Multiple synostoses syndrome 1

Summary

Multiple synostoses syndrome 1 (MONDO:0008519) is a disease caused by NOG (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: NOG (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple synostoses syndrome 1
Mondo ID	MONDO:0008519
OMIM	186500
DOID	DOID:0081317
UMLS	C0342282
MedGen	90977
GARD	0015115
Is cancer (heuristic)	no

Also known as: multiple synostoses syndrome 1 · multiple synostoses syndrome caused by mutation in NOG · multiple synostoses syndrome caused by mutation in nog · multiple synostoses syndrome type 1 · NOG multiple synostoses syndrome · nog multiple synostoses syndrome · symphalangism brachydactyly syndrome · synostoses multiple with brachydactyly · SYNS1

Data availability: 11 ClinVar variants · 2 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 › dysostosis › synostosis › multiple synostoses syndrome › multiple synostoses syndrome 1

Related subtypes (3): multiple synostoses syndrome 2, multiple synostoses syndrome 3, multiple synostoses syndrome 4

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:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
30290	NM_005450.6(NOG):c.696C>G (p.Cys232Trp)	NOG	Pathogenic	no assertion criteria provided
3237153	NM_005450.6(NOG):c.666C>G (p.Tyr222Ter)	NOG	Pathogenic	criteria provided, single submitter
3768446	NM_005450.6(NOG):c.461del (p.Phe154fs)	NOG	Pathogenic	criteria provided, single submitter
6693	NM_005450.6(NOG):c.649T>G (p.Trp217Gly)	NOG	Pathogenic	no assertion criteria provided
6701	NM_005450.6(NOG):c.58del (p.Leu20fs)	NOG	Pathogenic	no assertion criteria provided
6706	NM_005450.6(NOG):c.614G>A (p.Trp205Ter)	NOG	Pathogenic	no assertion criteria provided
6707	NM_005450.6(NOG):c.615G>C (p.Trp205Cys)	NOG	Pathogenic	no assertion criteria provided
827845	NM_005450.6(NOG):c.64dup (p.Ala22fs)	NOG	Pathogenic	criteria provided, single submitter
3382219	NM_005450.6(NOG):c.509del (p.Pro170fs)	NOG	Likely pathogenic	criteria provided, single submitter
375295	NM_005450.6(NOG):c.611G>A (p.Arg204Gln)	NOG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3382452	NM_005450.6(NOG):c.545G>C (p.Arg182Pro)	NOG	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
NOG	Definitive	Autosomal dominant	multiple synostoses syndrome 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOG	Orphanet:140908	Brachydactyly type B2
NOG	Orphanet:140917	Stapes ankylosis with broad thumbs and toes
NOG	Orphanet:1412	Tarsal-carpal coalition syndrome
NOG	Orphanet:3237	Multiple synostoses syndrome
NOG	Orphanet:3250	Proximal symphalangism

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
NOG	HGNC:7866	ENSG00000183691	Q13253	Noggin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOG	Noggin	Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite.

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)
NOG	Other/Unknown	no		Noggin, Cystine-knot_cytokine

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
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOG	155	broad	marker	pigmented layer of retina, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOG	2,338

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOG	Q13253	2

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
Formation of paraxial mesoderm	1	407.9×	0.003	NOG
Signaling by BMP	1	356.9×	0.003	NOG

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
negative regulation of cardiac epithelial to mesenchymal transition	1	16852.0×	0.002	NOG
positive regulation of glomerulus development	1	8426.0×	0.002	NOG
neural plate morphogenesis	1	5617.3×	0.002	NOG
cell differentiation in hindbrain	1	5617.3×	0.002	NOG
neural plate anterior/posterior regionalization	1	5617.3×	0.002	NOG
short-term synaptic potentiation	1	5617.3×	0.002	NOG
prostatic bud formation	1	4213.0×	0.002	NOG
axial mesoderm development	1	3370.4×	0.002	NOG
notochord morphogenesis	1	3370.4×	0.002	NOG
ventricular compact myocardium morphogenesis	1	2407.4×	0.002	NOG
regulation of fibroblast growth factor receptor signaling pathway	1	2407.4×	0.002	NOG
atrial cardiac muscle tissue morphogenesis	1	2407.4×	0.002	NOG
ureteric bud formation	1	2407.4×	0.002	NOG
negative regulation of cartilage development	1	2106.5×	0.002	NOG
negative regulation of cardiac muscle cell proliferation	1	1872.4×	0.002	NOG
heart trabecula morphogenesis	1	1872.4×	0.002	NOG
membranous septum morphogenesis	1	1685.2×	0.002	NOG
pharyngeal arch artery morphogenesis	1	1685.2×	0.002	NOG
negative regulation of astrocyte differentiation	1	1532.0×	0.002	NOG
embryonic skeletal joint morphogenesis	1	1532.0×	0.002	NOG
endoderm formation	1	1404.3×	0.002	NOG
endocardial cushion formation	1	1404.3×	0.002	NOG
nodal signaling pathway	1	1123.5×	0.003	NOG
somite development	1	1123.5×	0.003	NOG
lung morphogenesis	1	1053.2×	0.003	NOG
cranial skeletal system development	1	936.2×	0.003	NOG
positive regulation of branching involved in ureteric bud morphogenesis	1	802.5×	0.003	NOG
motor neuron axon guidance	1	702.2×	0.003	NOG
middle ear morphogenesis	1	702.2×	0.003	NOG
regulation of neuronal synaptic plasticity	1	674.1×	0.003	NOG

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
NOG	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	NOG

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)
NOG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.