epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

Summary

epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (MONDO:0010339) is a disease caused by SYN1 (GenCC Strong), with 5 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: SYN1 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 505
• Phenotypes (HPO): 4

Clinical features

Signs & symptoms

Clinical features (HPO)

4 HPO clinical features (Orphanet curated; top 4 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000718	Aggressive behavior	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	epilepsy, X-linked 1, with variable learning disabilities and behavior disorders
Mondo ID	MONDO:0010339
MeSH	C564505
OMIM	300491
Orphanet	85294
DOID	DOID:0112122
UMLS	C5774177
MedGen	1823951
GARD	0016748
Is cancer (heuristic)	no

Also known as: epilepsy, X-linked, with variable learning disabilities and behavior disorders, X-linked recessive, X-linked dominant · epilepsy, X-linked, with variable learning disabilities and behaviour disorders · epilepsy, X-linked, with variable learning disabilities and behaviour disorders, X-linked recessive, X-linked dominant · X-linked epilepsy-learning disabilities-behavior disorders syndrome

Data availability: 505 ClinVar variants · 5 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 › epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

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, 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, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, 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

505 retrieved; paginated sample, class counts are floors:

200 uncertain significance, 200 likely benign, 39 pathogenic, 28 conflicting classifications of pathogenicity, 14 benign, 13 likely pathogenic, 7 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2427222	NC_000023.10:g.(?46466387)(47489243_?)del	CFP	Pathogenic	criteria provided, single submitter
1067772	NM_006950.3(SYN1):c.1941_1947dup (p.Ala650fs)	SYN1	Pathogenic	criteria provided, single submitter
1068662	NM_006950.3(SYN1):c.700C>T (p.Arg234Ter)	SYN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074864	NM_006950.3(SYN1):c.433_434del (p.Gln145fs)	SYN1	Pathogenic	criteria provided, single submitter
1301801	NM_006950.3(SYN1):c.1166dup (p.Ser390fs)	SYN1	Pathogenic	criteria provided, single submitter
1326265	NM_006950.3(SYN1):c.122del (p.Gly41fs)	SYN1	Pathogenic	no assertion criteria provided
1451507	NM_006950.3(SYN1):c.1682dup (p.Gln562fs)	SYN1	Pathogenic	criteria provided, single submitter
1456713	NM_006950.3(SYN1):c.1258_1261dup (p.Gln421fs)	SYN1	Pathogenic	criteria provided, single submitter
1489277	NM_006950.3(SYN1):c.1385dup (p.Pro463fs)	SYN1	Pathogenic	criteria provided, single submitter
1700040	NM_006950.3(SYN1):c.39del (p.Phe13fs)	SYN1	Pathogenic	criteria provided, single submitter
1700042	NM_006950.3(SYN1):c.1258dup (p.Arg420fs)	SYN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1700045	NM_006950.3(SYN1):c.975del (p.Tyr326fs)	SYN1	Pathogenic	criteria provided, single submitter
1700046	NM_006950.3(SYN1):c.1729del (p.Ala577fs)	SYN1	Pathogenic	criteria provided, single submitter
1700047	NM_006950.3(SYN1):c.1794_1906del (p.Thr601fs)	SYN1	Pathogenic	criteria provided, single submitter
1700048	NM_006950.3(SYN1):c.1321dup (p.Ala441fs)	SYN1	Pathogenic	criteria provided, single submitter
1710316	NM_006950.3(SYN1):c.1444C>T (p.Gln482Ter)	SYN1	Pathogenic	no assertion criteria provided
1710318	NM_006950.3(SYN1):c.527+1G>T	SYN1	Pathogenic	no assertion criteria provided
1710320	NM_006950.3(SYN1):c.1406dup (p.Pro470fs)	SYN1	Pathogenic	no assertion criteria provided
1710321	NM_006950.3(SYN1):c.1266del (p.Gln423fs)	SYN1	Pathogenic	no assertion criteria provided
207469	NM_006950.3(SYN1):c.1264C>T (p.Arg422Ter)	SYN1	Pathogenic	criteria provided, multiple submitters, no conflicts
2133546	NM_006950.3(SYN1):c.1647_1650del (p.Ala550fs)	SYN1	Pathogenic	criteria provided, single submitter
2133935	NM_006950.3(SYN1):c.554_555insA (p.Arg186fs)	SYN1	Pathogenic	criteria provided, single submitter
2694635	NM_006950.3(SYN1):c.57_63del (p.Asn19fs)	SYN1	Pathogenic	criteria provided, single submitter
2714242	NM_006950.3(SYN1):c.1655del (p.Pro552fs)	SYN1	Pathogenic	criteria provided, single submitter
2766607	NM_006950.3(SYN1):c.98_114del (p.Pro33fs)	SYN1	Pathogenic	criteria provided, single submitter
2822546	NM_006950.3(SYN1):c.1287del (p.Arg430fs)	SYN1	Pathogenic	criteria provided, single submitter
2834690	NM_006950.3(SYN1):c.1594C>T (p.Gln532Ter)	SYN1	Pathogenic	criteria provided, single submitter
2849297	NM_006950.3(SYN1):c.1208_1211del (p.Lys403fs)	SYN1	Pathogenic	criteria provided, single submitter
3642869	NM_006950.3(SYN1):c.1769_1790dup (p.Gly599fs)	SYN1	Pathogenic	criteria provided, single submitter
3648627	NM_006950.3(SYN1):c.1500_1519del (p.Gly501fs)	SYN1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
SYN1	Strong	X-linked	epilepsy, X-linked 1, with variable learning disabilities and behavior disorders	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SYN1	Orphanet:85294	X-linked epilepsy-learning disabilities-behavior disorders syndrome
AKAP4	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
CFP	Orphanet:2966	Properdin deficiency

