rationale: >-
    PAFAH1B1/LIS1 and DCX share a migration-failure endpoint, but the human
    radiographic gradients and cellular branches differ: PAFAH1B1 has a
    LIS1/NUDEL/dynein motor branch plus a progenitor-spindle component, whereas
    DCX disease is typically anterior-predominant in males and SBH in
    heterozygous females. The unresolved issue is whether regional expression,
    different microtubule-motor versus lattice functions, X-inactivation
    mosaicism, or human-specific progenitor context best explains these
    genotype-specific patterns.
  evidence:
  - reference: PMID:11163259
    reference_title: "A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results suggest that LIS1 and NUDEL regulate CDHC activity during
      neuronal migration and axonal retrograde transport in a Cdk5/p35-dependent
      fashion.
    explanation: >-
      Supports the LIS1/NUDEL/dynein branch as a distinct molecular mechanism
      within the shared migration-failure endpoint.
  - reference: PMID:18267077
    reference_title: "Neuroepithelial stem cell proliferation requires LIS1 for precise spindle orientation and symmetric division."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lis1 is essential for precise control of mitotic spindle orientation in
      both neuroepithelial stem cells and radial glial progenitor cells.
    explanation: >-
      Supports a PAFAH1B1/LIS1 progenitor branch not captured by a purely
      postmitotic migration model.
  - reference: PMID:20301364
    reference_title: DCX-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      classic thick lissencephaly (more severe anteriorly), usually in males,
      and subcortical band heterotopia (SBH), primarily in females.
    explanation: >-
      Establishes the DCX anterior-predominant and sex-biased SBH pattern.
  proposed_experiments:
  - experiment_id: exp_lis1_dcx_isogenic_organoid_gradient_comparison
    name: PAFAH1B1/DCX isogenic cortical-organoid gradient comparison
    description: >-
      Generate matched human iPSC-derived dorsal forebrain organoids with
      PAFAH1B1 haploinsufficiency, DCX loss, and isogenic correction or knock-in
      rescue. Compare regional patterning markers, radial-glial spindle
      orientation, nucleokinesis, migration speed, microtubule lattice stability,
      and mosaic DCX expression effects to distinguish regional-expression,
      progenitor-spindle, and X-inactivation models.
    experiment_type:
      preferred_term: isogenic cerebral organoid migration and progenitor assay
    model_systems:
    - name: Human iPSC-derived dorsal forebrain organoid LIS/SBH model
      description: >-
        Isogenic human cortical organoids carrying PAFAH1B1 haploinsufficiency
        or DCX loss/knock-in variants, with corrected and non-disease donor
        controls.
      experimental_model_type: ORGANOID
      namo_type: namo:Organoid
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      tissue_term:
        preferred_term: cerebral cortex
        term:
          id: UBERON:0000956
          label: cerebral cortex
      cell_types:
      - preferred_term: radial glial cell
        term:
          id: CL:0000681
          label: radial glial cell
      - preferred_term: neuron
        term:
          id: CL:0000540
          label: neuron
      culture_system: Three-dimensional cerebral organoid with live-imaging and single-cell readouts
    perturbations:
    - name: PAFAH1B1 haploinsufficiency and DCX loss or mosaic knock-in
      description: >-
        CRISPR or patient-variant knock-in perturbations with isogenic repair,
        including mixed DCX-positive and DCX-negative neuronal populations to
        model female SBH mosaicism.
      target: pathophysiology#DCX Microtubule Stabilization Failure
    readouts:
    - name: Regional gradient and migration metrics
      target: pathophysiology#Impaired Neuronal Migration
      description: >-
        Quantify anterior/posterior patterning markers, radial-glial cleavage
        orientation, centrosome-nucleus coupling, nuclear translocation speed,
        tubulin polymerization/stability markers, and ectopic neuronal bands.
    controls:
    - name: Isogenic corrected controls
      description: >-
        Corrected PAFAH1B1 or DCX lines and non-disease donor organoids cultured
        in parallel.
    decision_criterion: >-
      A disease-specific gradient mechanism is supported if PAFAH1B1 and DCX
      perturbations diverge in regional patterning, progenitor-spindle, or
      mosaic migration readouts despite shared downstream dyslamination.
    would_support:
    - pathophysiology#LIS1-NUDEL-Dynein Nucleokinesis Failure
    - pathophysiology#DCX Microtubule Stabilization Failure
    - pathophysiology#LIS1 Progenitor Spindle Orientation Defect
- discussion_id: gap_dcx_knockout_mouse_neocortex_model_mismatch
  prompt: >-
    Does the germline Dcx-knockout mouse — the founding animal model of DCX
    disease — faithfully recapitulate the defining human DCX neocortical
    malformation (X-linked lissencephaly in hemizygous males, subcortical band
    heterotopia in heterozygous females), given that germline Dcx-null mice have
    a near-normal neocortex, that only acute in utero RNAi knockdown reproduces a
    radial-migration/heterotopia phenotype, and that even this RNAi phenotype
    forms in rat but not in mouse — so that the severity and very existence of the
    human neocortical lesion is systematically underdetermined by the standard
    mouse knockout and its faithful modeling may require an acute-knockdown, a
    redundancy-free (Dcx/Dclk compound), a rat, or a human-specific progenitor
    context?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#DCX Microtubule Stabilization Failure
  - pathophysiology#Impaired Neuronal Migration
  rationale: >-
    DCX is one of the most striking human/model discordances in the cortical
    malformation literature, and it bears directly on how strongly the mouse can
    validate the DCX branch of this entry. In humans, X-linked DCX mutations
    cause classic thick lissencephaly in males and subcortical band heterotopia
    in females — a severe, defining neocortical migration defect. Yet the
    germline Dcx-knockout mouse has neocortical lamination largely
    indistinguishable from wild type, with the migration/lamination phenotype
    restricted to the hippocampus; the neocortical malformation only appears when
    Dcx is acutely silenced by in utero RNAi rather than deleted in the germline.
    Two overlapping explanations are documented: (1) developmental compensation /
    genetic redundancy, whereby the paralog doublecortin-like kinase (Dclk)
    substitutes for Dcx in the germline knockout but not under acute knockdown,
    so that only Dcx/Dclk compound loss reproduces the migration defect; and (2)
    a genuine species difference, since the same in utero RNAi against Dcx induces
    band heterotopia in rat but fails to induce heterotopia in mouse. This is a
    concrete instance of two knowledge gaps flagged by the Romero, Bahi-Buisson &
    Francis 2018 cortical-malformation review that seeds this epic: that mouse
    models often fail to reproduce human MCD features, and that acute in utero
    knockdown can be more severe than germline knockout because of off-target
    effects, developmental compensation, or redundancy revealed only by double
    knockouts. Mechanistically it leaves open whether the human neocortical
    lesion reflects reduced Dcx/Dclk-family redundancy in human migrating
    neurons, a rat-like rather than mouse-like species requirement for Dcx in
    neocortical radial migration, or a human-specific progenitor/outer-radial-glia
    context — meaning the mouse germline knockout, taken alone, validates the DCX
    microtubule-stabilization mechanism only weakly for the human neocortical
    phenotype.
  proposed_experiments:
  - experiment_id: exp_dcx_dclk_compound_perturbation_rat_vs_mouse
    name: Dcx germline-KO versus acute-knockdown and Dcx/Dclk compound loss, compared across rat and mouse
    description: >-
      Systematically dissociate the redundancy and species-difference hypotheses
      by comparing germline Dcx knockout, acute in utero RNAi knockdown, and
      Dcx/Dclk compound loss for their ability to produce neocortical band
      heterotopia and laminar displacement, run in parallel in rat and mouse
      embryos with rescue-by-Dcx-overexpression specificity controls. This tests
      whether faithful modeling of the human neocortical phenotype requires
      removing paralog compensation, using acute rather than germline
      perturbation, and/or a rat rather than mouse substrate.
    experiment_type:
      preferred_term: in vivo rodent neuronal-migration perturbation study
    model_systems:
    - name: Rat and mouse embryonic neocortex (in utero electroporation)
      description: >-
        Developing rat and mouse cortex perturbed by in utero electroporation of
        RNAi or gene-edited alleles, the paired system that first revealed the
        rat-versus-mouse discrepancy in Dcx-knockdown heterotopia formation.
      experimental_model_type: OTHER
  - experiment_id: exp_dcx_human_ipsc_mosaic_migration_assay
    name: Human iPSC-derived cortical model of DCX loss and female SBH mosaicism
    description: >-
      Generate isogenic DCX-null and DCX-variant human iPSC-derived cortical
      organoids/assembloids, including mixed DCX-positive and DCX-negative
      neuronal populations to model heterozygous-female mosaicism, and quantify
      radial migration, laminar positioning, and heterotopic-band formation to
      test whether a human progenitor/neuronal context reproduces the severe
      neocortical phenotype that the mouse germline knockout does not.
    experiment_type:
      preferred_term: iPSC cortical organoid migration assay
    model_systems:
    - name: Human iPSC-derived cortical organoid/assembloid DCX model
      description: >-
        Isogenic human cortical organoids or assembloids carrying DCX loss or
        patient variants with mosaic DCX expression, preserving human-specific
        cortical progenitor biology absent from the mouse.
      experimental_model_type: ORGANOID
  evidence:
  - reference: PMID:12196578
    reference_title: "Doublecortin is required in mice for lamination of the hippocampus but not the neocortex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Dcx mutant mice show neocortical lamination that is largely
      indistinguishable from wild type and show normal patterns of neocortical
      neurogenesis and neuronal migration.
    explanation: >-
      The founding germline Dcx-knockout mouse report establishes the core
      mismatch: the mouse neocortex is essentially normal despite DCX loss,
      whereas the human neocortical phenotype (lissencephaly/SBH) is severe.
  - reference: PMID:14625554
    reference_title: "RNAi reveals doublecortin is required for radial migration in rat neocortex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Paradoxically, genetic deletion of Dcx in mice does not cause neocortical
      malformation.
    explanation: >-
      Documents the acute-knockdown-versus-germline-knockout discrepancy: acute
      in utero RNAi of DCX reproduces the migration defect that germline deletion
      does not, one of the Romero review's flagged model caveats.
  - reference: PMID:16292002
    reference_title: "Heterotopia formation in rat but not mouse neocortex after RNA interference knockdown of DCX."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In utero RNAi in the rat consistently leads to both the formation of SBH
      and laminar displacement of transfected cells in normotopic cortex, whereas
      the same treatment in mouse fails to induce SBH but does create laminar
      displacement.
    explanation: >-
      Demonstrates a genuine rat-versus-mouse species difference in the Dcx-loss
      neocortical phenotype, so even acute knockdown does not model the severe
      human heterotopia in mouse.
  - reference: PMID:16387639
    reference_title: "Doublecortin-like kinase functions with doublecortin to mediate fiber tract decussation and neuronal migration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Humans with mutations show profound alterations in cortical lamination,
      whereas in mouse, RNAi-mediated knockdown but not germline knockout shows
      abnormal positioning of cortical neurons.
    explanation: >-
      Identifies partially redundant Dclk compensation as a mechanistic
      explanation for why the germline Dcx-knockout mouse under-reproduces the
      human phenotype, supporting the redundancy arm of the mismatch.

