Lateral meningocele syndrome

Summary

Lateral meningocele syndrome (MONDO:0007537) is a disease caused by NOTCH3 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NOTCH3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 111
• Phenotypes (HPO): 41

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

41 HPO clinical features (Orphanet curated; top 41 by frequency):

HPO ID	Term	Frequency
HP:0000268	Dolichocephaly	Very frequent (80-99%)
HP:0000272	Malar flattening	Very frequent (80-99%)
HP:0000275	Narrow face	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000405	Conductive hearing impairment	Very frequent (80-99%)
HP:0000413	Atresia of the external auditory canal	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0002435	Meningocele	Very frequent (80-99%)
HP:0002645	Wormian bones	Very frequent (80-99%)
HP:0002705	High, narrow palate	Very frequent (80-99%)
HP:0100775	Dural ectasia	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000319	Smooth philtrum	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000678	Dental crowding	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0002162	Low posterior hairline	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003312	Abnormal form of the vertebral bodies	Frequent (30-79%)
HP:0004452	Abnormality of the middle ear ossicles	Frequent (30-79%)
HP:0004493	Craniofacial hyperostosis	Frequent (30-79%)
HP:0005487	Prominent metopic ridge	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000612	Iris coloboma	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0002308	Chiari malformation	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0003307	Hyperlordosis	Occasional (5-29%)
HP:0003396	Syringomyelia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lateral meningocele syndrome
Mondo ID	MONDO:0007537
MeSH	C537878
OMIM	130720
Orphanet	2789
DOID	DOID:0111343
UMLS	C1851710
MedGen	342070
GARD	0009873
Is cancer (heuristic)	no

Also known as: lateral meningocele syndrome · Lehman syndrome · LMNS

Data availability: 111 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › neural tube defect › lateral meningocele syndrome

Related subtypes (11): Chiari malformation type I, diastematomyelia, lipomyelomeningocele, sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome, leptomyelolipoma, primary tethered cord syndrome, neurenteric cyst, isolated amyelia, caudal regression sequence, parietal foramina, iniencephaly

