Lissencephaly type 1 due to doublecortin gene mutation

Summary

Lissencephaly type 1 due to doublecortin gene mutation (MONDO:0010239) is a disease caused by DCX (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: DCX (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 64
• Phenotypes (HPO): 30

Clinical features

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0002463	Language impairment	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0001302	Pachygyria	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0002197	Generalized-onset seizure	Frequent (30-79%)
HP:0003808	Abnormal muscle tone	Frequent (30-79%)
HP:0007015	Poor gross motor coordination	Frequent (30-79%)
HP:0007359	Focal-onset seizure	Frequent (30-79%)
HP:0012469	Infantile spasms	Frequent (30-79%)
HP:0012672	Akinetic mutism	Frequent (30-79%)
HP:0031882	Agyria	Frequent (30-79%)
HP:0100021	Cerebral palsy	Frequent (30-79%)
HP:0000713	Agitation	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002339	Abnormal caudate nucleus morphology	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002835	Aspiration	Occasional (5-29%)
HP:0005484	Secondary microcephaly	Occasional (5-29%)
HP:0006956	Dilation of lateral ventricles	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)
HP:0012520	Dilation of Virchow-Robin spaces	Occasional (5-29%)
HP:0012762	Cerebral white matter atrophy	Occasional (5-29%)
HP:0200134	Epileptic encephalopathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lissencephaly type 1 due to doublecortin gene mutation
Mondo ID	MONDO:0010239
OMIM	300067
Orphanet	2148
DOID	DOID:0112239
ICD-11	891064255
SNOMED CT	715780008
UMLS	C4551968
MedGen	1644310
GARD	0006914
Is cancer (heuristic)	no

Also known as: lissencephaly and agenesis of corpus callosum · lissencephaly type 1 due to doublecortin gene mutation · lissencephaly X-linked · lissencephaly, X-linked · lissencephaly, X-linked, 1 · lissencephaly, X-linked, type 1 · LISX · LISX1 · subcortical laminal heterotopia, X-linked · subcortical laminar heterotopia, X-linked, · X-linked lissencephaly · X-linked lissencephaly type 1 · XLIS

Data availability: 64 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › lissencephaly spectrum disorders › classic lissencephaly › lissencephaly type 1 due to doublecortin gene mutation

Related subtypes (3): Miller-Dieker lissencephaly syndrome, lissencephaly due to LIS1 mutation, isolated lissencephaly type 1 without known genetic defects

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

64 retrieved; paginated sample, class counts are floors:

