Ehlers-Danlos syndrome, spondylodysplastic type, 2

Summary

Ehlers-Danlos syndrome, spondylodysplastic type, 2 (MONDO:0014139) is a disease caused by B3GALT6 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: B3GALT6 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 296
• Phenotypes (HPO): 83

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		41	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

83 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000938	Osteopenia	Very frequent (80-99%)
HP:0001027	Soft, doughy skin	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002651	Spondyloepimetaphyseal dysplasia	Very frequent (80-99%)
HP:0002751	Kyphoscoliosis	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0002828	Multiple joint contractures	Very frequent (80-99%)
HP:0003016	Metaphyseal widening	Very frequent (80-99%)
HP:0004993	Slender long bones with narrow diaphyses	Very frequent (80-99%)
HP:0005008	Large joint dislocations	Very frequent (80-99%)
HP:0006487	Bowing of the long bones	Very frequent (80-99%)
HP:0008807	Acetabular dysplasia	Very frequent (80-99%)
HP:0008897	Postnatal growth retardation	Very frequent (80-99%)
HP:0010575	Dysplasia of the femoral head	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0012095	Multiple joint dislocation	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000592	Blue sclerae	Frequent (30-79%)
HP:0000691	Microdontia	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0000963	Thin skin	Frequent (30-79%)
HP:0000974	Hyperextensible skin	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001075	Atrophic scars	Frequent (30-79%)
HP:0001166	Arachnodactyly	Frequent (30-79%)
HP:0001181	Adducted thumb	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001319	Neonatal hypotonia	Frequent (30-79%)
HP:0001385	Hip dysplasia	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0001822	Hallux valgus	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0003300	Ovoid vertebral bodies	Frequent (30-79%)
HP:0004568	Beaking of vertebral bodies	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0006243	Phalangeal dislocation	Frequent (30-79%)
HP:0010646	Cervical spine instability	Frequent (30-79%)
HP:0010648	Dermal translucency	Frequent (30-79%)
HP:0000410	Mixed hearing impairment	Occasional (5-29%)
HP:0000473	Torticollis	Occasional (5-29%)
HP:0000482	Microcornea	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ehlers-Danlos syndrome, spondylodysplastic type, 2
Mondo ID	MONDO:0014139
OMIM	615349
Orphanet	536467
UMLS	C3809210
MedGen	815540
GARD	0015947
Is cancer (heuristic)	no

Also known as: B3GALT6 Ehlers-Danlos syndrome progeroid type · B3GALT6-related spEDS · B3GALT6-related spondylodysplastic EDS · Beta3GalT6-deficient EDS · EDSP2 · EDSSPD2 · Ehlers-Danlos syndrome progeroid type 2 · Ehlers-Danlos syndrome progeroid type caused by mutation in B3GALT6 · Ehlers-Danlos syndrome, progeroid type, 2 · Ehlers-Danlos syndrome, spondylodysplastic type, 2 · spEDS-B3GALT6

Data availability: 296 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › Ehlers-Danlos syndrome, spondylodysplastic type › Ehlers-Danlos syndrome, spondylodysplastic type, 2

Related subtypes (2): Ehlers-Danlos syndrome, spondylocheirodysplastic type, Ehlers-Danlos syndrome, spondylodysplastic type, 1

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

296 retrieved; paginated sample, class counts are floors:

146 uncertain significance, 93 likely benign, 26 conflicting classifications of pathogenicity, 16 pathogenic, 7 benign/likely benign, 5 pathogenic/likely pathogenic, 3 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
3250476	NM_080605.4(B3GALT6):c.1A>C (p.Met1Leu)	B3GALT6	Pathogenic	criteria provided, single submitter
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
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
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
996067	NM_080605.4(B3GALT6):c.766C>T (p.Arg256Trp)	B3GALT6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
996068	NM_080605.4(B3GALT6):c.227del (p.Ile76fs)	B3GALT6	Pathogenic	criteria provided, single submitter
1067539	NM_080605.4(B3GALT6):c.2T>A (p.Met1Lys)	B3GALT6	Likely pathogenic	criteria provided, single submitter
4795165	NM_080605.4(B3GALT6):c.2T>G (p.Met1Arg)	B3GALT6	Likely pathogenic	criteria provided, single submitter
60492	NM_080605.4(B3GALT6):c.588del (p.Arg197fs)	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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	Ehlers-Danlos syndrome, spondylodysplastic type, 2	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
MARVELD2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
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
MARVELD2	HGNC:26401	ENSG00000152939	Q8N4S9	MARVEL domain-containing protein 2	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.
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.
MARVELD2	MARVEL domain-containing protein 2	Plays a role in the formation of tricellular tight junctions and of epithelial barriers.

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
ARHGEF16	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain
ACAP3	Scaffold/PPI	no		ArfGAP_dom, PH_domain, Ankyrin_rpt
MARVELD2	Other/Unknown	no		Marvel, Occludin_ELL, ELL/occludin

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
ileal mucosa	1
metanephros cortex	1
mucosa of transverse colon	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
duodenum	1
islet of Langerhans	1
primordial germ cell in gonad	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
ARHGEF16	199	broad	marker	mucosa of transverse colon, metanephros cortex, ileal mucosa
ACAP3	221	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
MARVELD2	129	broad	marker	islet of Langerhans, primordial germ cell in gonad, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARHGEF16	1,269
ACAP3	927
MARVELD2	909
B3GALT6	797

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MARVELD2	Q8N4S9	3
B3GALT6	Q96L58	1
ARHGEF16	Q5VV41	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
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×	0.013	B3GALT6
dermatan sulfate proteoglycan biosynthetic process	1	421.3×	0.013	B3GALT6
regulation of Cdc42 protein signal transduction	1	351.1×	0.013	ARHGEF16
glycosaminoglycan biosynthetic process	1	210.7×	0.013	B3GALT6
proteoglycan biosynthetic process	1	210.7×	0.013	B3GALT6
establishment of endothelial barrier	1	191.5×	0.013	MARVELD2
activation of GTPase activity	1	183.2×	0.013	ARHGEF16
cell-cell junction organization	1	156.0×	0.013	MARVELD2
chondroitin sulfate proteoglycan biosynthetic process	1	156.0×	0.013	B3GALT6
heparan sulfate proteoglycan biosynthetic process	1	140.4×	0.013	B3GALT6
regulation of neuron projection development	1	108.0×	0.015	ACAP3
bicellular tight junction assembly	1	82.6×	0.018	MARVELD2
positive regulation of protein localization to plasma membrane	1	68.0×	0.020	ARHGEF16
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×	0.028	ARHGEF16
neuron migration	1	33.4×	0.031	ACAP3
sensory perception of sound	1	25.2×	0.039	MARVELD2

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
ARHGEF16	0	0
ACAP3	0	0
MARVELD2	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	ARHGEF16, ACAP3, MARVELD2

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	—
ARHGEF16	0	—
ACAP3	0	—
MARVELD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.