Seizures-scoliosis-macrocephaly syndrome

Summary

Seizures-scoliosis-macrocephaly syndrome (MONDO:0014731) is a disease caused by EXT2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: EXT2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 64
• Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0004349	Reduced bone mineral density	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000356	Abnormality of the outer ear	Frequent (30-79%)
HP:0000414	Bulbous nose	Frequent (30-79%)
HP:0000717	Autism	Frequent (30-79%)
HP:0000951	Abnormality of the skin	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001845	Overlapping toe	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002136	Broad-based gait	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000348	High forehead	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0004425	Flat forehead	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)
HP:0011220	Prominent forehead	Occasional (5-29%)
HP:0100777	Exostoses	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	seizures-scoliosis-macrocephaly syndrome
Mondo ID	MONDO:0014731
OMIM	616682
Orphanet	466926
UMLS	C4225248
MedGen	909039
GARD	0017836
Is cancer (heuristic)	no

Also known as: seizures, scoliosis, and macrocephaly syndrome · SSM syndrome · SSMS

Data availability: 64 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › congenital disorder of glycosylation › seizures-scoliosis-macrocephaly syndrome

Related subtypes (24): congenital disorder of glycosylation type I, congenital disorder of glycosylation type II, Larsen-like syndrome, B3GAT3 type, Ehlers-Danlos syndrome, musculocontractural type, temtamy preaxial brachydactyly syndrome, progressive myoclonic epilepsy type 3, autosomal recessive limb-girdle muscular dystrophy type 2P, disorder of protein N-glycosylation, disorder of protein O-glycosylation, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of multiple glycosylation, XYLT1-congenital disorder of glycosylation, congenital muscular dystrophy with intellectual disability, congenital disorder of glycosylation syndrome type 4, congenital disorder of glycosylation with defective fucosylation, SLC10A7-congenital disorder of glycosylation, ALG14-congenital disorder of glycosylation, B3GALT6-congenital disorder of glycosylation, A4GALT-congenital disorder of glycosylation, FAM20B-congenital disorder of glycosylation, ALG10-congenital disorder of glycosylation, congenital disorder of glycosylation, type Ibb, congenital disorder of glycosylation, type Iw, autosomal dominant, congenital disorder of glycosylation, type 1DD

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

64 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 11 conflicting classifications of pathogenicity, 8 pathogenic, 4 likely pathogenic, 2 benign/likely benign, 2 pathogenic/likely pathogenic, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
218894	NM_207122.1(EXT2):c.[260T>G;283C>T]		Pathogenic	no assertion criteria provided
2472	NM_207122.2(EXT2):c.514C>T (p.Gln172Ter)	EXT2	Pathogenic	criteria provided, multiple submitters, no conflicts
2474	NM_207122.2(EXT2):c.679G>A (p.Asp227Asn)	EXT2	Pathogenic	criteria provided, multiple submitters, no conflicts
2475	NM_207122.2(EXT2):c.666C>G (p.Tyr222Ter)	EXT2	Pathogenic	criteria provided, multiple submitters, no conflicts
265133	NM_207122.2(EXT2):c.544C>T (p.Arg182Ter)	EXT2	Pathogenic	criteria provided, multiple submitters, no conflicts
279805	NM_207122.2(EXT2):c.906_907dup (p.His303fs)	EXT2	Pathogenic	criteria provided, multiple submitters, no conflicts
3382526	NM_207122.2(EXT2):c.340dup (p.Tyr114fs)	EXT2	Pathogenic	criteria provided, single submitter
3599606	NM_207122.2(EXT2):c.940-2A>T	EXT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
534138	NM_207122.2(EXT2):c.67C>T (p.Arg23Ter)	EXT2	Pathogenic	criteria provided, multiple submitters, no conflicts
838313	NM_207122.2(EXT2):c.1945C>T (p.Arg649Ter)	EXT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324357	NM_207122.2(EXT2):c.1506G>A (p.Trp502Ter)	EXT2	Likely pathogenic	criteria provided, single submitter
1334100	NM_207122.2(EXT2):c.939+2T>C	EXT2	Likely pathogenic	criteria provided, single submitter
638619	NM_207122.2(EXT2):c.1823A>G (p.Tyr608Cys)	EXT2	Likely pathogenic	criteria provided, single submitter
816885	NM_207122.2(EXT2):c.1173G>A (p.Gln391=)	EXT2	Likely pathogenic	criteria provided, single submitter
1319798	NM_207122.2(EXT2):c.1305+2T>C	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134205	NM_207122.2(EXT2):c.1916C>T (p.Thr639Met)	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134215	NM_207122.2(EXT2):c.1022C>T (p.Pro341Leu)	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134218	NM_207122.2(EXT2):c.1178G>A (p.Arg393Gln)	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195446	NM_207122.2(EXT2):c.284G>A (p.Arg95His)	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2725403	NM_207122.2(EXT2):c.760C>T (p.Leu254Phe)	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304572	NM_207122.2(EXT2):c.11C>T (p.Ser4Leu)	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
580003	NM_207122.2(EXT2):c.1393C>T (p.Arg465Ter)	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
788070	NM_207122.2(EXT2):c.382C>T (p.Arg128Trp)	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
840828	NM_207122.2(EXT2):c.1726G>A (p.Glu576Lys)	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
970087	NM_207122.2(EXT2):c.1177C>T (p.Arg393Trp)	EXT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1184718	NM_207122.2(EXT2):c.626+3A>C	EXT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1402593	NM_207122.2(EXT2):c.1319T>A (p.Val440Glu)	EXT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1421787	NM_207122.2(EXT2):c.1669C>T (p.Arg557Trp)	EXT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1441831	NM_207122.2(EXT2):c.667C>T (p.Arg223Trp)	EXT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1710947	NM_207122.2(EXT2):c.1684C>T (p.Arg562Trp)	EXT2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
EXT2	Strong	Autosomal recessive	seizures-scoliosis-macrocephaly syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EXT2	Orphanet:321	Multiple osteochondromas
EXT2	Orphanet:466926	Seizures-scoliosis-macrocephaly syndrome
EXT2	Orphanet:52022	Potocki-Shaffer syndrome

