Autism spectrum disorder - epilepsy - arthrogryposis syndrome

Summary

Autism spectrum disorder - epilepsy - arthrogryposis syndrome (MONDO:0014248) is a disease caused by SLC35A3 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC35A3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 304
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000729	Autistic behavior	Obligate (100%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0004976	Knee dislocation	Frequent (30-79%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001765	Hammertoe	Occasional (5-29%)
HP:0002121	Generalized non-motor (absence) seizure	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autism spectrum disorder - epilepsy - arthrogryposis syndrome
Mondo ID	MONDO:0014248
OMIM	615553
Orphanet	370943
UMLS	C3809910
MedGen	816240
GARD	0017604
Is cancer (heuristic)	no

Also known as: AMRS · arthrogryposis, impaired intellectual development, and seizures · arthrogryposis, intellectual disability, and seizures · arthrogryposis, mental retardation, and seizures · SLC35A3-CDG

Data availability: 304 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › autism spectrum disorder - epilepsy - arthrogryposis syndrome

Related subtypes (56): Neu-Laxova syndrome, inborn mitochondrial metabolism disorder, Ehlers-Danlos syndrome, spondylodysplastic type, MGAT2-congenital disorder of glycosylation, ALDH18A1-related de Barsy syndrome, classic homocystinuria, Larsen-like syndrome, B3GAT3 type, Nijmegen breakage syndrome, Peters plus syndrome, Wiedemann-Rautenstrauch syndrome, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, SHORT syndrome, mucosulfatidosis, CHIME syndrome, creatine transporter deficiency, multiple congenital anomalies-hypotonia-seizures syndrome 2, SLC35A2-congenital disorder of glycosylation, SSR4-congenital disorder of glycosylation, Fabry disease, occipital horn syndrome, Ehlers-Danlos syndrome, musculocontractural type, temtamy preaxial brachydactyly syndrome, B4GALT1-congenital disorder of glycosylation, AICA-ribosiduria, COG7-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, Al-Gazali syndrome, COG1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, Nijmegen breakage syndrome-like disorder, multiple congenital anomalies-hypotonia-seizures syndrome 1, multiple congenital anomalies-hypotonia-seizures syndrome 3, cutis laxa, autosomal dominant 3, SLC39A8-CDG, transketolase deficiency, mucopolysaccharidosis-plus syndrome, Cockayne syndrome, pontocerebellar hypoplasia type 1, mandibuloacral dysplasia, hyperphosphatasia-intellectual disability syndrome, arthrogryposis-renal dysfunction-cholestasis syndrome, CADDS, XYLT1-congenital disorder of glycosylation, hypophosphatasia, sterol biosynthesis disorder, mucolipidosis, mucopolysaccharidosis, oligosaccharidosis, encephalopathy due to sulfite oxidase deficiency, Fanconi anemia, autosomal recessive cutis laxa type 2, Zellweger spectrum disorders, pseudohypoparathyroidism, developmental and epileptic encephalopathy, 77, glycosylphosphatidylinositol biosynthesis defect 15, progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN

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

304 retrieved; paginated sample, class counts are floors:

165 likely benign, 71 uncertain significance, 29 pathogenic, 18 likely pathogenic, 11 pathogenic/likely pathogenic, 7 benign, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425783	NC_000001.10:g.(?100316589)(100483381_?)del	AGL	Pathogenic	criteria provided, single submitter
3247631	NC_000001.10:g.(?100316599)(100459317_?)del	AGL	Pathogenic	criteria provided, single submitter
1069535	NM_012243.3(SLC35A3):c.234_235insTTTTTTTTNNNNNNNNNNTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCATGATGAAATTCTT (p.Asn79fs)	SLC35A3	Pathogenic	criteria provided, single submitter
1069573	NC_000001.10:g.(?100436083)(100480986_?)del	SLC35A3	Pathogenic	criteria provided, single submitter
1070256	NM_012243.3(SLC35A3):c.711dup (p.Gln238fs)	SLC35A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071574	NM_012243.3(SLC35A3):c.211C>T (p.Arg71Ter)	SLC35A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071714	NC_000001.10:g.(?100472580)(100477099_?)del	SLC35A3	Pathogenic	criteria provided, single submitter
1420251	NM_012243.3(SLC35A3):c.842C>A (p.Ser281Ter)	SLC35A3	Pathogenic	criteria provided, single submitter
1433891	NM_012243.3(SLC35A3):c.21C>G (p.Tyr7Ter)	SLC35A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1436503	NM_012243.3(SLC35A3):c.520del (p.Phe173_Val174insTer)	SLC35A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454316	NM_012243.3(SLC35A3):c.595G>T (p.Glu199Ter)	SLC35A3	Pathogenic	criteria provided, single submitter
1455157	NM_012243.3(SLC35A3):c.594_598del (p.Lys198fs)	SLC35A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456292	NM_012243.3(SLC35A3):c.38del (p.Leu13fs)	SLC35A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456328	NC_000001.10:g.(?100316589)(100488042_?)del	SLC35A3	Pathogenic	criteria provided, single submitter
1459700	NC_000001.10:g.(?100459083)(100459307_?)del	SLC35A3	Pathogenic	criteria provided, single submitter
1686985	NM_012243.3(SLC35A3):c.-18-1G>T	SLC35A3	Pathogenic	no assertion criteria provided
1996483	NM_012243.3(SLC35A3):c.45del (p.Gln16fs)	SLC35A3	Pathogenic	criteria provided, single submitter
2010868	NM_012243.3(SLC35A3):c.699del (p.Asn234fs)	SLC35A3	Pathogenic	criteria provided, single submitter
2045066	NM_012243.3(SLC35A3):c.615G>A (p.Trp205Ter)	SLC35A3	Pathogenic	criteria provided, single submitter
2078274	NM_012243.3(SLC35A3):c.735G>A (p.Trp245Ter)	SLC35A3	Pathogenic	criteria provided, single submitter
2103148	NM_012243.3(SLC35A3):c.783del (p.Ile262fs)	SLC35A3	Pathogenic	criteria provided, single submitter
2107218	NM_012243.3(SLC35A3):c.340C>T (p.Gln114Ter)	SLC35A3	Pathogenic	criteria provided, single submitter
2415865	NM_012243.3(SLC35A3):c.754_755del (p.Ala252fs)	SLC35A3	Pathogenic	criteria provided, single submitter
2425784	NC_000001.10:g.(?100436083)(100477099_?)del	SLC35A3	Pathogenic	criteria provided, single submitter
2736290	NM_012243.3(SLC35A3):c.588_589del (p.Leu197fs)	SLC35A3	Pathogenic	criteria provided, single submitter
2767724	NM_012243.3(SLC35A3):c.205del (p.Ala68_Leu69insTer)	SLC35A3	Pathogenic	criteria provided, single submitter
2783637	NM_012243.3(SLC35A3):c.811G>T (p.Gly271Ter)	SLC35A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2843303	NM_012243.3(SLC35A3):c.609_610del (p.Trp205fs)	SLC35A3	Pathogenic	criteria provided, single submitter
2850548	NM_012243.3(SLC35A3):c.605_606insGGAGGCAGAGGTTGCAGTGAGCCGAGATTGCACCACTGCACTCCACCCAGACAACAGAGCAAGACTCCGTCTCANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAGAAACAAAACA (p.Ser203fs)	SLC35A3	Pathogenic	criteria provided, single submitter
2983315	NM_012243.3(SLC35A3):c.423G>A (p.Trp141Ter)	SLC35A3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · 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
SLC35A3	Strong	Autosomal recessive	autism spectrum disorder - epilepsy - arthrogryposis syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC35A3	Orphanet:370943	Autism spectrum disorder-epilepsy-arthrogryposis syndrome
AGL	Orphanet:366	Glycogen storage disease due to glycogen debranching enzyme deficiency

