Spondyloepimetaphyseal dysplasia with joint laxity

Summary

Spondyloepimetaphyseal dysplasia with joint laxity (MONDO:0019675) is a disease caused by EXOC6B (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: EXOC6B (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 281

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepimetaphyseal dysplasia with joint laxity
Mondo ID	MONDO:0019675
MeSH	C562968
OMIM	271640
Orphanet	93359
DOID	DOID:0112197
SNOMED CT	254100000
UMLS	C0432243
MedGen	98148
GARD	0004982
Is cancer (heuristic)	no

Also known as: SEMD-JL · SEMDJL · SEMDJL1 · spondyloepimetaphyseal dysplasia joint laxity · spondyloepimetaphyseal dysplasia with joint laxity · spondyloepimetaphyseal dysplasia with joint laxity type 1 · spondyloepimetaphyseal dysplasia with joint laxity, Beighton type

Data availability: 281 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › spondyloepimetaphyseal dysplasia › spondyloepimetaphyseal dysplasia with joint laxity

Related subtypes (22): spondyloepimetaphyseal dysplasia-hypotrichosis syndrome, spondyloepimetaphyseal dysplasia, Maroteaux type, spondyloepimetaphyseal dysplasia, Strudwick type, spondyloepimetaphyseal dysplasia, sponastrime type, spondyloepimetaphyseal dysplasia, Irapa type, spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome, spondyloepimetaphyseal dysplasia, Bieganski type, spondyloepimetaphyseal dysplasia-abnormal dentition syndrome, spondyloepimetaphyseal dysplasia, Missouri type, spondyloepimetaphyseal dysplasia, Shohat type, spondyloepimetaphyseal dysplasia, matrilin-3 type, spondyloepimetaphyseal dysplasia, Genevieve type, spondyloepimetaphyseal dysplasia, aggrecan type, spondyloepimetaphyseal dysplasia, Handigodu type, spondyloepimetaphyseal dysplasia, Isidor type, spondyloepimetaphyseal dysplasia, PAPSS2 type, spondyloepimetaphyseal dysplasia, Krakow type, spondyloepimetaphyseal dysplasia, Isidor-Toutain type, spondyloepimetaphyseal dysplasia, di rocco type, COL2A1-related spondyloepiphyseal dysplasia, spondyloepimetaphyseal dysplasia, Guo-Campeau type, spondyloepimetaphyseal dysplasia, Li-Shao-Li type

Subtypes (3): spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures, spondyloepimetaphyseal dysplasia with multiple dislocations, spondyloepimetaphyseal dysplasia with joint laxity, type 3

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

281 retrieved; paginated sample, class counts are floors:

