X-linked hydrocephalus with stenosis of the aqueduct of Sylvius

Summary

X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (MONDO:0010611) is a disease caused by L1CAM (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide)
• Causal gene: L1CAM (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 94
• Phenotypes (HPO): 15
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.7	Worldwide	Not yet validated
Prevalence at birth	1-9 / 100 000	1.7	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000238	Hydrocephalus	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0002410	Aqueductal stenosis	Very frequent (80-99%)
HP:0002516	Increased intracranial pressure	Very frequent (80-99%)
HP:0004374	Hemiplegia/hemiparesis	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0001181	Adducted thumb	Frequent (30-79%)
HP:0000280	Coarse facial features	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001331	Absent septum pellucidum	Occasional (5-29%)
HP:0001360	Holoprosencephaly	Occasional (5-29%)
HP:0001387	Joint stiffness	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked hydrocephalus with stenosis of the aqueduct of Sylvius
Mondo ID	MONDO:0010611
MeSH	C536078
OMIM	307000
Orphanet	2182
ICD-11	1284135636
SNOMED CT	71779008
UMLS	C0265216
MedGen	75552
GARD	0000434
Is cancer (heuristic)	no

Also known as: Bickers-Adams syndrome · HSAS · HSAS1 · HYCX · hydrocephalus due to aqueductal stenosis, X-linked recessive · hydrocephalus due to congenital stenosis of aqueduct of Sylvius · hydrocephalus with congenital idiopathic intestinal pseudoobstruction, X-linked recessive · hydrocephalus with hirschsprung disease, X-linked recessive · hydrocephalus with stenosis of the aqueduct of Sylvius · X-linked acqueductal stenosis · X-linked HSAS · X-linked hydrocephalus · X-linked hydrocephalus with stenosis of aqueduct of Sylvius · X-linked hydrocephalus with stenosis of the aqueduct of Sylvius · XLAS

Data availability: 94 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked hydrocephalus with stenosis of the aqueduct of Sylvius

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

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

94 retrieved; paginated sample, class counts are floors:

30 pathogenic, 18 likely pathogenic, 17 uncertain significance, 12 conflicting classifications of pathogenicity, 9 pathogenic/likely pathogenic, 4 benign/likely benign, 3 benign, 1 likely benign

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
1339568	NM_001278116.2(L1CAM):c.2920G>T (p.Glu974Ter)	L1CAM	Pathogenic	criteria provided, single submitter
1344539	NM_001278116.2(L1CAM):c.3046+1G>A	L1CAM	Pathogenic	criteria provided, single submitter
1527928	NM_001278116.2(L1CAM):c.2596_2597del (p.Ile866fs)	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676774	NM_001278116.2(L1CAM):c.2296C>T (p.Gln766Ter)	L1CAM	Pathogenic	no assertion criteria provided
1805138	NM_001278116.2(L1CAM):c.1703+5G>A	L1CAM	Pathogenic	criteria provided, single submitter
198728	NM_001278116.2(L1CAM):c.924C>T (p.Gly308=)	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
211340	NM_001278116.2(L1CAM):c.2351A>G (p.Tyr784Cys)	L1CAM	Pathogenic	criteria provided, single submitter
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
265223	NM_001278116.2(L1CAM):c.1453C>T (p.Arg485Ter)	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
29986	NM_001278116.2(L1CAM):c.3458-1G>C	L1CAM	Pathogenic	no assertion criteria provided
3254679	NM_001278116.2(L1CAM):c.605A>G (p.Asp202Gly)	L1CAM	Pathogenic	criteria provided, single submitter
3382425	NM_001278116.2(L1CAM):c.3170_3174del	L1CAM	Pathogenic	criteria provided, single submitter
3382836	NM_001278116.2(L1CAM):c.2575_2576del (p.Arg859fs)	L1CAM	Pathogenic	criteria provided, single submitter
3764730	NM_001278116.2(L1CAM):c.421_425dup (p.Val143fs)	L1CAM	Pathogenic	criteria provided, single submitter
379893	NM_001278116.2(L1CAM):c.2433C>A (p.Tyr811Ter)	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3893228	NM_001278116.2(L1CAM):c.1380-1G>A	L1CAM	Pathogenic	criteria provided, single submitter
418278	NM_001278116.2(L1CAM):c.1408C>T (p.Gln470Ter)	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
419337	NM_001278116.2(L1CAM):c.1939+1G>A	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
4280615	NM_001278116.2(L1CAM):c.3458-2A>G	L1CAM	Pathogenic	criteria provided, single submitter
435689	NM_001278116.2(L1CAM):c.3053C>G (p.Ser1018Ter)	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
449047	NM_001278116.2(L1CAM):c.1267+1G>A	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531212	NM_001278116.2(L1CAM):c.554_557dup (p.Met187fs)	L1CAM	Pathogenic	criteria provided, single submitter
4531232	NM_001278116.2(L1CAM):c.3138del (p.Arg1046fs)	L1CAM	Pathogenic	criteria provided, single submitter
4531274	NM_001278116.2(L1CAM):c.458C>G (p.Ser153Ter)	L1CAM	Pathogenic	criteria provided, single submitter
804112	NM_001278116.2(L1CAM):c.2440dup (p.Ala814fs)	L1CAM	Pathogenic	criteria provided, single submitter
827844	NM_001278116.2(L1CAM):c.1268-1G>A	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 5 · 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	X-linked hydrocephalus with stenosis of the aqueduct of Sylvius	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
ATN1	Orphanet:101	Dentatorubral pallidoluysian atrophy

