epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive

Summary

epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive (MONDO:0010976) is a disease caused by KRT14 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KRT14 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 23
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000962	Hyperkeratosis	Frequent (30-79%)
HP:0000972	Palmoplantar hyperkeratosis	Frequent (30-79%)
HP:0001231	Abnormal fingernail morphology	Frequent (30-79%)
HP:0007446	Palmoplantar blistering	Frequent (30-79%)
HP:0008066	Abnormal blistering of the skin	Frequent (30-79%)
HP:0008388	Abnormal toenail morphology	Frequent (30-79%)
HP:0200041	Skin erosion	Frequent (30-79%)
HP:0200097	Oral mucosal blisters	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	Occasional (5-29%)
HP:0000989	Pruritus	Occasional (5-29%)
HP:0001010	Hypopigmentation of the skin	Occasional (5-29%)
HP:0001056	Milia	Occasional (5-29%)
HP:0001075	Atrophic scars	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001802	Absent toenail	Occasional (5-29%)
HP:0001807	Ridged nail	Occasional (5-29%)
HP:0001810	Dystrophic toenail	Occasional (5-29%)
HP:0003764	Nevus	Occasional (5-29%)
HP:0007589	Aplasia cutis congenita on trunk or limbs	Occasional (5-29%)
HP:0031464	Genital blistering	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive
Mondo ID	MONDO:0010976
MeSH	C563408
OMIM	601001
Orphanet	89838
UMLS	C3715082
MedGen	811576
GARD	0016778
Is cancer (heuristic)	no

Also known as: EBS, autosomal recessive K14 · EBS-AR KRT14 · EBSB1 · epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive · epidermolysis bullosa simplex, autosomal recessive 1 · epidermolysis bullosa simplex, autosomal recessive type 1 · KRT14-related autosomal recessive EBS · KRT14-related autosomal recessive epidermolysis bullosa simplex · KRT14-related epidermolysis bullosa simplex

Data availability: 23 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › vesiculobullous skin disease › epidermolysis bullosa › inherited epidermolysis bullosa › epidermolysis bullosa simplex › epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive

Related subtypes (19): epidermolysis bullosa simplex 1A, generalized severe, epidermolysis bullosa simplex 1C, localized, epidermolysis bullosa simplex 1B, generalized intermediate, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 2F, with mottled pigmentation, epidermolysis bullosa simplex 5B, with muscular dystrophy, epidermolysis bullosa simplex 7, with nephropathy and deafness, epidermolysis bullosa simplex 2E, with migratory circinate erythema, epidermolysis bullosa simplex 5C, with pyloric atresia, epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive, epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency, epidermolysis bullosa simplex with nail dystrophy, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, suprabasal epidermolysis bullosa simplex, epidermolysis bullosa simplex with anodontia/hypodontia, epidermolysis bullosa simplex 2A, generalized severe, epidermolysis bullosa simplex 2B, generalized intermediate, epidermolysis bullosa simplex 2C, localized, epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive

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

23 retrieved; paginated sample, class counts are floors:

9 pathogenic, 5 likely pathogenic, 4 benign, 2 benign/likely benign, 1 uncertain significance, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
14614	NM_000526.5(KRT14):c.431A>C (p.Glu144Ala)	KRT14	Pathogenic	no assertion criteria provided
14616	NM_000526.5(KRT14):c.612T>A (p.Tyr204Ter)	KRT14	Pathogenic	no assertion criteria provided
1526072	NM_000526.5(KRT14):c.766G>T (p.Glu256Ter)	KRT14	Pathogenic	criteria provided, multiple submitters, no conflicts
66309	NM_000526.5(KRT14):c.1186C>T (p.Gln396Ter)	KRT14	Pathogenic/Likely pathogenic	criteria provided, single submitter
66337	NM_000526.5(KRT14):c.313_314del (p.Ala105fs)	KRT14	Pathogenic	no assertion criteria provided
66348	NM_000526.5(KRT14):c.374G>C (p.Arg125Pro)	KRT14	Pathogenic	criteria provided, single submitter
66378	NM_000526.5(KRT14):c.815T>C (p.Met272Thr)	KRT14	Pathogenic	criteria provided, multiple submitters, no conflicts
66382	NM_000526.5(KRT14):c.915G>A (p.Trp305Ter)	KRT14	Pathogenic	criteria provided, multiple submitters, no conflicts
66385	NM_000526.5(KRT14):c.92del (p.Ile31fs)	KRT14	Pathogenic	criteria provided, multiple submitters, no conflicts
14641	NM_000424.4(KRT5):c.980T>C (p.Met327Thr)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
3391196	NM_000526.5(KRT14):c.120C>A (p.Cys40Ter)	KRT14	Likely pathogenic	criteria provided, single submitter
419836	NM_000526.5(KRT14):c.1163G>A (p.Arg388His)	KRT14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531283	NM_000526.5(KRT14):c.507del (p.Ile169fs)	KRT14	Likely pathogenic	criteria provided, single submitter
4849386	NM_000526.5(KRT14):c.1167C>A (p.Cys389Ter)	KRT14	Likely pathogenic	criteria provided, single submitter
66369	NM_000526.5(KRT14):c.526-2A>C	KRT14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
66381	NM_000526.5(KRT14):c.88C>T (p.Arg30Cys)	KRT14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2352985	NM_000526.5(KRT14):c.139G>A (p.Gly47Arg)	KRT14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1668287	NM_000526.5(KRT14):c.188G>A (p.Cys63Tyr)	KRT14	Benign	criteria provided, multiple submitters, no conflicts
66319	NM_000526.5(KRT14):c.1237G>A (p.Ala413Thr)	KRT14	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
66331	NM_000526.5(KRT14):c.189C>T (p.Cys63=)	KRT14	Benign	criteria provided, multiple submitters, no conflicts
66332	NM_000526.5(KRT14):c.193C>T (p.Leu65=)	KRT14	Benign	criteria provided, multiple submitters, no conflicts
66346	NM_000526.5(KRT14):c.369T>C (p.Asn123=)	KRT14	Benign	criteria provided, multiple submitters, no conflicts
781859	NM_000526.5(KRT14):c.166C>T (p.Arg56Cys)	KRT14	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 13 · 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
KRT14	Definitive	Autosomal recessive	epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive	25

