Nonsyndromic congenital nail disorder 4

Summary

Nonsyndromic congenital nail disorder 4 (MONDO:0008798) is a disease caused by RSPO4 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: RSPO4 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nonsyndromic congenital nail disorder 4
Mondo ID	MONDO:0008798
MeSH	C536377
OMIM	206800
Orphanet	94150
DOID	DOID:0050643, DOID:0080082
UMLS	C3277900
MedGen	479530
GARD	0016837
Is cancer (heuristic)	no

Also known as: isolated congenital anonychia caused by mutation in RSPO4 · nail disorder, nonsyndromic congenital, 4 · nail disorder, nonsyndromic congenital, type 4 · NDNC4 · nonsyndromic congenital nail disorder 4 · nonsyndromic congenital nail disorder type 4 · RSPO4 isolated congenital anonychia

Data availability: 15 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › nail disorder › inherited isolated nail anomaly › isolated congenital anonychia › nonsyndromic congenital nail disorder 4

Related subtypes (2): nonsyndromic congenital nail disorder 6, anonychia-onychodystrophy 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

15 retrieved; paginated sample, class counts are floors:

13 pathogenic, 1 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
29636	NM_000094.4(COL7A1):c.425A>G (p.Lys142Arg)	COL7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
374052	NM_000094.4(COL7A1):c.2005C>T (p.Arg669Ter)	COL7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
523369	NM_000422.3(KRT17):c.960+5G>A	KRT17	Pathogenic	criteria provided, single submitter
1190	NM_001029871.4(RSPO4):c.194A>G (p.Gln65Arg)	RSPO4	Pathogenic	no assertion criteria provided
1191	NM_001029871.4(RSPO4):c.319T>C (p.Cys107Arg)	RSPO4	Pathogenic	no assertion criteria provided
1192	NM_001029871.4(RSPO4):c.353G>A (p.Cys118Tyr)	RSPO4	Pathogenic	no assertion criteria provided
1193	NM_001029871.4(RSPO4):c.218G>A (p.Cys73Tyr)	RSPO4	Pathogenic	no assertion criteria provided
30845	NM_001029871.4(RSPO4):c.301C>T (p.Gln101Ter)	RSPO4	Pathogenic	no assertion criteria provided
30846	NM_001029871.4(RSPO4):c.190C>T (p.Arg64Cys)	RSPO4	Pathogenic	no assertion criteria provided
30847	NM_001029871.4(RSPO4):c.199G>C (p.Gly67Arg)	RSPO4	Pathogenic	no assertion criteria provided
3256625	NM_001029871.4(RSPO4):c.335_338del (p.Tyr112fs)	RSPO4	Pathogenic	criteria provided, single submitter
3256888	NM_001029871.4(RSPO4):c.76_79del (p.Gln26fs)	RSPO4	Pathogenic	criteria provided, single submitter
521270	NM_001029871.4(RSPO4):c.79+1G>A	RSPO4	Pathogenic	criteria provided, multiple submitters, no conflicts
4077476	NM_001029871.4(RSPO4):c.64C>T (p.Arg22Ter)	RSPO4	Likely pathogenic	criteria provided, single submitter
1194	NM_001029871.4(RSPO4):c.98dup (p.Asn34fs)	RSPO4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 12 · 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
RSPO4	Definitive	Autosomal recessive	nonsyndromic congenital nail disorder 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RSPO4	Orphanet:94150	Anonychia congenita totalis
COL7A1	Orphanet:158673	Localized dystrophic epidermolysis bullosa, acral form
COL7A1	Orphanet:158676	Localized dystrophic epidermolysis bullosa, nails only
COL7A1	Orphanet:231568	Autosomal dominant generalized dystrophic epidermolysis bullosa
COL7A1	Orphanet:79408	Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form
COL7A1	Orphanet:79409	Recessive dystrophic epidermolysis bullosa inversa
COL7A1	Orphanet:79410	Localized dystrophic epidermolysis bullosa, pretibial form
COL7A1	Orphanet:79411	Self-improving dystrophic epidermolysis bullosa
COL7A1	Orphanet:89842	Autosomal recessive generalized dystrophic epidermolysis bullosa, intermediate form
COL7A1	Orphanet:89843	Dystrophic epidermolysis bullosa pruriginosa
KRT17	Orphanet:2309	Pachyonychia congenita
KRT17	Orphanet:841	Sebocystomatosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RSPO4	HGNC:16175	ENSG00000101282	Q2I0M5	R-spondin-4	gencc,clinvar
COL7A1	HGNC:2214	ENSG00000114270	Q02388	Collagen alpha-1(VII) chain	clinvar
KRT17	HGNC:6427	ENSG00000128422	Q04695	Keratin, type I cytoskeletal 17	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RSPO4	R-spondin-4	Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors.
COL7A1	Collagen alpha-1(VII) chain	Stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV c…
KRT17	Keratin, type I cytoskeletal 17	Type I keratin involved in the formation and maintenance of various skin appendages, specifically in determining shape and orientation of hair.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RSPO4	Other/Unknown	no		TSP1_rpt, Furin_repeat, Growth_fac_rcpt_cys_sf
COL7A1	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom
KRT17	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hypothalamus	1
upper lobe of left lung	1
upper lobe of lung	1
skin of abdomen	1
skin of leg	1
stromal cell of endometrium	1
gingiva	1
gingival epithelium	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RSPO4	136	broad	yes	upper lobe of left lung, hypothalamus, upper lobe of lung
COL7A1	267	ubiquitous	marker	stromal cell of endometrium, skin of abdomen, skin of leg
KRT17	224	broad	marker	gingival epithelium, gingiva, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT17	2,523
COL7A1	1,767
RSPO4	984