📚

References & Deep Research

References

PMID:20301752

PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.

No top-level findings curated for this source.

PMID:20301364

DCX-Related Disorders.

No top-level findings curated for this source.

PMID:27010057

Tubulinopathies Overview.

No top-level findings curated for this source.

Deep Research

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.

Falcon ▸

1. Disease Information

Edison Scientific Literature 30 citations 2026-06-03T21:55:26.873496

1. Disease Information

1.1 Concise overview

Lissencephaly spectrum disorders are malformations of cortical development (MCDs) characterized by abnormal cortical folding (reduced gyrification) due primarily to impaired neuronal migration and cortical lamination during embryonic development. (uctepe2024biallelictruncatingvariants pages 1-2, alsafh2024multiplexconsanguineousfamily pages 1-2)

A concise definition from a 2024 European Journal of Human Genetics report states: “Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri.” (uctepe2024biallelictruncatingvariants pages 1-2)

1.2 Spectrum terminology (key concepts/definitions)

A core concept is that “lissencephaly” is not a single pattern but a spectrum that includes: - Agyria (near absence of gyri) - Pachygyria (broad, reduced number of gyri) - Subcortical band heterotopia (SBH) (a.k.a. double cortex) (uctepe2024biallelictruncatingvariants pages 1-2, tsai2024novellissencephalyassociatedndel1 pages 1-2)

A 2024 paper explicitly defines this: “LIS spectrum disorder includes agyria, pachygyria and subcortical band heterotopia.” (uctepe2024biallelictruncatingvariants pages 1-2)

1.3 Key identifiers and coding systems

From the tools used here, the disease has: - MONDO: MONDO:0018838 (OpenTargets Search: lissencephaly)

Other identifiers (OMIM disease numbers, Orphanet IDs, ICD-10/ICD-11, MeSH IDs) were not directly retrieved in the available evidence in this run and therefore are not reported here.

