L1 syndrome

Summary

L1 syndrome (MONDO:0017140) is a disease caused by L1CAM (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: L1CAM (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 27
• Phenotypes (HPO): 16

Clinical features

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000238	Hydrocephalus	Very frequent (80-99%)
HP:0000716	Depression	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0002315	Headache	Very frequent (80-99%)
HP:0002410	Aqueductal stenosis	Very frequent (80-99%)
HP:0002463	Language impairment	Very frequent (80-99%)
HP:0004374	Hemiplegia/hemiparesis	Very frequent (80-99%)
HP:0001181	Adducted thumb	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	L1 syndrome
Mondo ID	MONDO:0017140
Orphanet	275543
ICD-11	1457804873
UMLS	C5779710
MedGen	1830362
GARD	0012524
NORD	1343
Is cancer (heuristic)	no

Also known as: corpus callosum hypoplasia-retardation-adducted thumbs-spasticity-hydrocephalus syndrome · CRASH syndrome · L1 syndrome · L1CAM syndrome

Data availability: 27 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › L1 syndrome

Related subtypes (189): precocious puberty, complex cortical dysplasia with other brain malformations, imperforate anus, microcephaly, demyelinating disease, hypospadias, bone development disease, primary basilar invagination, familial bicuspid aortic valve, camptodactyly of fingers, isolated congenital digital clubbing, aorta coarctation, gingival fibromatosis-progressive deafness syndrome, Eng-Strom syndrome, Morgagni-Stewart-Morel syndrome, familial partial lipodystrophy, Dunnigan type, megalodactyly, odontomatosis-aortae esophagus stenosis syndrome, otodental syndrome, oculodental syndrome, Rutherfurd type, spina bifida, steatocystoma multiplex-natal teeth syndrome, distal symphalangism, thumb deformity-alopecia-pigmentation anomaly syndrome, double uterus-hemivagina-renal agenesis syndrome, amelogenesis imperfecta type 1G, Bloom syndrome, cardiac valvular defect, developmental, isolated cerebellar hypoplasia/agenesis, cleft palate-stapes fixation-oligodontia syndrome, Jalili syndrome, craniodiaphyseal dysplasia, craniofacial dyssynostosis, deafness-oligodontia syndrome, duodenal atresia, Fowler syndrome, multiple intestinal atresia, natal teeth-intestinal pseudoobstruction-patent ductus syndrome, atresia of small intestine, mulibrey nanism, oculocerebral hypopigmentation syndrome, Cross type, familial osteodysplasia, Anderson type, pancreatic agenesis, postaxial polydactyly-dental and vertebral anomalies syndrome, familial primary pulmonary hypoplasia, renal tubular dysgenesis of genetic origin, Rothmund-Thomson syndrome, familial isolated congenital asplenia, subaortic stenosis, membranous, non-eruption of teeth-maxillary hypoplasia-genu valgum syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, CK syndrome, Ogden syndrome, Nance-Horan syndrome, colonic atresia, Aicardi syndrome, torticollis-keloids-cryptorchidism-renal dysplasia syndrome, 46,XY complete gonadal dysgenesis, loose anagen syndrome, lung agenesis-heart defect-thumb anomalies syndrome, Chudley-McCullough syndrome, macrocephaly-autism syndrome, DNA ligase IV deficiency, horizontal gaze palsy with progressive scoliosis, cataract - congenital heart disease - neural tube defect syndrome, autosomal recessive frontotemporal pachygyria, craniofacial dysplasia - osteopenia syndrome, porencephaly-microcephaly-bilateral congenital cataract syndrome, congenital short bowel syndrome, familial median cleft of the upper and lower lips, progeroid features-hepatocellular carcinoma predisposition syndrome, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, aneurysm of sinus of