Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

Summary

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (MONDO:0014355) is a disease caused by DSP (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DSP (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 310

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis
Mondo ID	MONDO:0014355
OMIM	615821
Orphanet	476096
UMLS	C4014393
MedGen	862830
GARD	0016014
Is cancer (heuristic)	no

Also known as: cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis · DCWHKTA · dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis · dilated cardiomyopathy with wooly hair, keratoderma, and tooth agenesis · EKC syndrome · erythrokeratodermia-cardiomyopathy syndrome

Data availability: 310 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 › erythrokeratoderma › cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

Related subtypes (5): spinocerebellar ataxia type 34, MEDNIK syndrome, erythrokeratoderma en cocardes, erythrokeratodermia variabilis, pityriasis rubra pilaris

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

310 retrieved; paginated sample, class counts are floors:

155 conflicting classifications of pathogenicity, 75 uncertain significance, 19 likely benign, 18 likely pathogenic, 14 pathogenic/likely pathogenic, 13 benign/likely benign, 9 pathogenic, 7 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012338	NM_004415.4(DSP):c.748C>T (p.Gln250Ter)	DSP	Pathogenic	criteria provided, single submitter
143947	NM_004415.4(DSP):c.2131_2132del	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157671	NM_004415.4(DSP):c.1817_1846dup (p.Arg606_Ala615dup)	DSP	Pathogenic	no assertion criteria provided
157673	NM_004415.4(DSP):c.1691C>T (p.Thr564Ile)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
16844	NM_004415.4(DSP):c.6091_6092del (p.Leu2031fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
1748977	NM_004415.2(DSP):c.5671_*835+957del4738insAGAACAGTCTT	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1796736	NM_004415.4(DSP):c.2842del (p.Gln948fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
199881	NM_004415.4(DSP):c.3805C>T (p.Arg1269Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199884	NM_004415.4(DSP):c.4198C>T (p.Arg1400Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199916	NM_004415.4(DSP):c.928dup (p.Glu310fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
246676	NM_004415.4(DSP):c.8077_8080del (p.Lys2693fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
3544419	NM_004415.4(DSP):c.5834_5835del (p.Arg1945fs)	DSP	Pathogenic	criteria provided, single submitter
372125	NM_004415.4(DSP):c.1847A>C (p.Gln616Pro)	DSP	Pathogenic	no assertion criteria provided
372127	NM_004415.4(DSP):c.1865T>C (p.Leu622Pro)	DSP	Pathogenic	criteria provided, single submitter
405232	NM_004415.4(DSP):c.5680_5683del (p.Ser1894fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
432027	NM_004415.4(DSP):c.7641C>G (p.Tyr2547Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44885	NM_004415.4(DSP):c.2848dup (p.Ile950fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44946	NM_004415.4(DSP):c.699G>A (p.Trp233Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
452266	NM_004415.4(DSP):c.4882_4886delinsTTCT (p.Arg1628fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
489339	NM_004415.4(DSP):c.3241G>T (p.Glu1081Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
570298	NM_004415.4(DSP):c.4037_4041del (p.Asn1346fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
578291	NM_004415.4(DSP):c.6504_6507del (p.Ser2168fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620416	NM_004415.4(DSP):c.7066A>T (p.Lys2356Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1012339	NM_004415.4(DSP):c.5428del (p.Gln1810fs)	DSP	Likely pathogenic	no assertion criteria provided
157672	NM_004415.4(DSP):c.1790C>T (p.Ser597Leu)	DSP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
228254	NM_004415.4(DSP):c.3507C>A (p.Tyr1169Ter)	DSP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2628093	NM_004415.4(DSP):c.2290_2291dup (p.Leu764fs)	DSP	Likely pathogenic	criteria provided, single submitter
2664078	NM_004415.4(DSP):c.422+1G>A	DSP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382021	NM_004415.4(DSP):c.4407_4423del (p.Asp1470fs)	DSP	Likely pathogenic	criteria provided, single submitter
3382407	NM_004415.4(DSP):c.5024_5027dup (p.Lys1676fs)	DSP	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 11 · 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
DSP	Definitive	Autosomal dominant	arrhythmogenic cardiomyopathy with wooly hair and keratoderma	26

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DSP	Orphanet:154	Familial isolated dilated cardiomyopathy
DSP	Orphanet:158687	Lethal acantholytic erosive disorder
DSP	Orphanet:2032	Idiopathic pulmonary fibrosis
DSP	Orphanet:293165	Skin fragility-woolly hair-palmoplantar keratoderma syndrome
DSP	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSP	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSP	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSP	Orphanet:369992	Severe dermatitis-multiple allergies-metabolic wasting syndrome
DSP	Orphanet:476096	Erythrokeratodermia-cardiomyopathy syndrome
DSP	Orphanet:50942	Striate palmoplantar keratoderma
DSP	Orphanet:65282	Carvajal syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	gencc,clinvar
DSP-AS1	HGNC:56039	ENSG00000261189		DSP antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSP	Desmoplakin	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
DSP-AS1	Other/Unknown	no

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
hair follicle	1
skin of hip	1
upper leg skin	1
apex of heart	1
male germ line stem cell (sensu Vertebrata) in testis	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
DSP-AS1	162		marker	male germ line stem cell (sensu Vertebrata) in testis, apex of heart, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DSP	2,897
DSP-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DSP	P15924	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
Apoptotic cleavage of cell adhesion proteins	1	1038.2×	0.006	DSP
RND1 GTPase cycle	1	265.6×	0.008	DSP
RND3 GTPase cycle	1	259.6×	0.008	DSP
Formation of the cornified envelope	1	87.8×	0.017	DSP
Keratinization	1	55.7×	0.022	DSP
Neutrophil degranulation	1	23.1×	0.043	DSP

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
ventricular compact myocardium morphogenesis	1	2407.4×	0.002	DSP
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	1	2407.4×	0.002	DSP
desmosome organization	1	2106.5×	0.002	DSP
protein localization to cell-cell junction	1	1872.4×	0.002	DSP
peptide cross-linking	1	1404.3×	0.002	DSP
regulation of ventricular cardiac muscle cell action potential	1	1404.3×	0.002	DSP
epithelial cell-cell adhesion	1	1203.7×	0.002	DSP
intermediate filament cytoskeleton organization	1	936.2×	0.002	DSP
adherens junction organization	1	510.7×	0.003	DSP
skin development	1	443.5×	0.004	DSP
regulation of heart rate by cardiac conduction	1	374.5×	0.004	DSP
keratinocyte differentiation	1	247.8×	0.005	DSP
intermediate filament organization	1	240.7×	0.005	DSP
wound healing	1	227.7×	0.005	DSP
epidermis development	1	210.7×	0.005	DSP
cell-cell adhesion	1	101.5×	0.010	DSP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DSP	0	0
DSP-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DSP	2	Binding:2

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	2	DSP, DSP-AS1

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)
DSP	2	—
DSP-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.