1.4 Synonyms and alternative names

Subcortical band heterotopia (SBH) is also referred to as “double cortex”. (tsai2024novellissencephalyassociatedndel1 pages 1-2)

1.5 Evidence source type

The evidence in this report comes from: - Aggregated disease-level resources/knowledge graphs (Open Targets). (OpenTargets Search: lissencephaly) - Human clinical genomics cohort studies and gene discovery/expansion papers (exome sequencing, GeneMatcher collaborations). (kooshavar2024diagnosticutilityof pages 1-3, uctepe2024biallelictruncatingvariants pages 1-2) - Mechanistic human genetics with model-based functional validation (mouse in utero electroporation; scRNA-seq; spatial transcriptomics). (tsai2024novellissencephalyassociatedndel1 pages 1-2)

2. Etiology

2.1 Primary causal factors

Lissencephaly spectrum disorders are genetically heterogeneous, involving multiple pathways critical to neuronal migration, microtubule dynamics, dynein regulation, and cortical organization. Multiple papers emphasize microtubule/dynein/migration biology as central etiologic themes. (alsafh2024multiplexconsanguineousfamily pages 1-2, tsai2024novellissencephalyassociatedndel1 pages 1-2, pavone2023casereportstructural pages 1-2)

A 2024 NDEL1 paper highlights core upstream processes: “cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1.” (tsai2024novellissencephalyassociatedndel1 pages 1-2)

2.2 Genetic risk factors (causal genes and variant classes)

Open Targets provides disease–target associations for lissencephaly and for MONDO:0018838 lissencephaly spectrum disorders, including (not exhaustive): DCX, PAFAH1B1 (LIS1), TUBA1A, ARX, RELN, CEP85L, LAMB1, MACF1, KATNB1, TMTC3, DYNC1H1, NDE1. (OpenTargets Search: lissencephaly)

Recent (2023–2024) primary literature expands the gene spectrum and clarifies inheritance modes:

Autosomal recessive (AR) examples / emerging genes - CASP2: 2024 GeneMatcher-based series of 7 patients from 5 families with biallelic truncating/compound heterozygous variants, described as “compatible with an autosomal recessive pattern.” (uctepe2024biallelictruncatingvariants pages 1-2) - CLASP1: 2024 report of three affected siblings with a homozygous CLASP1 variant from a consanguineous family; the paper notes that segregation suggests “a possible autosomal recessive inheritance.” (alsafh2024multiplexconsanguineousfamily pages 1-2)

Autosomal dominant (AD), often de novo examples (notably tubulinopathies) - TUBA1A: a 2024 case report/literature review states that for TUBA1A “most cases show de novo autosomal dominant inheritance,” consistent with broader tubulinopathy patterns. (ren2024lissencephalycausedby pages 1-2)

Somatic mosaicism - NDEL1 p.Arg105Pro: 2024 Acta Neuropathologica paper identified “the same de novo somatic mosaic NDEL1 variant” in two unrelated patients with pachygyria ± SBH. (tsai2024novellissencephalyassociatedndel1 pages 1-2)

X-linked - DCX is a major X-linked lissencephaly-spectrum gene in Open Targets. (OpenTargets Search: lissencephaly)

2.3 Environmental risk factors / protective factors / gene–environment interactions

While environmental insults can contribute to cortical malformations, quantitative environmental risk/protective factor evidence specific to “lissencephaly spectrum disorders” was not retrieved in the evidence set used here. The available evidence emphasizes genetic causation in most described cases and cohorts. (kooshavar2024diagnosticutilityof pages 1-3, uctepe2024biallelictruncatingvariants pages 1-2)

3. Phenotypes (clinical features)

3.1 Core phenotype set

Commonly reported features include: - Global developmental delay / intellectual disability (ID) (uctepe2024biallelictruncatingvariants pages 1-2) - Hypotonia (uctepe2024biallelictruncatingvariants pages 1-2) - Seizures / epilepsy, often early-onset and refractory (alsafh2024multiplexconsanguineousfamily pages 1-2, uctepe2024biallelictruncatingvariants pages 1-2) - Neurobehavioral phenotypes in subsets (ADHD, autistic traits, poor social skills) in CASP2-related cases (uctepe2024biallelictruncatingvariants pages 1-2)

Abstract quote (CASP2 series): “Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits.” (uctepe2024biallelictruncatingvariants pages 1-2)

3.2 Age of onset and progression

Lissencephaly-spectrum disorders typically present congenitally (structural brain malformation present at birth), with clinical manifestations in infancy (developmental delay and seizures often beginning early). In a long-term lissencephaly cohort, the median age at suspected diagnosis was reported as 5 months for LIS1/PAFAH1B1 and 9 months for DCX. (proepper2026genespecificlongtermcourse pages 6-11)

3.3 Phenotype frequencies and quantitative data (recent cohort statistics)

A long-term cohort study (published 2026) provides quantitative complication frequencies and supportive-care utilization; although slightly outside the requested 2023–2024 priority, these data are currently among the most detailed quantitative real-world outcomes located in the retrieved evidence: - Recurrent respiratory infections: 14/38 (37%) in LIS1/PAFAH1B1; 1/4 (25%) in DCX (proepper2026genespecificlongtermcourse pages 6-11) - Dysphagia/vomiting: 23/37 (62%) in LIS1/PAFAH1B1; 2/4 (50%) in DCX (proepper2026genespecificlongtermcourse pages 6-11) - Tube feeding required: 15/38 (40%) in LIS1/PAFAH1B1; 1/5 (20%) in DCX (proepper2026genespecificlongtermcourse pages 6-11) - Supportive therapies: median 8 therapies per patient (range 1–17) (proepper2026genespecificlongtermcourse pages 6-11)

3.4 HPO term suggestions (non-exhaustive)

Based on the phenotypes explicitly present in the evidence: - Lissencephaly (HP:0001339 appears as a disease entity in the Open Targets output) (OpenTargets Search: lissencephaly) - Microcephaly (mentioned as common and as a prenatal abnormality in cohorts) (hu2026prenataldiagnosisof pages 1-2, proepper2026genespecificlongtermcourse pages 6-11) - Seizures / epilepsy (alsafh2024multiplexconsanguineousfamily pages 1-2, uctepe2024biallelictruncatingvariants pages 1-2) - Hypotonia (uctepe2024biallelictruncatingvariants pages 1-2) - Developmental delay / intellectual disability (uctepe2024biallelictruncatingvariants pages 1-2) - Subcortical band heterotopia / double cortex (tsai2024novellissencephalyassociatedndel1 pages 1-2, uctepe2024biallelictruncatingvariants pages 1-2)

Frequency-by-HPO mapping beyond these qualitative statements was not available in the retrieved sources.

