Robinow syndrome, autosomal recessive 2

Summary

Robinow syndrome, autosomal recessive 2 (MONDO:0032800) is a disease caused by NXN (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: NXN (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	robinow syndrome, autosomal recessive 2
Mondo ID	MONDO:0032800
OMIM	618529
DOID	DOID:0060974
UMLS	C5193143
MedGen	1676687
GARD	0025750
Is cancer (heuristic)	no

Also known as: RRS2

Data availability: 8 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Robinow syndrome › robinow syndrome, autosomal recessive 2

Related subtypes (2): autosomal dominant Robinow syndrome, autosomal recessive Robinow syndrome

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

8 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 benign/likely benign, 2 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
638809	NM_022463.5(NXN):c.-6172_361-75725del	LOC101927727	Pathogenic	no assertion criteria provided
488062	NM_022463.5(NXN):c.1231GAG[1] (p.Glu412del)	NXN	Pathogenic	no assertion criteria provided
984983	NM_022463.5(NXN):c.817C>T (p.Gln273Ter)	NXN	Pathogenic	criteria provided, single submitter
488056	NM_022463.5(NXN):c.625C>T (p.Arg209Ter)	NXN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
984984	GRCh37/hg19 17p13.3(chr17:1-1026797)x1	TLCD3A	Likely pathogenic	criteria provided, single submitter
3891869	NM_022463.5(NXN):c.811G>A (p.Gly271Arg)	NXN	Uncertain significance	criteria provided, single submitter
1600243	NM_022463.5(NXN):c.1000+13C>T	NXN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
712204	NM_022463.5(NXN):c.543C>T (p.Asn181=)	NXN	Benign/Likely 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
NXN	Strong	Autosomal recessive	robinow syndrome, autosomal recessive 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NXN	Orphanet:1507	Autosomal recessive Robinow syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NXN	HGNC:18008	ENSG00000167693	Q6DKJ4	Nucleoredoxin	gencc,clinvar
TLCD3A	HGNC:29646	ENSG00000167695	Q8TBR7	TLC domain-containing protein 3A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NXN	Nucleoredoxin	Functions as a redox-dependent negative regulator of the Wnt signaling pathway, possibly by preventing ubiquitination of DVL3 by the BCR(KLHL12) complex.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NXN	Other/Unknown	no		Thioredoxin-like_fold, Thioredoxin_domain, Thioredoxin-like_sf
TLCD3A	Other/Unknown	no		TLC-dom, TLCD

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cervix squamous epithelium	1
hair follicle	1
skeletal muscle tissue of rectus abdominis	1
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NXN	279	ubiquitous	marker	cervix squamous epithelium, hair follicle, skeletal muscle tissue of rectus abdominis
TLCD3A	228	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NXN	911
TLCD3A	804

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TLCD3A	Q8TBR7	92.98
NXN	Q6DKJ4	90.37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
circulatory system development	1	702.2×	0.010	NXN
negative regulation of Wnt signaling pathway	1	172.0×	0.012	NXN
lipid homeostasis	1	168.5×	0.012	TLCD3A
negative regulation of protein ubiquitination	1	142.8×	0.012	NXN
Wnt signaling pathway	1	49.9×	0.028	NXN
in utero embryonic development	1	36.0×	0.032	NXN
cell differentiation	1	14.6×	0.068	NXN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
NXN	0	0
TLCD3A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	NXN, TLCD3A

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NXN	0	—
TLCD3A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.