Central nervous system malformation

Summary

Central nervous system malformation (MONDO:0020022) is a disease (an umbrella term covering 54 Mondo subtypes) caused by NID1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: NID1 (GenCC Strong)
• Umbrella term: 54 Mondo subtypes
• Cohort genes: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	central nervous system malformation
Mondo ID	MONDO:0020022
MeSH	D009421
Orphanet	98044
ICD-10-CM	Q00-Q07
UMLS	C1839543
MedGen	374250
GARD	0019394
Is cancer (heuristic)	no

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 54 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation

Related subtypes (71): congenital nervous system disorder, central nervous system disorder, autoimmune disorder of the nervous system, cranial nerve neuropathy, peripheral nervous system disorder, neuronitis, diplegia of upper limb, retinal disorder, developmental disability, restless legs syndrome, movement disorder, toxic encephalopathy, Barre-Lieou syndrome, Gerstmann syndrome, drug-induced akathisia, drug-induced dyskinesia, stiff-person syndrome, Worster-Drought syndrome, corneal-cerebellar syndrome, pachygyria-intellectual disability-epilepsy syndrome, porencephaly-cerebellar hypoplasia-internal malformations syndrome, symmetrical thalamic calcifications, neonatal brainstem dysfunction, primary orthostatic hypotension, rippling muscle disease with myasthenia gravis, periodic paralysis, qualitative or quantitative protein defects in neuromuscular diseases, specific learning disability, cerebellar hypoplasia-tapetoretinal degeneration syndrome, locked-in syndrome, dopa-responsive dystonia, idiopathic recurrent stupor, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, spontaneous periodic hypothermia, Sydenham chorea, duplication of the pituitary gland, Balint syndrome, paraneoplastic neurologic syndrome, persistent idiopathic facial pain, serotonin syndrome, hypothalamic adipsic hypernatraemia syndrome, exercise-induced malignant hyperthermia, perineural cyst, neuromuscular disease, neuromyelitis optica, AL amyloidosis, AA amyloidosis, neuroleptic malignant syndrome, infectious disorder of the nervous system, synaptopathy, nervous system neoplasm, sensory ganglionopathy, radiculitis, wet beriberi, perceptual disorders, prepubertal anorexia nervosa, neurocutaneous syndrome, neurovascular disorder, Wallerian degeneration, nervous system injury, neurosarcoidosis, neuroendocrine disorder, tubulinopathy, atactic disorder, hereditary neurological disease, meningitis-retention syndrome, KIF1A related neurological disorder, neurological pain disorder, neurodevelopmental disorder, post 5-alpha-reductase inhibitors treatment syndrome, post-selective serotonin reuptake inhibitor sexual dysfunction

Subtypes (54): craniosynostosis-Dandy-Walker malformation-hydrocephalus syndrome, Aase-Smith syndrome, arachnoid cyst, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, Dandy-Walker malformation-postaxial polydactyly syndrome, cervical hypertrichosis-peripheral neuropathy syndrome, Joubert syndrome with oculorenal defect, NPHP3-related Meckel-like syndrome, orofaciodigital syndrome type 6, X-linked intellectual disability-cerebellar hypoplasia syndrome, syndromic X-linked intellectual disability Najm type, X-linked cerebral-cerebellar-coloboma syndrome syndrome, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, aprosencephaly cerebellar dysgenesis, Gomez-Lopez-Hernandez syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, pontine tegmental cap dysplasia, ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome, cerebellar-facial-dental syndrome, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal recessive spinocerebellar ataxia 20, SLC39A8-CDG, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, isolated cerebellar vermis hypoplasia, cerebral gigantism-jaw cysts syndrome, holoprosencephaly-caudal dysgenesis syndrome, Joubert syndrome with ocular defect, macrocephaly-short stature-paraplegia syndrome, glioependymal/ependymal cyst, isolated cerebellar vermis agenesis, isolated unilateral hemispheric cerebellar hypoplasia, isolated bilateral hemispheric cerebellar hypoplasia, Hoyeraal-Hreidarsson syndrome, neural tube defect, partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, tubulinopathy-associated dysgyria, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, rhombencephalosynapsis, Lhermitte-Duclos disease, Ritscher-Schinzel syndrome, spinal muscular atrophy-Dandy-Walker malformation-cataracts syndrome, cystic malformation of the posterior fossa, pontocerebellar hypoplasia, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, hereditary cerebral malformation, isolated arhinencephaly