4. Genetic/Molecular Information

4.1 Causal genes (representative list)

High-confidence, widely established genes: PAFAH1B1 (LIS1), DCX, ARX, RELN, TUBA1A, DYNC1H1, NDE1. (OpenTargets Search: lissencephaly, tsai2024novellissencephalyassociatedndel1 pages 1-2)

Recently expanded/implicated genes (2023–2024 evidence): - NDEL1 (somatic mosaic) (tsai2024novellissencephalyassociatedndel1 pages 1-2) - CASP2 (biallelic truncating variants; PIDDosome component) (uctepe2024biallelictruncatingvariants pages 1-2) - CLASP1 (candidate AR lissencephaly) (alsafh2024multiplexconsanguineousfamily pages 1-2)

4.2 Variant classes and functional consequences

Examples from recent evidence: - Truncating / splice-disrupting loss-of-function (AR): CASP2 truncating and splice-site variants, including frameshift and nonsense; RNA studies showed cryptic splicing generating premature stop codons. (uctepe2024biallelictruncatingvariants pages 1-2) - Missense variants with dominant effects (often de novo): NDEL1 p.Arg105Pro (somatic mosaic missense) (tsai2024novellissencephalyassociatedndel1 pages 1-2); TUBA1A p.Arg402Cys in a de novo case report (ren2024lissencephalycausedby pages 1-2)

4.3 Modifier genes / epigenetic information

Specific validated modifier genes or disease-specific epigenetic mechanisms were not retrieved in the evidence set.

4.4 Chromosomal abnormalities

General MCD resources emphasize chromosomal abnormalities as part of the etiologic spectrum, and Kooshavar et al. required prior chromosomal microarray (CMA) with exclusion of pathogenic CNVs. However, lissencephaly-specific CNV frequencies were not provided in the extracted evidence snippets. (kooshavar2024diagnosticutilityof pages 1-3)

5. Environmental Information

No disease-specific environmental or lifestyle contributors were identified in the retrieved evidence set; the evidence emphasizes genetic causation and genomics-guided diagnosis. (kooshavar2024diagnosticutilityof pages 1-3, uctepe2024biallelictruncatingvariants pages 1-2)

6. Mechanism / Pathophysiology

6.1 Core causal chain (current understanding)

A broadly supported mechanism is: 1) Pathogenic variants disrupt proteins governing neuronal migration/cytoskeletal dynamics (microtubules, dynein regulators, microtubule-associated proteins). (alsafh2024multiplexconsanguineousfamily pages 1-2, pavone2023casereportstructural pages 1-2) 2) This impairs nucleokinesis and/or radial migration and cortical layer formation. (tsai2024novellissencephalyassociatedndel1 pages 1-2) 3) The resulting cortical malformation manifests as agyria/pachygyria/SBH and commonly leads to epilepsy and neurodevelopmental disability. (uctepe2024biallelictruncatingvariants pages 1-2)

6.2 Dynein–LIS1–NDE1/NDEL1 and nucleokinesis (major 2024 advance)

The 2024 Acta Neuropathologica study provides unusually direct mechanistic linkage from variant → molecular interaction → cellular process → phenotype: - “p.R105P expression alone strongly disrupted neuronal migration … and impaired nucleus–centrosome coupling, suggesting a failure in nucleokinesis.” (tsai2024novellissencephalyassociatedndel1 pages 1-2) - “Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1.” (tsai2024novellissencephalyassociatedndel1 pages 1-2)

This paper also incorporates modern profiling approaches: “single-cell RNA sequencing and spatial transcriptomic analysis,” which showed complementary expression patterns (NDE1 in neural progenitors; NDEL1 in post-mitotic neurons). (tsai2024novellissencephalyassociatedndel1 pages 1-2)

6.3 PIDDosome/caspase-2 pathway (CASP2, CRADD, PIDD1)

The 2024 CASP2 study ties an apoptosis/inflammasome-like signaling complex to cortical development: “Recently, biallelic pathogenic variants in CRADD and PIDD1 have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2.” (uctepe2024biallelictruncatingvariants pages 1-2)

6.4 Microtubule biology and tubulinopathies

A 2023 review of TUBA1A tubulinopathies describes tubulinopathies as a heterogeneous group of tubulin-gene disorders with severe cortical and subcortical malformations, emphasizing microtubules as fundamental to neuronal migration, axonal transport, and connectivity. (pavone2023casereportstructural pages 1-2)

6.5 Ontology suggestions

GO biological process (examples): neuronal migration; nucleokinesis; microtubule-based process; cortical layer formation (supported conceptually by dynein/migration mechanism and explicitly by the NDEL1 paper’s focus on neuronal migration and nucleokinesis). (tsai2024novellissencephalyassociatedndel1 pages 1-2)

Cell Ontology (CL) suggestions (examples): - Radial glial cells / neural progenitors (the NDEL1 paper explicitly discusses neural progenitors and radial glial cells in the ventricular zone) (tsai2024novellissencephalyassociatedndel1 pages 1-2) - Post-mitotic neurons (explicitly referenced in expression analysis) (tsai2024novellissencephalyassociatedndel1 pages 1-2)

UBERON suggestions: cerebral cortex; ventricular zone; subventricular zone; cortical plate (explicitly referenced anatomical compartments in the NDEL1 study). (tsai2024novellissencephalyassociatedndel1 pages 1-2)

7. Anatomical Structures Affected

7.1 Organ/system level

Primary system: central nervous system, particularly the cerebral cortex (six-layered neocortex) and its gyral/sulcal architecture. (tsai2024novellissencephalyassociatedndel1 pages 1-2, uctepe2024biallelictruncatingvariants pages 1-2)

7.2 Tissue/cell level

Key developmental compartments and cell types include ventricular zone progenitors (radial glial cells) and migrating post-mitotic neurons. (tsai2024novellissencephalyassociatedndel1 pages 1-2)

8. Temporal Development

8.1 Onset

Structural malformation is congenital; clinical recognition often occurs in infancy. In one cohort, median suspected diagnosis age was 5–9 months depending on gene subgroup (LIS1 vs DCX). (proepper2026genespecificlongtermcourse pages 6-11)

8.2 Course

Neurodevelopmental impairment and epilepsy frequently persist long-term; supportive therapies are heavily used by families. (proepper2026genespecificlongtermcourse pages 6-11)

9. Inheritance and Population

9.1 Epidemiology (statistics)

A recent cohort study reports incidence estimates for classic lissencephaly of 11.7–40 per million births and cites substantial mortality burden (approximately 50% mortality by age 10 years). (proepper2026genespecificlongtermcourse pages 6-11)

9.2 Inheritance patterns (summary)

Autosomal dominant, often de novo: common for tubulinopathies (e.g., TUBA1A) (ren2024lissencephalycausedby pages 1-2)
Autosomal recessive: CASP2; CLASP1; and other emerging genes (uctepe2024biallelictruncatingvariants pages 1-2, alsafh2024multiplexconsanguineousfamily pages 1-2)
X-linked: DCX and ARX are prominent X-linked lissencephaly spectrum genes in Open Targets (OpenTargets Search: lissencephaly)
Somatic mosaicism: NDEL1 p.Arg105Pro (tsai2024novellissencephalyassociatedndel1 pages 1-2)

