Multiple synostoses syndrome 4

Summary

Multiple synostoses syndrome 4 (MONDO:0054752) is a disease caused by GDF6 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GDF6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple synostoses syndrome 4
Mondo ID	MONDO:0054752
OMIM	617898
DOID	DOID:0081320
UMLS	C4693531
MedGen	1638842
GARD	0025968
Is cancer (heuristic)	no

Also known as: multiple synostoses syndrome 4 · SYNS4

Data availability: 10 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › synostosis › multiple synostoses syndrome › multiple synostoses syndrome 4

Related subtypes (3): multiple synostoses syndrome 1, multiple synostoses syndrome 2, multiple synostoses syndrome 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

10 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 4 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
495116	NM_001001557.4(GDF6):c.1330T>A (p.Tyr444Asn)	GDF6	Pathogenic	criteria provided, single submitter
364042	NM_001001557.4(GDF6):c.1304C>T (p.Ala435Val)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8371	NM_001001557.4(GDF6):c.746C>A (p.Ala249Glu)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8372	NM_001001557.4(GDF6):c.866T>C (p.Leu289Pro)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8373	NM_001001557.4(GDF6):c.1271A>G (p.Lys424Arg)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1357180	NM_001001557.4(GDF6):c.416C>T (p.Ser139Leu)	GDF6	Uncertain significance	criteria provided, multiple submitters, no conflicts
495115	NM_001001557.4(GDF6):c.1287C>A (p.Ser429Arg)	GDF6	Uncertain significance	criteria provided, single submitter
835633	NM_001001557.4(GDF6):c.460A>G (p.Met154Val)	GDF6	Uncertain significance	criteria provided, multiple submitters, no conflicts
939495	NM_001001557.4(GDF6):c.785G>A (p.Ser262Asn)	GDF6	Uncertain significance	criteria provided, multiple submitters, no conflicts
256847	NM_001001557.4(GDF6):c.255G>T (p.Pro85=)	GDF6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
GDF6	Strong	Autosomal dominant	multiple synostoses syndrome 4	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GDF6	Orphanet:2345	Isolated Klippel-Feil syndrome
GDF6	Orphanet:3237	Multiple synostoses syndrome
GDF6	Orphanet:65	Leber congenital amaurosis
GDF6	Orphanet:98938	Colobomatous microphthalmia

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
GDF6	HGNC:4221	ENSG00000156466	Q6KF10	Growth/differentiation factor 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GDF6	Growth/differentiation factor 6	Growth factor that controls proliferation and cellular differentiation in the retina and bone formation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GDF6	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like

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
placenta	1
primordial germ cell in gonad	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GDF6	104	broad	marker	placenta, primordial germ cell in gonad, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GDF6	1,127

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GDF6	Q6KF10	70.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
cell migration involved in metanephros development	1	16852.0×	8e-04	GDF6
retinal cell apoptotic process	1	8426.0×	8e-04	GDF6
epithelial cell migration	1	936.2×	0.003	GDF6
activin receptor signaling pathway	1	887.0×	0.003	GDF6
positive regulation of chondrocyte differentiation	1	802.5×	0.003	GDF6
positive regulation of p38MAPK cascade	1	624.1×	0.003	GDF6
metanephros development	1	510.7×	0.004	GDF6
positive regulation of SMAD protein signal transduction	1	383.0×	0.004	GDF6
BMP signaling pathway	1	200.6×	0.007	GDF6
positive regulation of neuron differentiation	1	198.3×	0.007	GDF6
fat cell differentiation	1	181.2×	0.007	GDF6
apoptotic process	1	28.7×	0.036	GDF6
positive regulation of DNA-templated transcription	1	27.9×	0.036	GDF6

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
GDF6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GDF6

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)
GDF6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.