137 uncertain significance, 93 likely benign, 26 conflicting classifications of pathogenicity, 13 pathogenic, 7 benign/likely benign, 4 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1412663	NC_000001.10:g.(?861322)(3768971_?)del	ARHGEF16	Pathogenic	criteria provided, single submitter
1452181	NM_080605.4(B3GALT6):c.2T>C (p.Met1Thr)	B3GALT6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1498946	NM_080605.4(B3GALT6):c.513_520del (p.Glu174fs)	B3GALT6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2151860	NM_080605.4(B3GALT6):c.3G>A (p.Met1Ile)	B3GALT6	Pathogenic	criteria provided, single submitter
2925287	NM_080605.4(B3GALT6):c.235A>G (p.Thr79Ala)	B3GALT6	Pathogenic	criteria provided, multiple submitters, no conflicts
3748105	NM_080605.4(B3GALT6):c.636C>G (p.Tyr212Ter)	B3GALT6	Pathogenic	criteria provided, single submitter
3750880	NM_080605.4(B3GALT6):c.521_528del (p.Glu174fs)	B3GALT6	Pathogenic	criteria provided, single submitter
3760089	NC_000001.11:g.1232202_1232288del	B3GALT6	Pathogenic	criteria provided, single submitter
3760396	NM_080605.4(B3GALT6):c.84C>G (p.Tyr28Ter)	B3GALT6	Pathogenic	criteria provided, single submitter
4784715	NM_080605.4(B3GALT6):c.460A>T (p.Lys154Ter)	B3GALT6	Pathogenic	criteria provided, single submitter
4785201	NM_080605.4(B3GALT6):c.251_257del (p.Arg84fs)	B3GALT6	Pathogenic	criteria provided, single submitter
4786019	NM_080605.4(B3GALT6):c.117dup (p.Arg40fs)	B3GALT6	Pathogenic	criteria provided, single submitter
4788955	NM_080605.4(B3GALT6):c.197_253del (p.Ala66_Arg84del)	B3GALT6	Pathogenic	criteria provided, single submitter
4791228	NM_080605.4(B3GALT6):c.577A>T (p.Lys193Ter)	B3GALT6	Pathogenic	criteria provided, single submitter
60484	NM_080605.4(B3GALT6):c.1A>G (p.Met1Val)	B3GALT6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60489	NM_080605.4(B3GALT6):c.200C>T (p.Pro67Leu)	B3GALT6	Pathogenic	criteria provided, single submitter
60491	NM_080605.4(B3GALT6):c.925T>A (p.Ser309Thr)	B3GALT6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067539	NM_080605.4(B3GALT6):c.2T>A (p.Met1Lys)	B3GALT6	Likely pathogenic	criteria provided, single submitter
1035382	NM_080605.4(B3GALT6):c.538C>T (p.Arg180Cys)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1063834	NM_080605.4(B3GALT6):c.631C>T (p.Pro211Ser)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1313270	NM_080605.4(B3GALT6):c.956C>T (p.Ser319Leu)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1323966	NM_080605.4(B3GALT6):c.901_904dup (p.Arg302fs)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1323967	NM_080605.4(B3GALT6):c.201_210del (p.Arg68fs)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1438621	NM_080605.4(B3GALT6):c.109G>C (p.Gly37Arg)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1472063	NM_080605.4(B3GALT6):c.530GCC[5] (p.Arg180dup)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283369	NM_080605.4(B3GALT6):c.753G>A (p.Pro251=)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283589	NM_080605.4(B3GALT6):c.834G>A (p.Thr278=)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283597	NM_080605.4(B3GALT6):c.853G>A (p.Asp285Asn)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290128	NM_080605.4(B3GALT6):c.699C>T (p.Asp233=)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
373234	NM_080605.4(B3GALT6):c.515C>T (p.Ala172Val)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
B3GALT6	Definitive	Autosomal recessive	spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures	10
EXOC6B	Strong	Autosomal recessive	spondyloepimetaphyseal dysplasia with joint laxity, type 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
B3GALT6	Orphanet:536467	B3GALT6-related spondylodysplastic Ehlers-Danlos syndrome
B3GALT6	Orphanet:642099	Spondyloepimetaphyseal dysplasia with joint laxity, Beighton type
EXOC6B	Orphanet:642085	EXOC6B-related spondyloepimetaphyseal dysplasia with joint laxity

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
B3GALT6	HGNC:17978	ENSG00000176022	Q96L58	Beta-1,3-galactosyltransferase 6	gencc,clinvar
EXOC6B	HGNC:17085	ENSG00000144036	Q9Y2D4	Exocyst complex component 6B	gencc
ARHGEF16	HGNC:15515	ENSG00000130762	Q5VV41	Rho guanine nucleotide exchange factor 16	clinvar
ACAP3	HGNC:16754	ENSG00000131584	Q96P50	Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
B3GALT6	Beta-1,3-galactosyltransferase 6	Beta-1,3-galactosyltransferase that transfers galactose from UDP-galactose to substrates with a terminal beta-linked galactose residue.
EXOC6B	Exocyst complex component 6B	Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.
ARHGEF16	Rho guanine nucleotide exchange factor 16	Guanyl-nucleotide exchange factor of the RHOG GTPase stimulating the exchange of RHOG-associated GDP for GTP.
ACAP3	Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 3	GTPase-activating protein for the ADP ribosylation factor family.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.25

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
Scaffold/PPI	2	8.6×	0.056
Enzyme (other)	1	3.0×	0.441
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
B3GALT6	Enzyme (other)	yes	2.4.1.134	Glyco_trans_31
EXOC6B	Other/Unknown	no		EXOC6/Sec15, EXOC6PINT-1/Sec15/Tip20_C_dom2, EXOC6/Sec15_C_dom1
ARHGEF16	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain
ACAP3	Scaffold/PPI	no		ArfGAP_dom, PH_domain, Ankyrin_rpt

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
cartilage tissue	1
endothelial cell	1
calcaneal tendon	1
globus pallidus	1
medial globus pallidus	1
ileal mucosa	1
metanephros cortex	1
mucosa of transverse colon	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
B3GALT6	236	ubiquitous	yes	Brodmann (1909) area 23, endothelial cell, cartilage tissue
EXOC6B	259	ubiquitous	marker	calcaneal tendon, medial globus pallidus, globus pallidus
ARHGEF16	199	broad	marker	mucosa of transverse colon, metanephros cortex, ileal mucosa
ACAP3	221	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EXOC6B	1,353
ARHGEF16	1,269
ACAP3	927
B3GALT6	797

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
B3GALT6	Q96L58	1
ARHGEF16	Q5VV41	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EXOC6B	Q9Y2D4	80.08
ACAP3	Q96P50	76.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 4 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
Chondroitin sulfate/dermatan sulfate metabolism	1	475.8×	0.022	B3GALT6
Diseases associated with glycosaminoglycan metabolism	1	380.7×	0.022	B3GALT6
Defective B3GALT6 causes EDSP2 and SEMDJL1	1	285.5×	0.022	B3GALT6
Heparan sulfate/heparin (HS-GAG) metabolism	1	271.9×	0.022	B3GALT6
Glycosaminoglycan-protein linkage region biosynthesis	1	196.9×	0.024	B3GALT6
Glycosaminoglycan metabolism	1	109.8×	0.028	B3GALT6
Cell death signalling via NRAGE, NRIF and NADE	1	109.8×	0.028	ARHGEF16
p75 NTR receptor-mediated signalling	1	93.6×	0.028	ARHGEF16
NRAGE signals death through JNK	1	92.1×	0.028	ARHGEF16
RHOG GTPase cycle	1	74.2×	0.028	ARHGEF16
Death Receptor Signaling	1	69.6×	0.028	ARHGEF16
G alpha (12/13) signalling events	1	68.8×	0.028	ARHGEF16
Diseases of glycosylation	1	65.6×	0.028	B3GALT6
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.028	B3GALT6
Diseases of metabolism	1	40.2×	0.040	B3GALT6
CDC42 GTPase cycle	1	36.1×	0.041	ARHGEF16
RHO GTPase cycle	1	30.1×	0.047	ARHGEF16
GPCR downstream signalling	1	21.7×	0.061	ARHGEF16
Signaling by GPCR	1	20.0×	0.062	ARHGEF16
Signaling by Rho GTPases	1	17.1×	0.067	ARHGEF16
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.067	ARHGEF16
Disease	1	6.5×	0.160	B3GALT6
Metabolism	1	5.8×	0.172	B3GALT6
Signal Transduction	1	5.1×	0.187	ARHGEF16

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
glycosaminoglycan-protein linkage region biosynthetic process	1	1053.2×	0.014	B3GALT6
obsolete vesicle tethering involved in exocytosis	1	468.1×	0.014	EXOC6B
dermatan sulfate proteoglycan biosynthetic process	1	421.3×	0.014	B3GALT6
regulation of Cdc42 protein signal transduction	1	351.1×	0.014	ARHGEF16
glycosaminoglycan biosynthetic process	1	210.7×	0.014	B3GALT6
proteoglycan biosynthetic process	1	210.7×	0.014	B3GALT6
activation of GTPase activity	1	183.2×	0.014	ARHGEF16
obsolete vesicle docking involved in exocytosis	1	168.5×	0.014	EXOC6B
chondroitin sulfate proteoglycan biosynthetic process	1	156.0×	0.014	B3GALT6
Golgi to plasma membrane transport	1	140.4×	0.014	EXOC6B
heparan sulfate proteoglycan biosynthetic process	1	140.4×	0.014	B3GALT6
regulation of neuron projection development	1	108.0×	0.016	ACAP3
membrane fission	1	102.8×	0.016	EXOC6B
positive regulation of protein localization to plasma membrane	1	68.0×	0.021	ARHGEF16
mitotic cytokinesis	1	64.8×	0.021	EXOC6B
protein O-linked glycosylation	1	56.2×	0.023	B3GALT6
cell chemotaxis	1	46.3×	0.026	ARHGEF16
regulation of actin cytoskeleton organization	1	39.4×	0.029	ARHGEF16
exocytosis	1	38.0×	0.029	EXOC6B
neuron migration	1	33.4×	0.031	ACAP3
intracellular protein transport	1	16.2×	0.060	EXOC6B

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
B3GALT6	0	0
EXOC6B	0	0
ARHGEF16	0	0
ACAP3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
B3GALT6	2.4.1.134	galactosylxylosylprotein 3-beta-galactosyltransferase

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	1	B3GALT6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	EXOC6B, ARHGEF16, ACAP3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
B3GALT6	0	—
EXOC6B	0	—
ARHGEF16	0	—
ACAP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.