Peeling skin syndrome 1

Summary

Peeling skin syndrome 1 (MONDO:0024548) is a disease caused by CDSN (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CDSN (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	peeling skin syndrome 1
Mondo ID	MONDO:0024548
OMIM	270300
Orphanet	263553
DOID	DOID:0070520
UMLS	C5679693
MedGen	1885521
GARD	0017259
Is cancer (heuristic)	no

Also known as: CDSN peeling skin syndrome · generalised deciduous skin type B · generalised peeling skin syndrome type B · generalized deciduous skin type B · generalized peeling skin syndrome type B · inflammatory peeling skin syndrome · peeling skin syndrome 1 · peeling skin syndrome caused by mutation in CDSN · peeling skin syndrome type B · PSS · PSS type B · PSS1 · skin peeling, familial continuous generalised

Data availability: 14 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › ichthyosis › inherited ichthyosis › peeling skin syndrome › generalized peeling skin syndrome › peeling skin syndrome 1

Related subtypes (2): peeling skin syndrome type A, generalized peeling skin syndrome type C

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

14 retrieved; paginated sample, class counts are floors:

5 pathogenic, 4 likely pathogenic, 2 uncertain significance, 2 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2446051	Single allele	C6orf15	Pathogenic	criteria provided, single submitter
157563	NM_001264.5(CDSN):c.746del (p.Gly249fs)	CDSN	Pathogenic	no assertion criteria provided
157565	NM_001264.5(CDSN):c.424G>T (p.Gly142Ter)	CDSN	Pathogenic	no assertion criteria provided
30269	NM_001264.5(CDSN):c.175A>T (p.Lys59Ter)	CDSN	Pathogenic	criteria provided, multiple submitters, no conflicts
157570	NM_201631.4(TGM5):c.640del (p.Leu214fs)	TGM5	Pathogenic	criteria provided, single submitter
2444035	NM_001264.5(CDSN):c.484C>T (p.Gln162Ter)	CDSN	Likely pathogenic	criteria provided, single submitter
3393421	NM_001264.5(CDSN):c.30dup (p.Arg11fs)	CDSN	Likely pathogenic	criteria provided, single submitter
802195	NM_001264.5(CDSN):c.1459G>A (p.Gly487Ser)	CDSN	Likely pathogenic	criteria provided, single submitter
803071	NM_201631.4(TGM5):c.684+1G>A	TGM5	Likely pathogenic	criteria provided, single submitter
1184405	NM_001264.5(CDSN):c.239G>A (p.Ser80Asn)	CDSN	Uncertain significance	criteria provided, single submitter
157564	NM_001264.5(CDSN):c.164_167dup (p.Thr57fs)	CDSN	Uncertain significance	criteria provided, single submitter
1209846	NM_001264.5(CDSN):c.1579A>G (p.Asn527Asp)	CDSN	Benign	criteria provided, multiple submitters, no conflicts
716000	NM_001264.5(CDSN):c.1525C>T (p.Leu509=)	CDSN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
802196	NM_001264.5(CDSN):c.1358G>A (p.Ser453Asn)	CDSN	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
CDSN	Strong	Autosomal recessive	peeling skin syndrome 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDSN	Orphanet:263553	Peeling skin syndrome type B
CDSN	Orphanet:90368	Hypotrichosis simplex of the scalp
TGM5	Orphanet:263534	Acral peeling skin syndrome

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
CDSN	HGNC:1802	ENSG00000204539	Q15517	Corneodesmosin	gencc,clinvar
TGM5	HGNC:11781	ENSG00000104055	O43548	Protein-glutamine gamma-glutamyltransferase 5	clinvar
C6orf15	HGNC:13927	ENSG00000204542	Q6UXA7	Uncharacterized protein C6orf15	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDSN	Corneodesmosin	Important for the epidermal barrier integrity.
TGM5	Protein-glutamine gamma-glutamyltransferase 5	Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.

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)
CDSN	Other/Unknown	no		Corneodesmosin
TGM5	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
C6orf15	Other/Unknown	no		C6orf15

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	3
skin of leg	3
zone of skin	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDSN	101	tissue_specific	yes	skin of abdomen, zone of skin, skin of leg
TGM5	155	tissue_specific	marker	skin of leg, skin of abdomen, zone of skin
C6orf15	31	tissue_specific	yes	skin of leg, zone of skin, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C6orf15	1,420
CDSN	1,223
TGM5	845

Intra-cohort edges

A	B	Sources
CDSN	TGM5	string_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TGM5	O43548	91.68
C6orf15	Q6UXA7	43.65
CDSN	Q15517	38.13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the cornified envelope	2	87.8×	4e-04	CDSN, TGM5
Keratinization	2	55.7×	5e-04	CDSN, TGM5
Developmental Biology	2	14.5×	0.005	CDSN, TGM5

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
epidermis development	2	140.4×	7e-04	CDSN, TGM5
negative regulation of cornification	1	5617.3×	9e-04	CDSN
corneocyte desquamation	1	2808.7×	0.001	CDSN
skin morphogenesis	1	468.1×	0.005	CDSN
amyloid fibril formation	1	200.6×	0.010	CDSN
keratinocyte differentiation	1	82.6×	0.017	CDSN
protein modification process	1	81.4×	0.017	TGM5
extracellular matrix organization	1	40.7×	0.030	C6orf15
cell-cell adhesion	1	33.8×	0.033	CDSN
cell adhesion	1	12.5×	0.078	CDSN

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
CDSN	0	0
TGM5	0	0
C6orf15	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGM5	2.3.2.13	protein-glutamine gamma-glutamyltransferase

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	TGM5
E	Difficult family or no structure, no drug	2	CDSN, C6orf15

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)
CDSN	0	—
TGM5	0	—
C6orf15	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.