Tetraamelia syndrome 2

Summary

Tetraamelia syndrome 2 (MONDO:0060732) is a disease caused by RSPO2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: RSPO2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	tetraamelia syndrome 2
Mondo ID	MONDO:0060732
OMIM	618021
DOID	DOID:0112193
UMLS	C4747923
MedGen	1648284
GARD	0016286
Is cancer (heuristic)	no

Also known as: TETAMS2 · tetraamelia syndrome 2

Data availability: 4 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › tetraamelia-multiple malformations syndrome › tetraamelia syndrome 2

Related subtypes (1): tetraamelia syndrome 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

4 retrieved; paginated sample, class counts are floors:

2 benign, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
545633	NM_178565.5(RSPO2):c.409G>T (p.Glu137Ter)	RSPO2	Pathogenic	no assertion criteria provided
545632	NM_178565.5(RSPO2):c.125del (p.Gly42fs)	RSPO2	Likely pathogenic	criteria provided, single submitter
1230819	NM_178565.5(RSPO2):c.616+42_616+43dup	RSPO2	Benign	criteria provided, multiple submitters, no conflicts
1280490	NM_178565.5(RSPO2):c.557T>C (p.Leu186Pro)	RSPO2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
RSPO2	Strong	Autosomal recessive	tetraamelia syndrome 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RSPO2	Orphanet:3301	Tetraamelia-multiple malformations syndrome

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
RSPO2	HGNC:28583	ENSG00000147655	Q6UXX9	R-spondin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RSPO2	R-spondin-2	Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors.

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)
RSPO2	Other/Unknown	no		TSP1_rpt, Furin_repeat, Growth_fac_rcpt_cys_sf

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
mucosa of stomach	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RSPO2	156	broad	marker	secondary oocyte, oocyte, mucosa of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RSPO2	2,024

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RSPO2	Q6UXX9	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Regulation of FZD by ubiquitination	1	519.1×	0.008	RSPO2
TCF dependent signaling in response to WNT	1	117.7×	0.012	RSPO2
Signaling by WNT	1	112.0×	0.012	RSPO2
Signal Transduction	1	10.2×	0.098	RSPO2

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 odontogenesis of dentin-containing tooth	1	8426.0×	8e-04	RSPO2
lung growth	1	8426.0×	8e-04	RSPO2
trachea cartilage morphogenesis	1	5617.3×	8e-04	RSPO2
epithelial tube branching involved in lung morphogenesis	1	842.6×	0.004	RSPO2
dopaminergic neuron differentiation	1	624.1×	0.004	RSPO2
embryonic hindlimb morphogenesis	1	581.1×	0.004	RSPO2
embryonic forelimb morphogenesis	1	495.6×	0.004	RSPO2
limb development	1	411.0×	0.004	RSPO2
positive regulation of Wnt signaling pathway	1	383.0×	0.004	RSPO2
bone mineralization	1	271.8×	0.005	RSPO2
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.007	RSPO2
canonical Wnt signaling pathway	1	153.2×	0.007	RSPO2
osteoblast differentiation	1	121.2×	0.008	RSPO2

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
RSPO2	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	RSPO2

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)
RSPO2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.