9.3 Consanguinity

The CLASP1 report explicitly involves a “multiplex consanguineous” family and demonstrates a recessive segregation pattern, supporting consanguinity as a practical risk factor for AR forms. (alsafh2024multiplexconsanguineousfamily pages 1-2)

10. Diagnostics

10.1 Imaging

MRI is foundational for diagnosis and for defining the malformation subtype. Kooshavar et al. recruited only children with MRI-defined malformations. (kooshavar2024diagnosticutilityof pages 1-3)

10.2 Genetic testing strategy and real-world yields (key 2024 dataset)

Kooshavar et al. (Brain Communications; accepted Feb 2024; advance access publication Feb 28, 2024) provides “real-world” yield data for exome sequencing in pediatric brain malformations, including lissencephaly and tubulinopathies:

Direct abstract quotes: - “The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up.” (kooshavar2024diagnosticutilityof pages 1-3) - “The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene–disease associations. One additional diagnosis was made by trio exome sequencing.” (kooshavar2024diagnosticutilityof pages 1-3)

This cohort also provides subtype frequencies in their 102-patient series: polymicrogyria 36%, tubulinopathy 10%, lissencephaly 10%, among others. (kooshavar2024diagnosticutilityof pages 1-3)

The study required CMA first and excluded cases with pathogenic CNVs, highlighting the common diagnostic workflow: CMA → exome → research reanalysis/trio when indicated. (kooshavar2024diagnosticutilityof pages 1-3)

10.3 Prenatal diagnostics

A 2026 prenatal MCD review quantifies the high de novo burden and limitations of routine prenatal screening: - “De novo mutations account for the majority of pathogenic genetic alterations identified in MCD (50.6%); up to 75.1% of pathogenic mutations cannot be detected by routine prenatal screening.” (hu2026prenataldiagnosisof pages 1-2)

Although not lissencephaly-specific, this is directly relevant to prenatal detection of lissencephaly-spectrum malformations because gyral/sulcal abnormalities are linked to microtubule/migration genes in that review. (hu2026prenataldiagnosisof pages 1-2)

11. Outcome/Prognosis

Quantitative real-world morbidity and family impact includes high complication burdens (feeding difficulties, respiratory infections) and substantial caregiver HRQL impact. In one cohort, parental HRQL mean was 61.23 (SD 16.79) by PedsQL Family Impact Module. (proepper2026genespecificlongtermcourse pages 6-11)

12. Treatment

12.1 Current applications and real-world management

There are no established disease-modifying therapies in the retrieved evidence set; care is multidisciplinary and supportive: - Antiseizure medications (illustrated by a TUBA1A case with infantile spasms treated with valproate and vigabatrin) (ren2024lissencephalycausedby pages 1-2) - Feeding and dysphagia management including tube feeding/PEG when needed (quantified in a cohort) (proepper2026genespecificlongtermcourse pages 6-11) - Respiratory therapy and infection management (proepper2026genespecificlongtermcourse pages 6-11) - Physiotherapy and other developmental therapies (proepper2026genespecificlongtermcourse pages 6-11)

In a lissencephaly cohort, “physiotherapy and respiratory therapy [were] considered the most effective,” and families used a median of eight supportive therapies per patient. (proepper2026genespecificlongtermcourse pages 6-11)

12.2 MAXO suggestions (examples)

Based on management described: - Antiepileptic drug therapy (seizure management) (ren2024lissencephalycausedby pages 1-2) - Enteral feeding / tube feeding (proepper2026genespecificlongtermcourse pages 6-11) - Physiotherapy (proepper2026genespecificlongtermcourse pages 6-11) - Respiratory therapy (proepper2026genespecificlongtermcourse pages 6-11)

13. Prevention

Primary prevention is generally not feasible for monogenic lissencephaly-spectrum disorders, but genetic counseling and reproductive options (prenatal diagnosis, preimplantation genetic testing) are practical prevention strategies once a familial pathogenic variant is known. This is supported indirectly by the emphasis on the importance of a precise genetic diagnosis for counseling and reproductive planning in genomic-diagnostic cohort work. (kooshavar2024diagnosticutilityof pages 1-3)

14. Other Species / Natural Disease

Evidence for naturally occurring non-human disease was not retrieved in this run.

15. Model Organisms and Experimental Systems

Mechanistic validation in modern lissencephaly genetics increasingly uses functional neurodevelopmental assays and advanced transcriptomics: - The 2024 NDEL1 study used “single-cell RNA sequencing and spatial transcriptomic analysis” and in utero electroporation knockdown to test neuronal migration phenotypes. (tsai2024novellissencephalyassociatedndel1 pages 1-2)

This supports the use of mouse neurodevelopmental systems and multi-omic profiling as key current research implementations for lissencephaly-spectrum gene discovery and mechanism elucidation. (tsai2024novellissencephalyassociatedndel1 pages 1-2)

Clinical trials (real-world implementation of research)

ClinicalTrials.gov includes an interventional study explicitly focused on genetic/transcriptomic diagnosis of lissencephalies: - NCT05185414 “Combining Exome and Transcriptome Data to Unravel the Genetic Basis of the Lissencephalies” (Universitair Ziekenhuis Brussel; enrollment 50; status unknown). (OpenTargets Search: lissencephaly)

Summary artifact (high-yield structured facts)