Valsalva, blepharoptosis-cleft palate-ectrodactyly-dental anomalies syndrome, medullary sponge kidney, isolated congenital syngnathia, cleft lip and alveolus, diprosopus, T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency, high anorectal malformation, intermediate anorectal malformation, low anorectal malformation, microcephaly-polymicrogyria-corpus callosum agenesis syndrome, cordiform uterus, septate uterus, bicornuate uterus, uterine hypoplasia, agenesis and aplasia of uterine body, uterine cervical aplasia and agenesis, longitudinal vaginal septum, transverse vaginal septum, axial mesodermal dysplasia spectrum, multicystic dysplastic kidney, diabetic embryopathy, congenital microgastria, isolated cleft lip, cleft lip/palate, hereditary gingival fibromatosis, congenital bronchobiliary fistula, congenital hydrocephalus, maternal hyperthermia induced birth defects, diphallia, epibulbar lipodermoid-preauricular appendage-polythelia syndrome, bronchogenic cyst, duplication of urethra, hypohidrotic ectodermal dysplasia, Lowe-Kohn-Cohen syndrome, biliary atresia with splenic malformation syndrome, congenital pulmonary airway malformation, familial intestinal malrotation-facial anomalies syndrome, megalencephaly, cephalocele, cerebral cortical dysplasia, familial omphalocele syndrome with facial dysmorphism, penoscrotal transposition, pericardial and diaphragmatic defect, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, congenital deformities of limbs, familial isolated clinodactyly of fingers, congenital shoulder dislocation, congenital elbow dislocation, congenital knee dislocation, congenital patella dislocation, macrodactyly of fingers, macrodactyly of toes, upper limb hypertrophy, lower limb hypertrophy, duplication of the pituitary gland, diencephalic-mesencephalic junction dysplasia, steroid dehydrogenase deficiency-dental anomalies syndrome, congenital achiasma, tracheal agenesis, renal agenesis, hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, isolated splenogonadal fusion, Joubert syndrome, congenital generalized hypercontractile muscle stiffness syndrome, congenital bilateral absence of vas deferens, congenital portosystemic shunt, lissencephaly spectrum disorders, Berardinelli-Seip congenital lipodystrophy, congenital primary megaureter, craniorachischisis, vaginal atresia, bronchopulmonary dysplasia, dentinogenesis imperfecta-short stature-hearing loss-intellectual disability syndrome, aniridia, atypical Werner syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, anterior segment dysgenesis, congenital esophageal diverticulum, renal hypoplasia, renal dysplasia, overgrowth syndrome, developmental defect during embryogenesis, acalvaria, congenital aortic valve insufficiency, congenital anomaly of superior vena cava, congenital anomaly of hepatic vein, posterior hypospadias, isolated micropenis, isolated partial vaginal agenesis, anorectal malformation, pulmonary agenesis, congenital tricuspid malformation, Noonan syndrome and Noonan-related syndrome, coronary sinus stenosis, coronary sinus atresia, cartilage development disorder, syndactyly, polydactyly, brachydactyly, neurocristopathy, congenital absence of septum pellucidum, branchial arch disease, congenital anomaly of cardiovascular system, atelencephaly, aprosencephaly, aortic valve stenosis, hereditary lethal multiple congenital anomalies/dysmorphic syndrome, congenital agenesis of the scrotum, keratinization disease, lactation disease, COACH syndrome, constitutional delay of growth and puberty, isolated congenital femoral bifurcation, congenital peritoneal encapsulation, isolated short stature, congenital high airway obstruction syndrome