21 pathogenic, 15 uncertain significance, 11 likely pathogenic, 9 pathogenic/likely pathogenic, 8 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579273	GRCh38/hg38 Xq23(chrX:111250820-111333251)x1	CAPN6	Pathogenic	criteria provided, single submitter
11597	NM_001195553.2(DCX):c.184G>A (p.Asp62Asn)	DCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11598	NM_001195553.2(DCX):c.574C>T (p.Arg192Trp)	DCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11599	NM_001195553.2(DCX):c.373T>C (p.Tyr125His)	DCX	Pathogenic	no assertion criteria provided
11601	NM_001195553.2(DCX):c.176G>T (p.Arg59Leu)	DCX	Pathogenic	no assertion criteria provided
11602	NM_001195553.2(DCX):c.608C>G (p.Thr203Arg)	DCX	Pathogenic	criteria provided, single submitter
11609	NM_001195553.2(DCX):c.587G>A (p.Arg196His)	DCX	Pathogenic	criteria provided, multiple submitters, no conflicts
11610	NM_001195553.2(DCX):c.211G>T (p.Ala71Ser)	DCX	Pathogenic	no assertion criteria provided
1210701	NM_001195553.2(DCX):c.478dup (p.Gln160fs)	DCX	Pathogenic	criteria provided, multiple submitters, no conflicts
1285488	NM_001195553.2(DCX):c.478del (p.Gln160fs)	DCX	Pathogenic	criteria provided, multiple submitters, no conflicts
1320092	NM_001195553.2(DCX):c.304C>A (p.Arg102Ser)	DCX	Pathogenic	criteria provided, single submitter
1342885	NM_001195553.2(DCX):c.628del (p.Val210fs)	DCX	Pathogenic	criteria provided, single submitter
158425	NM_001195553.2(DCX):c.115C>T (p.Arg39Ter)	DCX	Pathogenic	criteria provided, multiple submitters, no conflicts
158433	NM_001195553.2(DCX):c.176G>A (p.Arg59His)	DCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158441	NM_001195553.2(DCX):c.226C>T (p.Arg76Cys)	DCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158443	NM_001195553.2(DCX):c.233G>T (p.Arg78Leu)	DCX	Pathogenic	criteria provided, multiple submitters, no conflicts
158472	NM_001195553.2(DCX):c.532C>T (p.Arg178Cys)	DCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158478	NM_001195553.2(DCX):c.557G>T (p.Arg186Leu)	DCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158485	NM_001195553.2(DCX):c.586C>T (p.Arg196Cys)	DCX	Pathogenic	criteria provided, multiple submitters, no conflicts
158508	NM_001195553.2(DCX):c.809-1G>A	DCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158509	NM_001195553.2(DCX):c.814C>T (p.Arg272Ter)	DCX	Pathogenic	criteria provided, multiple submitters, no conflicts
158511	NM_001195553.2(DCX):c.907C>T (p.Arg303Ter)	DCX	Pathogenic	criteria provided, multiple submitters, no conflicts
1685689	NM_001195553.2(DCX):c.266G>A (p.Arg89Gln)	DCX	Pathogenic	criteria provided, single submitter
210828	NM_001195553.2(DCX):c.280A>G (p.Asn94Asp)	DCX	Pathogenic	criteria provided, single submitter
3382940	NM_001195553.2(DCX):c.41_42del (p.Thr14fs)	DCX	Pathogenic	criteria provided, single submitter
3769854	NM_001195553.2(DCX):c.536C>G (p.Pro179Arg)	DCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
419990	NM_001195553.2(DCX):c.505C>T (p.Gln169Ter)	DCX	Pathogenic	criteria provided, multiple submitters, no conflicts
434900	NM_001195553.2(DCX):c.684_685del (p.Tyr229fs)	DCX	Pathogenic	criteria provided, multiple submitters, no conflicts
434901	NM_001195553.2(DCX):c.544G>T (p.Val182Phe)	DCX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
619981	NM_001195553.2(DCX):c.226C>G (p.Arg76Gly)	DCX	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DCX	Definitive	X-linked	lissencephaly spectrum disorders	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DCX	Orphanet:2148	Lissencephaly type 1 due to doublecortin gene mutation
DCX	Orphanet:99796	Subcortical band heterotopia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DCX	HGNC:2714	ENSG00000077279	O43602	Neuronal migration protein doublecortin	gencc,clinvar
CAPN6	HGNC:1483	ENSG00000077274	Q9Y6Q1	Calpain-6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DCX	Neuronal migration protein doublecortin	Microtubule-associated protein required for initial steps of neuronal dispersion and cortex lamination during cerebral cortex development.
CAPN6	Calpain-6	Microtubule-stabilizing protein that may be involved in the regulation of microtubule dynamics and cytoskeletal organization.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DCX	Other/Unknown	no		Doublecortin_dom, DCX_chordates, Doublecortin_dom_sf
CAPN6	Protease	yes	3.4.22.B26	C2_dom, Peptidase_C2_calpain_cat, Calpain_domain_III

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
ganglionic eminence	1
ventricular zone	1
caput epididymis	1
cauda epididymis	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DCX	114	broad	marker	cortical plate, ganglionic eminence, ventricular zone
CAPN6	161	broad	marker	cauda epididymis, caput epididymis, tibia

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DCX	2,112
CAPN6	1,211

Intra-cohort edges

A	B	Sources
CAPN6	DCX	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DCX	O43602	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CAPN6	Q9Y6Q1	91.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neurofascin interactions	1	713.8×	0.004	DCX
Degradation of the extracellular matrix	1	58.9×	0.025	CAPN6
Extracellular matrix organization	1	31.6×	0.031	CAPN6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of cytoskeleton organization	1	324.1×	0.010	CAPN6
axoneme assembly	1	271.8×	0.010	DCX
microtubule bundle formation	1	255.3×	0.010	CAPN6
retina development in camera-type eye	1	127.7×	0.016	DCX
neuron migration	1	66.9×	0.023	DCX
central nervous system development	1	57.7×	0.023	DCX
nervous system development	1	23.0×	0.049	DCX
intracellular signal transduction	1	19.1×	0.052	DCX

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DCX	0	0
CAPN6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DCX	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CAPN6	3.4.22.B26

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CAPN6
E	Difficult family or no structure, no drug	1	DCX

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DCX	1	—
CAPN6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.