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYN1	HGNC:11494	ENSG00000008056	P17600	Synapsin-1	gencc,clinvar
NUDT11	HGNC:18011	ENSG00000196368	Q96G61	Diphosphoinositol polyphosphate phosphohydrolase 3-beta	clinvar
LINC01560	HGNC:27333	ENSG00000196741	Q8TB33	Putative uncharacterized protein encoded by LINC01560	clinvar
AKAP4	HGNC:374	ENSG00000147081	Q5JQC9	A-kinase anchor protein 4	clinvar
CFP	HGNC:8864	ENSG00000126759	P27918	Properdin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYN1	Synapsin-1	Neuronal phosphoprotein that coats synaptic vesicles, and binds to the cytoskeleton.
NUDT11	Diphosphoinositol polyphosphate phosphohydrolase 3-beta	Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate), suggesting that it may play a role in signal transduction.
AKAP4	A-kinase anchor protein 4	Major structural component of sperm fibrous sheath.
CFP	Properdin	A positive regulator of the alternate pathway (AP) of complement.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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
Enzyme (other)	1	2.4×	0.353
Other/Unknown	4	1.4×	0.353

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYN1	Other/Unknown	no		Synapsin, ATP_grasp_subdomain_1, PreATP-grasp_dom_sf
NUDT11	Enzyme (other)	yes	3.6.1.52	NUDIX_hydrolase_dom, NUDIX_hydrolase-like_dom_sf, NUDIX_hydrolase_CS
LINC01560	Other/Unknown	no
AKAP4	Other/Unknown	no		SPHK1-interactor_AKAP_110, AKAP_110_C, RII-bd_1
CFP	Other/Unknown	no		TSP1_rpt, TSP1_rpt_sf, CFP_TSR-0

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
prefrontal cortex	1
right frontal lobe	1
right hemisphere of cerebellum	1
Brodmann (1909) area 23	1
cortical plate	1
orbitofrontal cortex	1
buccal mucosa cell	1
ganglionic eminence	1
primordial germ cell in gonad	1
left testis	1
male germ cell	1
sperm	1
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYN1	190	broad	marker	right frontal lobe, right hemisphere of cerebellum, prefrontal cortex
NUDT11	220	ubiquitous	marker	cortical plate, orbitofrontal cortex, Brodmann (1909) area 23
LINC01560	207	ubiquitous	yes	buccal mucosa cell, primordial germ cell in gonad, ganglionic eminence
AKAP4	62	tissue_specific	marker	sperm, male germ cell, left testis
CFP	136	broad	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SYN1	3,188
CFP	2,269
AKAP4	1,149
NUDT11	1,081
LINC01560	0