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 3 · 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
NID1	Strong	Autosomal dominant	central nervous system malformation
ARHGAP39	Limited	Autosomal recessive	central nervous system malformation
LMNB2	Limited	Autosomal recessive	central nervous system malformation	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LMNB2	Orphanet:457265	Progressive myoclonic epilepsy type 9
LMNB2	Orphanet:79087	Acquired partial lipodystrophy
NID1	Orphanet:269215	Isolated Dandy-Walker malformation without hydrocephalus

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARHGAP39	HGNC:29351	ENSG00000147799	Q9C0H5	Rho GTPase-activating protein 39	gencc
LMNB2	HGNC:6638	ENSG00000176619	Q03252	Lamin-B2	gencc
NID1	HGNC:7821	ENSG00000116962	P14543	Nidogen-1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LMNB2	Lamin-B2	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.
NID1	Nidogen-1	Sulfated glycoprotein widely distributed in basement membranes and tightly associated with laminin.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARHGAP39	Scaffold/PPI	no		RhoGAP_dom, MyTH4_dom, WW_dom
LMNB2	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
NID1	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, Thyroglobulin_1

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oviduct epithelium	1
right uterine tube	1
sural nerve	1
left testis	1
right testis	1
ventricular zone	1
lower lobe of lung	1
mucosa of stomach	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARHGAP39	191	ubiquitous	marker	sural nerve, oviduct epithelium, right uterine tube
LMNB2	194	ubiquitous	marker	ventricular zone, left testis, right testis
NID1	262	ubiquitous	marker	stromal cell of endometrium, mucosa of stomach, lower lobe of lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNB2	3,562
NID1	1,702
ARHGAP39	1,449

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMNB2	Q03252	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NID1	P14543	78.50
ARHGAP39	Q9C0H5	59.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 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
Inactivation of CDC42 and RAC1	1	713.8×	0.018	ARHGAP39
Laminin interactions	1	190.3×	0.022	NID1
RHOF GTPase cycle	1	129.8×	0.022	ARHGAP39
RHOD GTPase cycle	1	102.0×	0.022	ARHGAP39
RHOB GTPase cycle	1	77.2×	0.022	ARHGAP39
RHOG GTPase cycle	1	74.2×	0.022	ARHGAP39
RHOC GTPase cycle	1	73.2×	0.022	ARHGAP39
RAC2 GTPase cycle	1	63.4×	0.022	ARHGAP39
RAC3 GTPase cycle	1	59.5×	0.022	ARHGAP39
Degradation of the extracellular matrix	1	58.9×	0.022	NID1
RHOA GTPase cycle	1	37.3×	0.030	ARHGAP39
CDC42 GTPase cycle	1	36.1×	0.030	ARHGAP39
RAC1 GTPase cycle	1	30.5×	0.032	ARHGAP39

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nuclear pore localization	1	1123.5×	0.006	LMNB2
regulation of basement membrane organization	1	936.2×	0.006	NID1
postsynapse organization	1	802.5×	0.006	ARHGAP39
protein localization to nuclear envelope	1	702.2×	0.006	LMNB2
glomerular basement membrane development	1	510.7×	0.006	NID1
positive regulation of integrin-mediated signaling pathway	1	432.1×	0.006	NID1
positive regulation of muscle cell differentiation	1	374.5×	0.006	NID1
nuclear envelope organization	1	330.4×	0.006	LMNB2
nuclear migration	1	244.2×	0.007	LMNB2
basement membrane organization	1	170.2×	0.009	NID1
positive regulation of cell-substrate adhesion	1	165.2×	0.009	NID1
positive regulation of cell adhesion	1	90.6×	0.014	NID1
heterochromatin formation	1	85.1×	0.014	LMNB2
cell-matrix adhesion	1	54.5×	0.021	NID1
regulation of small GTPase mediated signal transduction	1	48.0×	0.022	ARHGAP39
signal transduction	1	5.3×	0.176	ARHGAP39

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARHGAP39	0	0
LMNB2	0	0
NID1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LMNB2	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	0
E	Difficult family or no structure, no drug	3	ARHGAP39, LMNB2, NID1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARHGAP39	0	—
LMNB2	2	—
NID1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.