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
EXT2	HGNC:3513	ENSG00000151348	Q93063	Exostosin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EXT2	Exostosin-2	Glycosyltransferase forming with EXT1 the heterodimeric heparan sulfate polymerase which catalyzes the elongation of the heparan sulfate glycan backbone.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EXT2	Enzyme (other)	yes	2.4.1.224	Exostosin, GT64_dom, Nucleotide-diphossugar_trans

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
cartilage tissue	1
smooth muscle tissue	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EXT2	269	ubiquitous	marker	stromal cell of endometrium, cartilage tissue, smooth muscle tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EXT2	1,242

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EXT2	Q93063	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Defective EXT2 causes exostoses 2	1	815.7×	0.002	EXT2
Defective EXT1 causes exostoses 1, TRPS2 and CHDS	1	815.7×	0.002	EXT2
HS-GAG biosynthesis	1	346.1×	0.003	EXT2

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
fluid transport	1	5617.3×	0.002	EXT2
endochondral bone morphogenesis	1	4213.0×	0.002	EXT2
polysaccharide biosynthetic process	1	2407.4×	0.002	EXT2
heparin proteoglycan biosynthetic process	1	1685.2×	0.002	EXT2
multicellular organismal-level water homeostasis	1	1685.2×	0.002	EXT2
sulfation	1	1053.2×	0.003	EXT2
sodium ion homeostasis	1	936.2×	0.003	EXT2
glycosaminoglycan biosynthetic process	1	842.6×	0.003	EXT2
heart contraction	1	766.0×	0.003	EXT2
heparan sulfate proteoglycan biosynthetic process	1	561.7×	0.003	EXT2
cellular response to fibroblast growth factor stimulus	1	543.6×	0.003	EXT2
mesoderm formation	1	495.6×	0.003	EXT2
vasodilation	1	366.4×	0.004	EXT2
chondrocyte differentiation	1	300.9×	0.004	EXT2
protein N-linked glycosylation	1	263.3×	0.005	EXT2
ossification	1	227.7×	0.005	EXT2
regulation of blood pressure	1	221.7×	0.005	EXT2
gene expression	1	79.9×	0.013	EXT2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EXT2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EXT2	2.4.1.224, 2.4.1.225	glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase

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	EXT2
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)
EXT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.