Item	Key details	Evidence/PMID/DOI/URL	Publication date	Context citation id(s)
Disease spectrum / definition	Lissencephaly spectrum disorders are malformations of cortical development caused chiefly by defective neuronal migration; the spectrum includes agyria, pachygyria, and subcortical band heterotopia (SBH, “double cortex”). Clinical comorbidity commonly includes developmental delay/intellectual disability, hypotonia progressing to spasticity, and seizures.	Uctepe et al., Eur J Hum Genet 2024, DOI: 10.1038/s41431-023-01461-2, https://doi.org/10.1038/s41431-023-01461-2	2024-10	(uctepe2024biallelictruncatingvariants pages 1-2)
Spectrum subtypes / pathology	Classic lissencephaly is linked to cortical dyslamination genes such as PAFAH1B1, DCX, ARX; cobblestone lissencephaly shows distinct neuropathology associated with glycosylation pathway genes such as POMGNT1, POMT1, POMT2.	Brock et al., systematic review; summarized neuropathology of genetically defined MCDs	n/a	(brockUnknownyearneuropathologyofgenetically pages 13-13)
Standardized disease concept	MONDO includes lissencephaly spectrum disorders = MONDO:0018838; Open Targets links high-confidence associated targets including DCX, PAFAH1B1, TUBA1A, ARX, RELN, CEP85L, LAMB1, MACF1.	Open Targets disease-target association, https://platform.opentargets.org	current platform query	(OpenTargets Search: lissencephaly)
Key genes / common established causes	The most common established genes across classic lissencephaly are PAFAH1B1 (LIS1) and DCX; major additional genes include TUBA1A, DYNC1H1, TUBG1, ARX, RELN, CEP85L, LAMB1, MACF1, KATNB1.	Open Targets; Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z	2026-05; platform current	(OpenTargets Search: lissencephaly, proepper2026genespecificlongtermcourse pages 6-11)
Inheritance pattern: AD / de novo	Many lissencephaly-spectrum disorders are autosomal dominant, often de novo, especially tubulinopathies. TUBA1A is reported as the most commonly mutated tubulin gene; “most cases” show de novo autosomal dominant inheritance.	Ren et al., Front Pediatr 2024, DOI: 10.3389/fped.2024.1367305, https://doi.org/10.3389/fped.2024.1367305	2024-05	(ren2024lissencephalycausedby pages 1-2)
Inheritance pattern: X-linked	DCX is an X-linked cause: males often show classic lissencephaly, while females may show SBH/double cortex; mosaic/non-coding variation can yield milder phenotypes.	Gao et al., Heliyon 2023, DOI: 10.1016/j.heliyon.2023.e22323, https://doi.org/10.1016/j.heliyon.2023.e22323; Open Targets	2023-11	(OpenTargets Search: lissencephaly)
Inheritance pattern: AR	Recessive forms are increasingly recognized, including CASP2, CLASP1, TUBGCP2, and earlier CRADD/PIDD1-related anterior-predominant LIS.	Uctepe et al. 2024; Alsafh et al. 2024; Yu et al. 2025	2024-10; 2024-08; 2025-02	(uctepe2024biallelictruncatingvariants pages 1-2, alsafh2024multiplexconsanguineousfamily pages 1-2, yu2025tubgcp2variantscause pages 1-2)
Inheritance pattern: somatic mosaic	NDEL1 p.Arg105Pro was identified as a de novo somatic mosaic cause of pachygyria with or without SBH, establishing mosaic dynein-pathway disease within the lissencephaly spectrum.	Tsai et al., Acta Neuropathol 2024, DOI: 10.1007/s00401-023-02665-y, https://doi.org/10.1007/s00401-023-02665-y	2024-01	(tsai2024novellissencephalyassociatedndel1 pages 1-2)
Quantitative stat: exome diagnostic yield	In 102 children with brain malformations, singleton clinical exome had 36% diagnostic yield, increasing to 43% after research follow-up/reanalysis; one additional diagnosis came from trio exome. Lissencephaly represented 10% of the cohort, and the highest phenotype-based yields were for cobblestone malformation, tubulinopathy, and lissencephaly.	Kooshavar et al., Brain Communications 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056	2024-02-28	(kooshavar2024diagnosticutilityof pages 1-3)
Quantitative stat: malformation subtype mix	Among the Kooshavar cohort, commonest subtypes were polymicrogyria 36%, pontocerebellar hypoplasia 14%, periventricular nodular heterotopia 11%, tubulinopathy 10%, lissencephaly 10%, cortical dysplasia 9%.	Kooshavar et al., Brain Communications 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056	2024-02-28	(kooshavar2024diagnosticutilityof pages 1-3, kooshavar2024diagnosticutilityof pages 3-4)
Quantitative stat: recurrent gene in diagnostics	In the Kooshavar series, the most frequent genetic diagnosis was TUBA1A.	Kooshavar et al., Brain Communications 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056	2024-02-28	(kooshavar2024diagnosticutilityof pages 1-3)
Quantitative stat: prenatal genetics	In prenatal MCD literature synthesized by Hu et al., de novo mutations accounted for 50.6% of pathogenic alterations, and up to 75.1% of pathogenic mutations were not detectable by routine prenatal screening; proliferation-phase abnormalities were 62.9% of prenatal MCD phenotypes.	Hu et al., Biomedicines 2026, DOI: 10.3390/biomedicines14010107, https://doi.org/10.3390/biomedicines14010107	2026-01	(hu2026prenataldiagnosisof pages 1-2)
Quantitative stat: incidence / mortality	A recent long-term cohort summary cites classic lissencephaly incidence of 11.7–40 per million births, infantile epileptic spasms syndrome in 57%, and approximately 50% mortality by age 10 years.	Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z	2026-05	(proepper2026genespecificlongtermcourse pages 6-11)
Quantitative stat: prenatal abnormalities and age at recognition	In the Proepper cohort, prenatal abnormalities were seen in 14/37 (38%) of PAFAH1B1/LIS1 and 2/5 (40%) of DCX cases; median age at suspected diagnosis was 5 months for LIS1-related and 9 months for DCX-related disease.	Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z	2026-05	(proepper2026genespecificlongtermcourse pages 6-11, proepper2026genespecificlongtermcourse pages 11-16)
Quantitative stat: complications / feeding / respiratory	In the Proepper cohort, frequent complications included recurrent respiratory infections 14/38 (37%) in LIS1 and 1/4 (25%) in DCX; dysphagia/vomiting 23/37 (62%) in LIS1 and 2/4 (50%) in DCX; tube feeding required in 15/38 (40%) in LIS1 and 1/5 (20%) in DCX.	Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z	2026-05	(proepper2026genespecificlongtermcourse pages 6-11)
Quantitative stat: supportive care burden / QoL	Families reported a median of 8 supportive therapies per patient (range 1–17); physiotherapy and respiratory therapy were rated most effective. Parental HRQL mean was 61.23 (SD 16.79), indicating substantial caregiver burden.	Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z	2026-05	(proepper2026genespecificlongtermcourse pages 6-11)
Recent expansion: NDEL1	First lissencephaly-associated NDEL1 variant: two unrelated patients with pachygyria ± SBH carried the same de novo somatic mosaic p.Arg105Pro; mechanism implicated failure of nucleokinesis via disrupted NDEL1–LIS1 interaction.	Tsai et al., Acta Neuropathol 2024, DOI: 10.1007/s00401-023-02665-y, https://doi.org/10.1007/s00401-023-02665-y	2024-01	(tsai2024novellissencephalyassociatedndel1 pages 1-2)
Recent expansion: CASP2	CASP2 added to the PIDDosome-related lissencephaly genes: 7 patients from 5 families with biallelic truncating/splice variants had anterior/frontotemporal LIS and pachygyria resembling CRADD/PIDD1 disease.	Uctepe et al., Eur J Hum Genet 2024, DOI: 10.1038/s41431-023-01461-2, https://doi.org/10.1038/s41431-023-01461-2	2024-10	(uctepe2024biallelictruncatingvariants pages 1-2)
Recent expansion: CLASP1	CLASP1 emerged as a candidate recessive lissencephaly gene in a multiplex consanguineous family; 3 siblings had homozygous c.4442G>A p.Arg1481His with classic lissencephaly, microcephaly, severe developmental delay, and early refractory epilepsy.	Alsafh et al., Neurology Genetics 2024, DOI: 10.1212/NXG.0000000000200172, https://doi.org/10.1212/NXG.0000000000200172	2024-08	(alsafh2024multiplexconsanguineousfamily pages 1-2)
Diagnostic approach: imaging	Brain MRI remains the core diagnostic modality for defining the malformation pattern and guiding gene prioritization. Recognizable signatures include anterior/frontotemporal LIS in CASP2/CRADD/PIDD1, posterior>anterior classic LIS plus thin splenium/pontine hypoplasia in CLASP1, and pachygyria ± SBH in mosaic NDEL1.	Uctepe et al. 2024; Alsafh et al. 2024; Tsai et al. 2024	2024	(uctepe2024biallelictruncatingvariants pages 1-2, alsafh2024multiplexconsanguineousfamily pages 1-2, tsai2024novellissencephalyassociatedndel1 pages 1-2)
Diagnostic approach: genetics	Recommended workflow supported by recent evidence: CMA first to detect CNVs; then exome sequencing; then periodic reanalysis because reanalysis contributed more to added diagnoses than trio expansion in a real-world MCD cohort.	Kooshavar et al., Brain Communications 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056	2024-02-28	(kooshavar2024diagnosticutilityof pages 1-3, kooshavar2024diagnosticutilityof pages 3-4)
Diagnostic approach: prenatal	For suspected fetal cortical malformations, fetal neurosonography + fetal MRI + NGS/WES are increasingly emphasized; routine prenatal screens miss many pathogenic variants.	Hu et al., Biomedicines 2026, DOI: 10.3390/biomedicines14010107, https://doi.org/10.3390/biomedicines14010107	2026-01	(hu2026prenataldiagnosisof pages 1-2)
Management / supportive therapies	No disease-modifying therapy is established; current care is multidisciplinary and supportive: antiepileptic therapy, feeding support including tube feeding/PEG when needed, physiotherapy, respiratory therapy, developmental therapies, and caregiver support. Physiotherapy and respiratory therapy were reported as most effective in family surveys.	Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z; Ren et al. 2024	2026-05; 2024-05	(proepper2026genespecificlongtermcourse pages 6-11, ren2024lissencephalycausedby pages 1-2)