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

111 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 20 benign, 17 conflicting classifications of pathogenicity, 14 benign/likely benign, 13 pathogenic/likely pathogenic, 10 pathogenic, 8 likely benign, 4 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1805968	NM_000435.3(NOTCH3):c.6405_6406del (p.Leu2137fs)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208069	NM_000435.3(NOTCH3):c.6247A>T (p.Lys2083Ter)	NOTCH3	Pathogenic	criteria provided, single submitter
208501	NM_000435.3(NOTCH3):c.457C>T (p.Arg153Cys)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
224880	NM_000435.3(NOTCH3):c.6461_6486del (p.Gly2154fs)	NOTCH3	Pathogenic	criteria provided, single submitter
224881	NM_000435.3(NOTCH3):c.6692dup (p.Ala2233fs)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
224882	NM_000435.3(NOTCH3):c.6732C>A (p.Tyr2244Ter)	NOTCH3	Pathogenic	criteria provided, single submitter
224883	NM_000435.3(NOTCH3):c.6663C>G (p.Tyr2221Ter)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
2736837	NM_000435.3(NOTCH3):c.617G>A (p.Cys206Tyr)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374637	NM_000435.3(NOTCH3):c.1819C>T (p.Arg607Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447791	NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447794	NM_000435.3(NOTCH3):c.1672C>T (p.Arg558Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447825	NM_000435.3(NOTCH3):c.3062A>G (p.Tyr1021Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447832	NM_000435.3(NOTCH3):c.3296G>A (p.Cys1099Tyr)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447846	NM_000435.3(NOTCH3):c.421C>T (p.Arg141Cys)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
447849	NM_000435.3(NOTCH3):c.437G>A (p.Cys146Tyr)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
447862	NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
546089	NM_000435.3(NOTCH3):c.1630C>T (p.Arg544Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
585596	NM_000435.3(NOTCH3):c.145T>G (p.Cys49Gly)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694718	NM_000435.3(NOTCH3):c.6626dup (p.Pro2210fs)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
811998	NM_000435.3(NOTCH3):c.316T>G (p.Cys106Gly)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
870211	NM_000435.3(NOTCH3):c.1918C>T (p.Arg640Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9219	NM_000435.3(NOTCH3):c.505C>T (p.Arg169Cys)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
9225	NM_000435.3(NOTCH3):c.397C>T (p.Arg133Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1508045	NM_000435.3(NOTCH3):c.1441G>T (p.Gly481Cys)	NOTCH3	Likely pathogenic	criteria provided, single submitter
2581716	NM_000435.3(NOTCH3):c.6409_6410del (p.Leu2137fs)	NOTCH3	Likely pathogenic	criteria provided, single submitter
3384037	NM_000435.3(NOTCH3):c.4581_4594del (p.Ser1528fs)	NOTCH3	Likely pathogenic	criteria provided, single submitter
4293074	NM_000435.3(NOTCH3):c.6695dup (p.Ala2233fs)	NOTCH3	Likely pathogenic	criteria provided, single submitter
1256515	NM_000435.3(NOTCH3):c.359C>T (p.Pro120Leu)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1299384	NM_000435.3(NOTCH3):c.2960C>G (p.Thr987Ser)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339489	NM_000435.3(NOTCH3):c.1759C>T (p.Arg587Cys)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
NOTCH3	Strong	Autosomal dominant	lateral meningocele syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOTCH3	Orphanet:136	Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy
NOTCH3	Orphanet:2591	Infantile myofibromatosis
NOTCH3	Orphanet:2789	Lateral meningocele syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NOTCH3	HGNC:7883	ENSG00000074181	Q9UM47	Neurogenic locus notch homolog protein 3	gencc,clinvar
MIR6795	HGNC:50031	ENSG00000275711		microRNA 6795	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOTCH3	Neurogenic locus notch homolog protein 3	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOTCH3	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
MIR6795	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
popliteal artery	1
right coronary artery	1
tibial artery	1
intestine	1
stomach	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOTCH3	273	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery
MIR6795	34		yes	sural nerve, intestine, stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH3	4,403
MIR6795	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH3	Q9UM47	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective LFNG causes SCDO3	1	2284.0×	0.002	NOTCH3
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	1903.3×	0.002	NOTCH3
Noncanonical activation of NOTCH3	1	1427.5×	0.002	NOTCH3
Pre-NOTCH Processing in Golgi	1	634.4×	0.003	NOTCH3
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.003	NOTCH3
NOTCH3 Intracellular Domain Regulates Transcription	1	439.2×	0.003	NOTCH3
Notch-HLH transcription pathway	1	407.9×	0.003	NOTCH3
Pre-NOTCH Transcription and Translation	1	122.8×	0.008	NOTCH3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glomerular capillary formation	1	5617.3×	0.002	NOTCH3
neuroblast differentiation	1	2106.5×	0.003	NOTCH3
neuron fate commitment	1	802.5×	0.004	NOTCH3
artery morphogenesis	1	674.1×	0.004	NOTCH3
forebrain development	1	351.1×	0.006	NOTCH3
positive regulation of smooth muscle cell proliferation	1	330.4×	0.006	NOTCH3
positive regulation of miRNA transcription	1	290.6×	0.006	NOTCH3
negative regulation of neuron differentiation	1	271.8×	0.006	NOTCH3
Notch signaling pathway	1	141.6×	0.009	NOTCH3
axon guidance	1	90.6×	0.013	NOTCH3
negative regulation of transcription by RNA polymerase II	1	17.7×	0.062	NOTCH3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	NOTCH3

Therapeutics

Drug target analysis

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

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
NOTCH3	1	2
MIR6795	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH3	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
VAREGACESTAT	2	NOTCH3

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	1	NOTCH3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MIR6795

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MIR6795	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.