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
SLC35A3	HGNC:11023	ENSG00000117620	Q9Y2D2	UDP-N-acetylglucosamine transporter	gencc,clinvar
AGL	HGNC:321	ENSG00000162688	P35573	Glycogen debranching enzyme	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC35A3	UDP-N-acetylglucosamine transporter	Transports diphosphate-N-acetylglucosamine (UDP-GlcNAc) from the cytosol into the lumen of the Golgi apparatus, functioning as an antiporter that exchanges UDP-N-acetyl-alpha-D-glucosamine for UMP.
AGL	Glycogen debranching enzyme	Multifunctional enzyme acting as 1,4-alpha-D-glucan:1,4-alpha-D-glucan 4-alpha-D-glycosyltransferase and amylo-1,6-glucosidase in glycogen degradation.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC35A3	Other/Unknown	no		Nuc_sug_transpt, EmrE-like
AGL	Enzyme (other)	yes	3.2.1.33	Glycogen_debranch_met, 6-hairpin_glycosidase_sf, AGL/Gdb1

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
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC35A3	287	ubiquitous	marker	mucosa of sigmoid colon, jejunal mucosa, colonic mucosa
AGL	294	ubiquitous	marker	vastus lateralis, biceps brachii, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGL	1,726
SLC35A3	982

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AGL	P35573	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC35A3	Q9Y2D2	89.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Defective SLC35A3 causes arthrogryposis, mental retardation, and seizures (AMRS)	1	5710.0×	0.002	SLC35A3
Transport of nucleotide sugars	1	571.0×	0.009	SLC35A3
Glycogen breakdown (glycogenolysis)	1	380.7×	0.009	AGL
Transport of vitamins, nucleosides, and related molecules	1	135.9×	0.018	SLC35A3
SLC transporter disorders	1	102.0×	0.020	SLC35A3
Disorders of transmembrane transporters	1	69.6×	0.024	SLC35A3
SLC-mediated transmembrane transport	1	29.6×	0.048	SLC35A3
Transport of small molecules	1	12.6×	0.094	SLC35A3
Neutrophil degranulation	1	11.5×	0.094	AGL
Disease	1	6.5×	0.147	SLC35A3

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
UDP-N-acetylglucosamine transmembrane transport	1	2808.7×	0.002	SLC35A3
UDP-N-acetylglucosamine metabolic process	1	1404.3×	0.002	SLC35A3
glycogen catabolic process	1	601.9×	0.004	AGL
glycogen biosynthetic process	1	468.1×	0.004	AGL
response to glucocorticoid	1	162.0×	0.008	AGL
response to nutrient	1	147.8×	0.008	AGL
transmembrane transport	1	84.3×	0.012	SLC35A3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
AGL	MIGLUSTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AGL	4	4
SLC35A3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGLUSTAT	4	AGL
MIGALASTAT	4	AGL
LUCERASTAT	3	AGL
DUVOGLUSTAT	2	AGL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
AGL	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGL	3.2.1.33	amylo-alpha-1,6-glucosidase

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

4 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)
MIGLUSTAT	4	AGL
MIGALASTAT	4	AGL
LUCERASTAT	3	AGL
DUVOGLUSTAT	2	AGL

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AGL
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC35A3

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)
SLC35A3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.