Table: This table condenses high-yield definitions, genetics, quantitative clinical statistics, recent gene discoveries, and current diagnostic/management points for lissencephaly spectrum disorders. It is useful as a structured reference for building a disease knowledge-base entry with linked evidence.

Key recent developments (2023–2024 emphasis)

1) Diagnostic genomics evidence in real-world cohorts (2024): singleton exome yield 36% rising to 43% with reanalysis; reanalysis is a major contributor to additional diagnoses, and TUBA1A is a frequent diagnosis. (kooshavar2024diagnosticutilityof pages 1-3) 2) New mechanistic gene association with modern multi-omics (2024): somatic mosaic NDEL1 p.Arg105Pro linked to nucleokinesis failure via disrupted LIS1 binding, with scRNA-seq/spatial transcriptomics and functional migration assays. (tsai2024novellissencephalyassociatedndel1 pages 1-2) 3) Expansion of AR lissencephaly genes (2024): CASP2 biallelic truncating variants implicate the PIDDosome/caspase-2 axis in cortical development; CLASP1 is a candidate AR lissencephaly gene in a consanguineous family, supporting microtubule minus-end stabilization biology in disease. (uctepe2024biallelictruncatingvariants pages 1-2, alsafh2024multiplexconsanguineousfamily pages 1-2)

URLs and publication dates (selected high-authority recent sources)

Kooshavar et al. Brain Communications (Advance access publication 2024-02-28): https://doi.org/10.1093/braincomms/fcae056 (kooshavar2024diagnosticutilityof pages 1-3)
Tsai et al. Acta Neuropathologica (2024, accepted 2023-11-24; published 2024): https://doi.org/10.1007/s00401-023-02665-y (tsai2024novellissencephalyassociatedndel1 pages 1-2)
Uctepe et al. European Journal of Human Genetics (Published online 2023-10-26, journal year 2024): https://doi.org/10.1038/s41431-023-01461-2 (uctepe2024biallelictruncatingvariants pages 1-2)
Alsafh et al. Neurology Genetics (2024): https://doi.org/10.1212/NXG.0000000000200172 (alsafh2024multiplexconsanguineousfamily pages 1-2)
Pavone et al. Frontiers in Pediatrics (2023-09): https://doi.org/10.3389/fped.2023.1210272 (pavone2023casereportstructural pages 1-2)
Ren et al. Frontiers in Pediatrics (2024-05): https://doi.org/10.3389/fped.2024.1367305 (ren2024lissencephalycausedby pages 1-2)