Structural data

PDB: 1 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFP	P27918	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NUDT11	Q96G61	89.37
SYN1	P17600	69.86
AKAP4	Q5JQC9	53.52
LINC01560	Q8TB33	40.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alternative complement activation	1	761.3×	0.013	CFP
Activation of C3 and C5	1	423.0×	0.013	CFP
Synthesis of pyrophosphates in the cytosol	1	380.7×	0.013	NUDT11
Serotonin Neurotransmitter Release Cycle	1	211.5×	0.017	SYN1
Dopamine Neurotransmitter Release Cycle	1	165.5×	0.017	SYN1
Neurotransmitter release cycle	1	146.4×	0.017	SYN1
Defective B3GALTL causes PpS	1	102.9×	0.017	CFP
Sensory processing of sound	1	102.9×	0.017	SYN1
O-glycosylation of TSR domain-containing proteins	1	100.2×	0.017	CFP
Regulation of Complement cascade	1	77.7×	0.019	CFP
Sensory processing of sound by inner hair cells of the cochlea	1	54.4×	0.025	SYN1
Sensory Perception	1	31.7×	0.039	SYN1
Transmission across Chemical Synapses	1	25.4×	0.045	SYN1
Neuronal System	1	14.8×	0.071	SYN1
Neutrophil degranulation	1	7.7×	0.124	CFP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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 complement activation, alternative pathway	1	4213.0×	0.007	CFP
diphosphoinositol polyphosphate metabolic process	1	842.6×	0.007	NUDT11
diadenosine pentaphosphate catabolic process	1	842.6×	0.007	NUDT11
diadenosine hexaphosphate catabolic process	1	842.6×	0.007	NUDT11
adenosine 5’-(hexahydrogen pentaphosphate) catabolic process	1	842.6×	0.007	NUDT11
positive regulation of opsonization	1	421.3×	0.011	CFP
synaptic vesicle clustering	1	351.1×	0.012	SYN1
regulation of synaptic vesicle cycle	1	280.9×	0.013	SYN1
complement activation, alternative pathway	1	247.8×	0.013	CFP
regulation of neurotransmitter secretion	1	191.5×	0.013	SYN1
cell surface receptor protein serine/threonine kinase signaling pathway	1	183.2×	0.013	AKAP4
neurotransmitter secretion	1	175.5×	0.013	SYN1
sperm flagellum assembly	1	168.5×	0.013	AKAP4
complement activation	1	156.0×	0.013	CFP
positive regulation of immune response	1	120.4×	0.016	CFP
regulation of synaptic vesicle exocytosis	1	113.9×	0.016	SYN1
establishment of protein localization	1	108.0×	0.016	AKAP4
synapse organization	1	70.2×	0.023	SYN1
neuron development	1	63.8×	0.024	SYN1
single fertilization	1	45.8×	0.031	AKAP4
establishment of localization in cell	1	40.1×	0.034	AKAP4
flagellated sperm motility	1	29.3×	0.044	AKAP4
defense response to bacterium	1	27.0×	0.046	CFP
intracellular protein localization	1	26.2×	0.046	AKAP4
chemical synaptic transmission	1	19.3×	0.059	SYN1
protein stabilization	1	16.7×	0.065	CFP
immune response	1	11.8×	0.088	CFP
spermatogenesis	1	8.8×	0.113	AKAP4
signal transduction	1	4.0×	0.227	AKAP4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SYN1	0	0
NUDT11	0	0
LINC01560	0	0
AKAP4	0	0
CFP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NUDT11	4	ADMET:2, Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NUDT11	3.6.1.52, 3.6.1.60	diphosphoinositol-polyphosphate diphosphatase, diadenosine hexaphosphate hydrolase (AMP-forming)

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	NUDT11
E	Difficult family or no structure, no drug	4	SYN1, LINC01560, AKAP4, CFP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SYN1	0	—
NUDT11	4	—
LINC01560	0	—
AKAP4	0	—
CFP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.