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT17	Q04695	79.28
RSPO4	Q2I0M5	78.46
COL7A1	Q02388

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring fibril formation	1	253.8×	0.030	COL7A1
Fibronectin matrix formation	1	190.3×	0.030	COL7A1
Regulation of FZD by ubiquitination	1	173.0×	0.030	RSPO4
Laminin interactions	1	126.9×	0.030	COL7A1
Cargo concentration in the ER	1	112.0×	0.030	COL7A1
Collagen chain trimerization	1	86.5×	0.030	COL7A1
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.030	KRT17
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.030	COL7A1
Collagen degradation	1	58.6×	0.030	COL7A1
Collagen biosynthesis and modifying enzymes	1	56.8×	0.030	COL7A1
COPII-mediated vesicle transport	1	54.4×	0.030	COL7A1
Integrin cell surface interactions	1	44.8×	0.033	COL7A1
TCF dependent signaling in response to WNT	1	39.2×	0.034	RSPO4
Signaling by WNT	1	37.3×	0.034	RSPO4
Formation of the cornified envelope	1	29.3×	0.041	KRT17
Keratinization	1	18.6×	0.060	KRT17
Developmental Biology	1	4.8×	0.205	KRT17
Signal Transduction	1	3.4×	0.267	RSPO4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nail development	1	802.5×	0.009	RSPO4
positive regulation of hair follicle development	1	802.5×	0.009	KRT17
hair follicle morphogenesis	1	165.2×	0.021	KRT17
endodermal cell differentiation	1	165.2×	0.021	COL7A1
positive regulation of Wnt signaling pathway	1	127.7×	0.021	RSPO4
morphogenesis of an epithelium	1	114.6×	0.021	KRT17
intermediate filament organization	1	80.2×	0.021	KRT17
keratinization	1	78.0×	0.021	KRT17
positive regulation of translation	1	75.9×	0.021	KRT17
epidermis development	1	70.2×	0.021	COL7A1
positive regulation of cell growth	1	61.1×	0.021	KRT17
epithelial cell differentiation	1	58.5×	0.021	KRT17
positive regulation of canonical Wnt signaling pathway	1	51.5×	0.022	RSPO4
Wnt signaling pathway	1	33.2×	0.032	RSPO4
cell adhesion	1	12.5×	0.078	COL7A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RSPO4	0	0
COL7A1	0	0
KRT17	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	COL7A1
E	Difficult family or no structure, no drug	2	RSPO4, KRT17

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RSPO4	0	—
COL7A1	0	—
KRT17	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.