Subtypes (4): MASA syndrome, X-linked complicated corpus callosum dysgenesis, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, X-linked complicated spastic paraplegia type 1

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

27 retrieved; paginated sample, class counts are floors:

12 pathogenic, 8 pathogenic/likely pathogenic, 7 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10001	NM_001278116.2(L1CAM):c.719C>T (p.Pro240Leu)	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1697985	NM_001278116.2(L1CAM):c.3671C>T (p.Ser1224Leu)	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
211339	NM_001278116.2(L1CAM):c.2278C>T (p.Arg760Ter)	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
226120	NM_001278116.2(L1CAM):c.2380C>T (p.Gln794Ter)	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265221	NM_001278116.2(L1CAM):c.807-6G>A	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265222	NM_001278116.2(L1CAM):c.523+12C>T	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265224	NM_001278116.2(L1CAM):c.1417C>T (p.Arg473Cys)	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3063668	NM_001278116.2(L1CAM):c.3638del (p.Gly1213fs)	L1CAM	Pathogenic	criteria provided, single submitter
3377355	NM_001278116.2(L1CAM):c.1268-2A>T	L1CAM	Pathogenic	criteria provided, single submitter
3629972	NM_001278116.2(L1CAM):c.2878G>T (p.Glu960Ter)	L1CAM	Pathogenic	criteria provided, single submitter
3768659	NM_001278116.2(L1CAM):c.1098G>A (p.Trp366Ter)	L1CAM	Pathogenic	criteria provided, single submitter
449047	NM_001278116.2(L1CAM):c.1267+1G>A	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4688744	NM_001278116.2(L1CAM):c.2472del (p.Asn825fs)	L1CAM	Pathogenic	criteria provided, single submitter
635331	NM_001278116.2(L1CAM):c.3166+1G>A	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
635332	NM_001278116.2(L1CAM):c.749del (p.Ser250fs)	L1CAM	Pathogenic	criteria provided, single submitter
838485	NM_001278116.2(L1CAM):c.925G>A (p.Glu309Lys)	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
996255	NM_001278116.2(L1CAM):c.2712del (p.Ala906fs)	L1CAM	Pathogenic	criteria provided, single submitter
9990	NM_001278116.2(L1CAM):c.1354G>A (p.Gly452Arg)	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
9991	NM_001278116.2(L1CAM):c.551G>A (p.Arg184Gln)	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
9998	NM_001278116.2(L1CAM):c.2254G>A (p.Val752Met)	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
1705249	NM_001278116.2(L1CAM):c.2269C>T (p.Gln757Ter)	L1CAM	Likely pathogenic	criteria provided, single submitter
1723339	NM_001278116.2(L1CAM):c.2432-1G>A	L1CAM	Likely pathogenic	criteria provided, single submitter
1878415	NM_001278116.2(L1CAM):c.1829-2A>G	L1CAM	Likely pathogenic	criteria provided, single submitter
2500928	NM_001278116.2(L1CAM):c.3500dup (p.Met1168fs)	L1CAM	Likely pathogenic	criteria provided, single submitter
4532167	NM_001278116.2(L1CAM):c.992-1G>C	L1CAM	Likely pathogenic	criteria provided, single submitter
4532168	NM_001278116.2(L1CAM):c.694+2T>C	L1CAM	Likely pathogenic	criteria provided, single submitter
974976	NM_001278116.2(L1CAM):c.3241C>T (p.Gln1081Ter)	L1CAM	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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
L1CAM	Definitive	X-linked	L1 syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
L1CAM	Orphanet:1497	X-linked complicated corpus callosum dysgenesis
L1CAM	Orphanet:2182	Hydrocephalus with stenosis of the aqueduct of Sylvius
L1CAM	Orphanet:2466	MASA syndrome
L1CAM	Orphanet:306617	X-linked complicated spastic paraplegia type 1

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
L1CAM	HGNC:6470	ENSG00000198910	P32004	Neural cell adhesion molecule L1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
L1CAM	Neural cell adhesion molecule L1	Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
L1CAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
cortical plate	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
L1CAM	239	ubiquitous	marker	cortical plate, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
L1CAM	2,937

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
L1CAM	P32004	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 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
Signal transduction by L1	1	519.1×	0.009	L1CAM
Basigin interactions	1	439.2×	0.009	L1CAM
Interaction between L1 and Ankyrins	1	368.4×	0.009	L1CAM
Recycling pathway of L1	1	223.9×	0.011	L1CAM
L1CAM interactions	1	120.2×	0.017	L1CAM
Cell surface interactions at the vascular wall	1	95.2×	0.018	L1CAM
Axon guidance	1	45.1×	0.029	L1CAM
Nervous system development	1	42.9×	0.029	L1CAM
Hemostasis	1	36.0×	0.031	L1CAM
Developmental Biology	1	14.5×	0.069	L1CAM

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
positive regulation of axon extension	1	510.7×	0.012	L1CAM
axon development	1	455.5×	0.012	L1CAM
synapse organization	1	280.9×	0.013	L1CAM
cell-matrix adhesion	1	163.6×	0.013	L1CAM
homophilic cell-cell adhesion	1	140.4×	0.013	L1CAM
chemotaxis	1	135.9×	0.013	L1CAM
neuron projection development	1	122.1×	0.013	L1CAM
axon guidance	1	90.6×	0.015	L1CAM
cell migration	1	61.5×	0.020	L1CAM
nervous system development	1	45.9×	0.024	L1CAM
cell adhesion	1	37.5×	0.027	L1CAM

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
L1CAM	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
L1CAM	2	Binding:2

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

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	1	L1CAM
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
L1CAM	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.