Immunoskeletal dysplasia with neurodevelopmental abnormalities

Summary

Immunoskeletal dysplasia with neurodevelopmental abnormalities (MONDO:0044312) is a disease caused by EXTL3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: EXTL3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunoskeletal dysplasia with neurodevelopmental abnormalities
Mondo ID	MONDO:0044312
OMIM	617425
UMLS	C4479452
MedGen	1381460
GARD	0025889
Is cancer (heuristic)	no

Also known as: ISDNA

Data availability: 11 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › spondyloepiphyseal dysplasia › immunoskeletal dysplasia with neurodevelopmental abnormalities

Related subtypes (43): hip dysplasia, Beukes type, spondyloepiphyseal dysplasia with congenital joint dislocations, Marshall syndrome, metatropic dysplasia, spondyloepiphyseal dysplasia with punctate corneal dystrophy, spondyloepiphyseal dysplasia, MacDermot type, progressive pseudorheumatoid arthropathy of childhood, otospondylomegaepiphyseal dysplasia, Dyggve-Melchior-Clausen disease, dyssegmental dysplasia, Rolland-Desbuquois type, Silverman-Handmaker type dyssegmental dysplasia, Wolcott-Rallison syndrome, Schimke immuno-osseous dysplasia, Richieri Costa-da Silva syndrome, Schwartz-Jampel syndrome, X-linked spondyloepimetaphyseal dysplasia, CODAS syndrome, spondyloepiphyseal dysplasia, Reardon type, brachyolmia-amelogenesis imperfecta syndrome, spondyloepiphyseal dysplasia with coronal craniosynostosis, cataracts, cleft palate, and intellectual disability, anauxetic dysplasia, spondyloepiphyseal dysplasia, Kimberley type, spondyloepiphyseal dysplasia, Cantu type, Ehlers-Danlos syndrome, spondylocheirodysplastic type, spondylo-megaepiphyseal-metaphyseal dysplasia, brachydactylous dwarfism, Mseleni type, TMEM165-congenital disorder of glycosylation, Steel syndrome, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Roifman syndrome, progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome, even-plus syndrome, Smith-McCort dysplasia, cono-spondylar dysplasia, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, Stickler syndrome, spondyloepiphyseal dysplasia tarda, spondyloepiphyseal dysplasia, kondo-fu type, spondyloepiphyseal dysplasia, nishimura type, COL2A1-related spondyloepiphyseal dysplasia, MIR140-related spondyloepiphyseal dysplasia, MGP-related spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia, Holling type

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

11 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 1 likely benign, 1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
623480	NM_001440.4(EXTL3):c.953C>T (p.Pro318Leu)	EXTL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
996966	NM_001440.4(EXTL3):c.472C>T (p.Arg158Ter)	EXTL3	Likely pathogenic	criteria provided, single submitter
1033843	NM_001440.4(EXTL3):c.22C>T (p.Arg8Trp)	EXTL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1358908	NM_001440.4(EXTL3):c.1519G>T (p.Ala507Ser)	EXTL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1364782	NM_001440.4(EXTL3):c.2486T>C (p.Ile829Thr)	EXTL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1695625	NM_001440.4(EXTL3):c.2207A>G (p.Glu736Gly)	EXTL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
417794	NM_001440.4(EXTL3):c.1382C>T (p.Pro461Leu)	EXTL3	Uncertain significance	criteria provided, single submitter
417795	NM_001440.4(EXTL3):c.1970A>G (p.Asn657Ser)	EXTL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
417796	NM_001440.4(EXTL3):c.1015C>T (p.Arg339Trp)	EXTL3	Uncertain significance	criteria provided, single submitter
1647439	NM_001440.4(EXTL3):c.2277-15_2277-3dup	EXTL3	Likely benign	criteria provided, multiple submitters, no conflicts
446049	NM_001440.4(EXTL3):c.1324G>C (p.Val442Leu)	EXTL3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
EXTL3	Strong	Autosomal recessive	immunoskeletal dysplasia with neurodevelopmental abnormalities	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EXTL3	Orphanet:508533	Skeletal dysplasia-T-cell immunodeficiency-developmental delay 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
EXTL3	HGNC:3518	ENSG00000012232	O43909	Exostosin-like 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EXTL3	Exostosin-like 3	Glycosyltransferase which regulates the biosynthesis of heparan sulfate (HS).

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)
EXTL3	Enzyme (other)	yes	2.4.1.223	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
cortical plate	1
stromal cell of endometrium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EXTL3	210	ubiquitous	marker	stromal cell of endometrium, ventricular zone, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EXTL3	1,202

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EXTL3	O43909	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
HS-GAG biosynthesis	1	346.1×	0.005	EXTL3
XBP1(S) activates chaperone genes	1	215.5×	0.005	EXTL3

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 detection of glucose	1	8426.0×	0.001	EXTL3
negative regulation of keratinocyte differentiation	1	1685.2×	0.002	EXTL3
negative regulation of inflammatory response to wounding	1	1685.2×	0.002	EXTL3
quinolinate biosynthetic process	1	1532.0×	0.002	EXTL3
positive regulation of keratinocyte proliferation	1	991.3×	0.002	EXTL3
heparan sulfate proteoglycan biosynthetic process	1	561.7×	0.003	EXTL3
negative regulation of cytokine production involved in inflammatory response	1	421.3×	0.003	EXTL3
positive regulation of cell growth	1	183.2×	0.007	EXTL3
response to lipopolysaccharide	1	124.8×	0.009	EXTL3
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.013	EXTL3

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
EXTL3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EXTL3	2.4.1.223	glucuronosyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase

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	EXTL3
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)
EXTL3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.