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
L1CAM	HGNC:6470	ENSG00000198910	P32004	Neural cell adhesion molecule L1	gencc,clinvar
ATN1	HGNC:3033	ENSG00000111676	P54259	Atrophin-1	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.
ATN1	Atrophin-1	Transcriptional corepressor.

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
L1CAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
ATN1	Other/Unknown	no		Atrophin-like, Atrophin-1

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
right hemisphere of cerebellum	2
cerebellar hemisphere	1
cortical plate	1
adenohypophysis	1
right uterine tube	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
ATN1	223	ubiquitous	marker	right hemisphere of cerebellum, adenohypophysis, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
L1CAM	2,937
ATN1	1,732

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
L1CAM	P32004	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATN1	P54259	49.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Signal transduction by L1	1	259.6×	0.027	L1CAM
Basigin interactions	1	219.6×	0.027	L1CAM
Interaction between L1 and Ankyrins	1	184.2×	0.027	L1CAM
PTEN Regulation	1	114.2×	0.027	ATN1
Recycling pathway of L1	1	112.0×	0.027	L1CAM
Regulation of PTEN gene transcription	1	89.2×	0.028	ATN1
L1CAM interactions	1	60.1×	0.036	L1CAM
Cell surface interactions at the vascular wall	1	47.6×	0.036	L1CAM
Intracellular signaling by second messengers	1	45.7×	0.036	ATN1
PIP3 activates AKT signaling	1	33.4×	0.045	ATN1
Axon guidance	1	22.6×	0.058	L1CAM
Nervous system development	1	21.5×	0.058	L1CAM
Hemostasis	1	18.0×	0.063	L1CAM
Developmental Biology	1	7.2×	0.143	L1CAM
Signal Transduction	1	5.1×	0.187	ATN1

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
cell killing	1	4213.0×	0.003	ATN1
cell migration	2	61.5×	0.003	L1CAM, ATN1
maintenance of cell polarity	1	1203.7×	0.006	ATN1
positive regulation of axon extension	1	255.3×	0.015	L1CAM
response to food	1	247.8×	0.015	ATN1
axon development	1	227.7×	0.015	L1CAM
determination of adult lifespan	1	216.1×	0.015	ATN1
synapse organization	1	140.4×	0.020	L1CAM
post-embryonic development	1	102.8×	0.022	ATN1
neuron apoptotic process	1	92.6×	0.022	ATN1
cell-matrix adhesion	1	81.8×	0.022	L1CAM
male gonad development	1	78.0×	0.022	ATN1
homophilic cell-cell adhesion	1	70.2×	0.022	L1CAM
multicellular organism growth	1	68.5×	0.022	ATN1
chemotaxis	1	68.0×	0.022	L1CAM
neuron projection development	1	61.1×	0.022	L1CAM
central nervous system development	1	57.7×	0.022	ATN1
axon guidance	1	45.3×	0.027	L1CAM
nervous system development	1	23.0×	0.050	L1CAM
cell adhesion	1	18.7×	0.058	L1CAM
spermatogenesis	1	17.6×	0.059	ATN1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	ATN1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
ATN1	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
ATN1	5	Binding:5
L1CAM	2	Binding:2

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	1	L1CAM
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ATN1

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)
L1CAM	2	—
ATN1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06147414	Not specified	RECRUITING	Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders