Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures

Summary

Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures (MONDO:0010075) is a disease caused by B3GALT6 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: B3GALT6 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures
Mondo ID	MONDO:0010075
OMIM	271640
Orphanet	642099
DOID	DOID:0112198
UMLS	C4017377
MedGen	865814
GARD	0024706
Is cancer (heuristic)	no

Also known as: B3GALT6 spondyloepimetaphyseal dysplasia with joint laxity · SEMDJL · SEMDJL1 · spondyloepimetaphyseal dysplasia with joint laxity caused by mutation in B3GALT6 · spondyloepimetaphyseal dysplasia with joint laxity, Beighton type · spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures

Data availability: 27 ClinVar variants · 3 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 › spondyloepimetaphyseal dysplasia › spondyloepimetaphyseal dysplasia with joint laxity › spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures

Related subtypes (2): 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

27 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 8 conflicting classifications of pathogenicity, 8 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2925287	NM_080605.4(B3GALT6):c.235A>G (p.Thr79Ala)	B3GALT6	Pathogenic	criteria provided, multiple submitters, no conflicts
3250476	NM_080605.4(B3GALT6):c.1A>C (p.Met1Leu)	B3GALT6	Pathogenic	criteria provided, single submitter
522415	NM_080605.4(B3GALT6):c.556T>C (p.Phe186Leu)	B3GALT6	Pathogenic	criteria provided, multiple submitters, no conflicts
60484	NM_080605.4(B3GALT6):c.1A>G (p.Met1Val)	B3GALT6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60486	NM_080605.4(B3GALT6):c.466G>A (p.Asp156Asn)	B3GALT6	Pathogenic	no assertion criteria provided
60487	NM_080605.4(B3GALT6):c.899G>C (p.Cys300Ser)	B3GALT6	Pathogenic	no assertion criteria provided
60488	NM_080605.4(B3GALT6):c.193A>G (p.Ser65Gly)	B3GALT6	Pathogenic	no assertion criteria provided
60489	NM_080605.4(B3GALT6):c.200C>T (p.Pro67Leu)	B3GALT6	Pathogenic	criteria provided, single submitter
60495	NM_080605.4(B3GALT6):c.619G>C (p.Asp207His)	B3GALT6	Pathogenic	criteria provided, single submitter
1063834	NM_080605.4(B3GALT6):c.631C>T (p.Pro211Ser)	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
1472063	NM_080605.4(B3GALT6):c.530GCC[5] (p.Arg180dup)	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
427130	NM_080605.4(B3GALT6):c.588dup (p.Arg197fs)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60485	NM_080605.4(B3GALT6):c.694C>T (p.Arg232Cys)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800197	NM_080605.4(B3GALT6):c.110G>A (p.Gly37Glu)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
986387	NM_080605.4(B3GALT6):c.447C>G (p.Phe149Leu)	B3GALT6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020063	NC_000001.10:g.(?1146915)(1168668_?)dup	B3GALT6	Uncertain significance	criteria provided, single submitter
1208606	NM_080605.4(B3GALT6):c.895C>A (p.Leu299Met)	B3GALT6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1419814	NM_080605.4(B3GALT6):c.148C>G (p.Pro50Ala)	B3GALT6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1436880	NM_080605.4(B3GALT6):c.520G>C (p.Glu174Gln)	B3GALT6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1691282	NM_080605.4(B3GALT6):c.749C>T (p.Ala250Val)	B3GALT6	Uncertain significance	criteria provided, single submitter
2582333	NM_080605.4(B3GALT6):c.598G>A (p.Glu200Lys)	B3GALT6	Uncertain significance	criteria provided, single submitter
3065882	NM_080605.4(B3GALT6):c.547T>A (p.Trp183Arg)	B3GALT6	Uncertain significance	criteria provided, single submitter
3255367	NM_080605.4(B3GALT6):c.451T>A (p.Phe151Ile)	B3GALT6	Uncertain significance	no assertion criteria provided
429685	NM_080605.4(B3GALT6):c.17G>A (p.Arg6Gln)	B3GALT6	Uncertain significance	criteria provided, multiple submitters, no conflicts
623665	NM_080605.4(B3GALT6):c.313G>C (p.Glu105Gln)	B3GALT6	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
B3GALT6	Definitive	Autosomal recessive	spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures	10

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

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
B3GALT6	HGNC:17978	ENSG00000176022	Q96L58	Beta-1,3-galactosyltransferase 6	gencc,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.

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)
B3GALT6	Enzyme (other)	yes	2.4.1.134	Glyco_trans_31

Expression context

Cohort genes with no expression data: 0.

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
Brodmann (1909) area 23	1
cartilage tissue	1
endothelial cell	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
B3GALT6	797

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
B3GALT6	Q96L58	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Chondroitin sulfate/dermatan sulfate metabolism	1	951.7×	0.005	B3GALT6
Diseases associated with glycosaminoglycan metabolism	1	761.3×	0.005	B3GALT6
Defective B3GALT6 causes EDSP2 and SEMDJL1	1	571.0×	0.005	B3GALT6
Heparan sulfate/heparin (HS-GAG) metabolism	1	543.8×	0.005	B3GALT6
Glycosaminoglycan-protein linkage region biosynthesis	1	393.8×	0.006	B3GALT6
Glycosaminoglycan metabolism	1	219.6×	0.008	B3GALT6
Diseases of glycosylation	1	131.3×	0.011	B3GALT6
Metabolism of carbohydrates and carbohydrate derivatives	1	120.2×	0.011	B3GALT6
Diseases of metabolism	1	80.4×	0.015	B3GALT6
Disease	1	13.1×	0.084	B3GALT6
Metabolism	1	11.6×	0.086	B3GALT6

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
glycosaminoglycan-protein linkage region biosynthetic process	1	4213.0×	0.002	B3GALT6
dermatan sulfate proteoglycan biosynthetic process	1	1685.2×	0.002	B3GALT6
glycosaminoglycan biosynthetic process	1	842.6×	0.002	B3GALT6
proteoglycan biosynthetic process	1	842.6×	0.002	B3GALT6
chondroitin sulfate proteoglycan biosynthetic process	1	624.1×	0.002	B3GALT6
heparan sulfate proteoglycan biosynthetic process	1	561.7×	0.002	B3GALT6
protein O-linked glycosylation	1	224.7×	0.004	B3GALT6

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
B3GALT6	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: 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	B3GALT6
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)
B3GALT6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.