MASA syndrome

Summary

MASA syndrome (MONDO:0010559) is a disease caused by L1CAM (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: L1CAM (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 59
• Phenotypes (HPO): 13

Clinical features

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001188	Hand clenching	Very frequent (80-99%)
HP:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002381	Aphasia	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004374	Hemiplegia/hemiparesis	Very frequent (80-99%)
HP:0004209	Clinodactyly of the 5th finger	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	MASA syndrome
Mondo ID	MONDO:0010559
OMIM	303350
Orphanet	2466
DOID	DOID:0060246
ICD-11	1973644723
NCIT	C129930
SNOMED CT	716996008
UMLS	C0795953
MedGen	162894
GARD	0006986
Is cancer (heuristic)	no

Also known as: adducted thumb with mental retardation · Clasped thumb and mental retardation · Gareis-Mason syndrome · intellectual disability aphasia shuffling Gait adducted thumbs (MASA) · intellectual disability-aphasia-shuffling gait-adducted thumbs syndrome · MASA syndrome · masa syndrome, X-linked recessive · mental retardation aphasia shuffling Gait adducted thumbs (MASA) · mental retardation, aphasia, shuffling Gait, and adducted thumbs · spastic paraplegia 1 · spastic paraplegia, X-linked · thumb congenital clasped with intellectual disability · thumb congenital clasped with mental retardation · thumb, congenital Clasped, with mental retardation

Data availability: 59 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › MASA syndrome

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, hereditary spastic paraplegia 23, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 18, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 45, hereditary spastic paraplegia 44, hereditary spastic paraplegia 46, hereditary spastic paraplegia 53, hereditary spastic paraplegia 49, hereditary spastic paraplegia 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, glutamate pyruvate transaminase 2 deficiency, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

59 retrieved; paginated sample, class counts are floors:

15 pathogenic, 14 uncertain significance, 11 conflicting classifications of pathogenicity, 9 likely pathogenic, 6 pathogenic/likely pathogenic, 4 benign/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
1343116	NM_001278116.2(L1CAM):c.3234G>A (p.Trp1078Ter)	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
265221	NM_001278116.2(L1CAM):c.807-6G>A	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
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
4071959	NM_001278116.2(L1CAM):c.2750-1G>A	L1CAM	Pathogenic	criteria provided, single submitter
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
488700	NM_001278116.2(L1CAM):c.1672C>T (p.Arg558Ter)	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
647732	NM_001278116.2(L1CAM):c.3496C>T (p.Arg1166Ter)	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
9988	NM_001278116.2(L1CAM):c.630C>A (p.His210Gln)	L1CAM	Pathogenic	no assertion criteria provided
9989	NM_001278116.2(L1CAM):c.1792G>A (p.Asp598Asn)	L1CAM	Pathogenic	no assertion criteria provided
9992	NM_001278116.2(L1CAM):c.3489_3490del (p.Glu1164fs)	L1CAM	Pathogenic	criteria provided, single submitter
9993	NM_001278116.2(L1CAM):c.3581C>T (p.Ser1194Leu)	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9994	NM_001278116.2(L1CAM):c.536T>G (p.Ile179Ser)	L1CAM	Pathogenic	no assertion criteria provided
9995	NM_001278116.2(L1CAM):c.1108G>A (p.Gly370Arg)	L1CAM	Pathogenic	criteria provided, multiple submitters, no conflicts
3062265	NM_001278116.2(L1CAM):c.2848_2849del (p.Gly950fs)	L1CAM	Likely pathogenic	criteria provided, single submitter
3062318	NM_001278116.2(L1CAM):c.3233G>A (p.Trp1078Ter)	L1CAM	Likely pathogenic	criteria provided, single submitter
3573920	NM_001278116.2(L1CAM):c.1228C>G (p.His410Asp)	L1CAM	Likely pathogenic	criteria provided, single submitter
3598160	NM_001278116.2(L1CAM):c.3047-2A>T	L1CAM	Likely pathogenic	criteria provided, single submitter
4293322	NM_001278116.2(L1CAM):c.2455del (p.Glu819fs)	L1CAM	Likely pathogenic	criteria provided, single submitter
4294442	NM_001278116.2(L1CAM):c.3096_3123dup (p.Gln1042fs)	L1CAM	Likely pathogenic	criteria provided, single submitter
981505	NM_001278116.2(L1CAM):c.1222A>G (p.Asn408Asp)	L1CAM	Likely pathogenic	criteria provided, single submitter
982574	NM_001278116.2(L1CAM):c.32_33del (p.Leu11fs)	L1CAM	Likely pathogenic	criteria provided, single submitter
996551	NM_001278116.2(L1CAM):c.649A>G (p.Arg217Gly)	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	Strong	X-linked	MASA 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.