References

(OpenTargets Search: lissencephaly): Open Targets Query (lissencephaly, 25 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(uctepe2024biallelictruncatingvariants pages 1-2): Eyyup Uctepe, Barbara Vona, Fatma Nisa Esen, F. Mujgan Sonmez, Thomas Smol, Sait Tümer, Hanifenur Mancılar, Dilan Ece Geylan Durgun, Odile Boute, Meysam Moghbeli, Ehsan Ghayoor Karimiani, Narges Hashemi, Behnoosh Bakhshoodeh, Hyung Goo Kim, Reza Maroofian, and Ahmet Yesilyurt. Bi-allelic truncating variants in casp2 underlie a neurodevelopmental disorder with lissencephaly. European Journal of Human Genetics, 32:52-60, Oct 2024. URL: https://doi.org/10.1038/s41431-023-01461-2, doi:10.1038/s41431-023-01461-2. This article has 13 citations and is from a domain leading peer-reviewed journal.
(alsafh2024multiplexconsanguineousfamily pages 1-2): Rawan Alsafh, Amal Alhashem, Aly Elsyed, Zafer Yüksel, Kalthoum Graiess-Tlili, Khalid Hundallah, Farah Thabet, and Brahim Tabarki. Multiplex consanguineous family highlights clasp1 as a candidate gene for lissencephaly. Aug 2024. URL: https://doi.org/10.1212/nxg.0000000000200172, doi:10.1212/nxg.0000000000200172. This article has 6 citations.
(tsai2024novellissencephalyassociatedndel1 pages 1-2): Meng-Han Tsai, Hao-Chen Ke, Wan-Cian Lin, Fang-Shin Nian, Chia-Wei Huang, Haw-Yuan Cheng, Chi-Sin Hsu, Tiziana Granata, Chien-Hui Chang, Barbara Castellotti, Shin-Yi Lin, Fabio M. Doniselli, Cheng-Ju Lu, Silvana Franceschetti, Francesca Ragona, Pei-Shan Hou, Laura Canafoglia, Chien-Yi Tung, Mei-Hsuan Lee, Won-Jing Wang, and Jin-Wu Tsai. Novel lissencephaly-associated ndel1 variant reveals distinct roles of nde1 and ndel1 in nucleokinesis and human cortical malformations. Acta Neuropathologica, Jan 2024. URL: https://doi.org/10.1007/s00401-023-02665-y, doi:10.1007/s00401-023-02665-y. This article has 11 citations and is from a highest quality peer-reviewed journal.
(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.
(pavone2023casereportstructural pages 1-2): Piero Pavone, Pasquale Striano, Giovanni Cacciaguerra, Simona Domenica Marino, Enrico Parano, Xena Giada Pappalardo, Raffaele Falsaperla, and Martino Ruggieri. Case report: structural brain abnormalities in tuba1a-tubulinopathies: a narrative review. Frontiers in Pediatrics, Sep 2023. URL: https://doi.org/10.3389/fped.2023.1210272, doi:10.3389/fped.2023.1210272. This article has 7 citations.
(ren2024lissencephalycausedby pages 1-2): Sijing Ren, Yu Kong, Ruihan Liu, Qiu-bo Li, Xuehua Shen, and Qing-xia Kong. Lissencephaly caused by a de novo mutation in tubulin tuba1a: a case report and literature review. Frontiers in Pediatrics, May 2024. URL: https://doi.org/10.3389/fped.2024.1367305, doi:10.3389/fped.2024.1367305. This article has 5 citations.
(proepper2026genespecificlongtermcourse pages 6-11): Christiane R. Proepper, Lisa-Maria Schwarz, Sofia M. Schuetz, Katja von Au, Thomas Bast, Nathalie Beaud, Ingo Borggraefe, Friedrich Bosch, Melanie Busse, Jena Chung, Otfried Debus, Katharina Diepold, Thomas Fries, Gero von Gersdorff, Martin Haeussler, Andreas Hahn, Till Hartlieb, Ralf Heiming, Peter Herkenrath, Gerhard Kluger, Jonas H. Kreth, Gerhard Kurlemann, Peter Moeller, Deborah J. Morris-Rosendahl, Axel Panzer, Heike Philippi, Sophia Ruegner, Carolina Toepfer, Silvia Vieker, Adelheid Wiemer-Kruel, Anika Winter, Gerhard Schuierer, Ute Hehr, and Tobias Geis. Gene-specific long-term course, neurodevelopmental outcome and quality of life in patients with lis1/pafah1b1-, dcx-, dync1h1-, tuba1a- and tubg1-related lissencephaly. Orphanet Journal of Rare Diseases, May 2026. URL: https://doi.org/10.1186/s13023-026-04398-z, doi:10.1186/s13023-026-04398-z. This article has 0 citations and is from a peer-reviewed journal.
(hu2026prenataldiagnosisof pages 1-2): Jinhua Hu, Xiaogang Xu, Ping Jiang, Ruibin Huang, Jiani Yuan, Long Lu, and Jin Han. Prenatal diagnosis of malformations of cortical development: a review of genetic and imaging advances. Biomedicines, 14:107, Jan 2026. URL: https://doi.org/10.3390/biomedicines14010107, doi:10.3390/biomedicines14010107. This article has 1 citations.
(brockUnknownyearneuropathologyofgenetically pages 13-13): S Brock, F Cools, and AC Jansen. Neuropathology of genetically defined malformations of cortical development-a systematic. Unknown journal, Unknown year.
(yu2025tubgcp2variantscause pages 1-2): Tao Yu, Miao Yu, Xueyan Liu, and Hua Wang. Tubgcp2 variants cause lissencephaly spectrum disorders: a case report and literature review. Frontiers in Pediatrics, Feb 2025. URL: https://doi.org/10.3389/fped.2025.1476390, doi:10.3389/fped.2025.1476390. This article has 1 citations.
(kooshavar2024diagnosticutilityof pages 3-4): 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.
(proepper2026genespecificlongtermcourse pages 11-16): Christiane R. Proepper, Lisa-Maria Schwarz, Sofia M. Schuetz, Katja von Au, Thomas Bast, Nathalie Beaud, Ingo Borggraefe, Friedrich Bosch, Melanie Busse, Jena Chung, Otfried Debus, Katharina Diepold, Thomas Fries, Gero von Gersdorff, Martin Haeussler, Andreas Hahn, Till Hartlieb, Ralf Heiming, Peter Herkenrath, Gerhard Kluger, Jonas H. Kreth, Gerhard Kurlemann, Peter Moeller, Deborah J. Morris-Rosendahl, Axel Panzer, Heike Philippi, Sophia Ruegner, Carolina Toepfer, Silvia Vieker, Adelheid Wiemer-Kruel, Anika Winter, Gerhard Schuierer, Ute Hehr, and Tobias Geis. Gene-specific long-term course, neurodevelopmental outcome and quality of life in patients with lis1/pafah1b1-, dcx-, dync1h1-, tuba1a- and tubg1-related lissencephaly. Orphanet Journal of Rare Diseases, May 2026. URL: https://doi.org/10.1186/s13023-026-04398-z, doi:10.1186/s13023-026-04398-z. This article has 0 citations and is from a peer-reviewed journal.

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Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 Concise overview

1.2 Spectrum terminology (key concepts/definitions)

1.3 Key identifiers and coding systems

1.4 Synonyms and alternative names

1.5 Evidence source type

2. Etiology

2.1 Primary causal factors

2.2 Genetic risk factors (causal genes and variant classes)

2.3 Environmental risk factors / protective factors / gene–environment interactions

3. Phenotypes (clinical features)

3.1 Core phenotype set

3.2 Age of onset and progression

3.3 Phenotype frequencies and quantitative data (recent cohort statistics)

3.4 HPO term suggestions (non-exhaustive)

4. Genetic/Molecular Information

4.1 Causal genes (representative list)

4.2 Variant classes and functional consequences

4.3 Modifier genes / epigenetic information

4.4 Chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Core causal chain (current understanding)

6.2 Dynein–LIS1–NDE1/NDEL1 and nucleokinesis (major 2024 advance)

6.3 PIDDosome/caspase-2 pathway (CASP2, CRADD, PIDD1)

6.4 Microtubule biology and tubulinopathies

6.5 Ontology suggestions

7. Anatomical Structures Affected

7.1 Organ/system level

7.2 Tissue/cell level

8. Temporal Development

8.1 Onset

8.2 Course

9. Inheritance and Population

9.1 Epidemiology (statistics)

9.2 Inheritance patterns (summary)

9.3 Consanguinity

10. Diagnostics

10.1 Imaging

10.2 Genetic testing strategy and real-world yields (key 2024 dataset)

10.3 Prenatal diagnostics

11. Outcome/Prognosis

12. Treatment

12.1 Current applications and real-world management

12.2 MAXO suggestions (examples)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms and Experimental Systems

Clinical trials (real-world implementation of research)

Summary artifact (high-yield structured facts)

Key recent developments (2023–2024 emphasis)

URLs and publication dates (selected high-authority recent sources)

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