Nonsyndromic congenital nail disorder 1

Summary

Nonsyndromic congenital nail disorder 1 (MONDO:0008060) is a disease caused by FZD6 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: FZD6 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 10
• Phenotypes (HPO): 17

Clinical features

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0008404	Nail dystrophy	Very frequent (80-99%)
HP:0001598	Concave nail	Frequent (30-79%)
HP:0001803	Nail pits	Frequent (30-79%)
HP:0001807	Ridged nail	Frequent (30-79%)
HP:0001808	Fragile nails	Frequent (30-79%)
HP:0001816	Thin nail	Frequent (30-79%)
HP:0100798	Fingernail dysplasia	Frequent (30-79%)
HP:0100803	Abnormality of the periungual region	Frequent (30-79%)
HP:0002232	Patchy alopecia	Occasional (5-29%)
HP:0008399	Circumungual hyperkeratosis	Occasional (5-29%)
HP:0100797	Toenail dysplasia	Occasional (5-29%)
HP:0012531	Pain	Excluded (0%)
HP:0001045	Vitiligo	Very rare (<1-4%)
HP:0001047	Atopic dermatitis	Very rare (<1-4%)
HP:0001973	Autoimmune thrombocytopenia	Very rare (<1-4%)
HP:0008064	Ichthyosis	Very rare (<1-4%)
HP:0011034	Amyloidosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	nonsyndromic congenital nail disorder 1
Mondo ID	MONDO:0008060
MeSH	C562907
OMIM	161050
Orphanet	79153
DOID	DOID:0080079, DOID:0080088
SNOMED CT	238719003
UMLS	C0406443
MedGen	96056
GARD	0010363
Is cancer (heuristic)	no

Also known as: FZD6 inherited isolated nail anomaly · inherited isolated nail anomaly caused by mutation in FZD6 · nail disorder, nonsyndromic congenital 1 · nail disorder, nonsyndromic congenital, 1 · nail disorder, nonsyndromic congenital, 10 · nail disorder, nonsyndromic congenital, type 10 · NDNC1 · NDNC10 · nonsyndromic congenital nail disorder 10 · nonsyndromic congenital nail disorder type 1 · nonsyndromic congenital nail disorder type 10 · onychodystrophy totalis · sandpaper nails · trachyonychia · twenty nail dystrophy · twenty-nail dystrophy

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

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › nail disorder › inherited isolated nail anomaly › nonsyndromic congenital nail disorder 1

Related subtypes (8): isolated congenital digital clubbing, nonsyndromic congenital nail disorder 2, nonsyndromic congenital nail disorder 3, nonsyndromic congenital nail disorder 5, nonsyndromic congenital nail disorder 7, nonsyndromic congenital nail disorder 8, leukonychia totalis, isolated congenital anonychia

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:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
30355	NM_003506.4(FZD6):c.1750G>T (p.Glu584Ter)	FZD6	Pathogenic	no assertion criteria provided
30356	NM_003506.4(FZD6):c.1531C>T (p.Arg511Cys)	FZD6	Pathogenic	no assertion criteria provided
3775575	NM_003506.4(FZD6):c.1622del (p.Lys541fs)	FZD6	Pathogenic	criteria provided, single submitter
827757	NM_003506.4(FZD6):c.1525C>T (p.Arg509Ter)	FZD6	Pathogenic	criteria provided, single submitter
827759	NM_003506.4(FZD6):c.1312G>A (p.Glu438Lys)	FZD6	Pathogenic	no assertion criteria provided
993016	NM_003506.4(FZD6):c.1393-2A>G	FZD6	Likely pathogenic	no assertion criteria provided
190461	NM_003506.4(FZD6):c.869A>G (p.Tyr290Cys)	FZD6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
499653	NM_003506.4(FZD6):c.286C>T (p.Arg96Cys)	FZD6	Uncertain significance	criteria provided, single submitter
1285287	NM_003506.4(FZD6):c.97A>G (p.Met33Val)	FZD6	Benign	criteria provided, multiple submitters, no conflicts
802432	NM_003506.4(FZD6):c.1214G>A (p.Arg405Gln)	FZD6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
FZD6	Definitive	Autosomal recessive	nonsyndromic congenital nail disorder 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FZD6	Orphanet:280654	Autosomal recessive nail dysplasia

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
FZD6	HGNC:4044	ENSG00000164930	O60353	Frizzled-6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FZD6	Frizzled-6	Receptor for Wnt proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FZD6	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM

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
bronchial epithelial cell	1
caput epididymis	1
epithelium of bronchus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FZD6	260	ubiquitous	marker	bronchial epithelial cell, caput epididymis, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FZD6	1,337

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FZD6	O60353	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Signaling by RNF43 mutants	1	1268.9×	0.004	FZD6
Regulation of FZD by ubiquitination	1	519.1×	0.005	FZD6
PCP/CE pathway	1	300.5×	0.006	FZD6
Class B/2 (Secretin family receptors)	1	190.3×	0.006	FZD6
Ca2+ pathway	1	178.4×	0.006	FZD6

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
midbrain morphogenesis	1	4213.0×	1e-03	FZD6
cell proliferation in midbrain	1	3370.4×	1e-03	FZD6
embryonic nail plate morphogenesis	1	3370.4×	1e-03	FZD6
establishment of body hair planar orientation	1	3370.4×	1e-03	FZD6
non-canonical Wnt signaling pathway	1	581.1×	0.004	FZD6
Wnt signaling pathway, planar cell polarity pathway	1	455.5×	0.005	FZD6
hair follicle development	1	383.0×	0.005	FZD6
inner ear morphogenesis	1	300.9×	0.005	FZD6
platelet activation	1	267.5×	0.005	FZD6
neural tube closure	1	187.2×	0.007	FZD6
canonical Wnt signaling pathway	1	153.2×	0.008	FZD6
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.009	FZD6
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	FZD6

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
FZD6	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	1	FZD6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
FZD6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.