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT14	Orphanet:69087	Naegeli-Franceschetti-Jadassohn syndrome
KRT14	Orphanet:79396	Autosomal dominant generalized epidermolysis bullosa simplex, severe form
KRT14	Orphanet:79397	Epidermolysis bullosa simplex with mottled pigmentation
KRT14	Orphanet:79399	Autosomal dominant generalized epidermolysis bullosa simplex, intermediate form
KRT14	Orphanet:79400	Localized epidermolysis bullosa simplex
KRT14	Orphanet:86920	Dermatopathia pigmentosa reticularis
KRT14	Orphanet:89838	Autosomal recessive generalized epidermolysis bullosa simplex
KRT5	Orphanet:158681	Epidermolysis bullosa simplex with circinate migratory erythema
KRT5	Orphanet:79145	Dowling-Degos disease
KRT5	Orphanet:79396	Autosomal dominant generalized epidermolysis bullosa simplex, severe form
KRT5	Orphanet:79397	Epidermolysis bullosa simplex with mottled pigmentation
KRT5	Orphanet:79399	Autosomal dominant generalized epidermolysis bullosa simplex, intermediate form
KRT5	Orphanet:79400	Localized epidermolysis bullosa simplex

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
KRT14	HGNC:6416	ENSG00000186847	P02533	Keratin, type I cytoskeletal 14	gencc,clinvar
KRT5	HGNC:6442	ENSG00000186081	P13647	Keratin, type II cytoskeletal 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT14	Keratin, type I cytoskeletal 14	The nonhelical tail domain is involved in promoting KRT5-KRT14 filaments to self-organize into large bundles and enhances the mechanical properties involved in resilience of keratin intermediate filaments in vitro.
KRT5	Keratin, type II cytoskeletal 5	Required for the formation of keratin intermediate filaments in the basal epidermis and maintenance of the skin barrier in response to mechanical stress.

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)
KRT14	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom
KRT5	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head

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
gingiva	2
gingival epithelium	1
upper arm skin	1
lower esophagus mucosa	1
pharyngeal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT14	193	broad	marker	gingiva, gingival epithelium, upper arm skin
KRT5	211	broad	marker	lower esophagus mucosa, pharyngeal mucosa, gingiva

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT5	3,406
KRT14	3,351

Intra-cohort edges

A	B	Sources
KRT14	KRT5	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT14	P02533	2
KRT5	P13647	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 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
Type I hemidesmosome assembly	2	1038.2×	9e-06	KRT14, KRT5
Developmental Lineage of Mammary Gland Myoepithelial Cells	2	543.8×	2e-05	KRT14, KRT5
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	2	278.5×	5e-05	KRT14, KRT5
Developmental Cell Lineages	2	223.9×	5e-05	KRT14, KRT5
Cell junction organization	2	187.2×	6e-05	KRT14, KRT5
Cell-Cell communication	2	137.6×	1e-04	KRT14, KRT5
Formation of the cornified envelope	2	87.8×	2e-04	KRT14, KRT5
Keratinization	2	55.7×	4e-04	KRT14, KRT5
Developmental Lineage of Mammary Stem Cells	1	380.7×	0.003	KRT5
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	228.4×	0.005	KRT5
Developmental Biology	2	14.5×	0.005	KRT14, KRT5

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
intermediate filament organization	2	240.7×	1e-04	KRT14, KRT5
epidermis development	2	210.7×	1e-04	KRT14, KRT5
intermediate filament polymerization	1	8426.0×	5e-04	KRT5
intermediate filament bundle assembly	1	1404.3×	0.002	KRT14
response to radiation	1	601.9×	0.004	KRT14
hair cycle	1	468.1×	0.005	KRT14
morphogenesis of an epithelium	1	172.0×	0.010	KRT14
response to mechanical stimulus	1	150.5×	0.010	KRT5
stem cell differentiation	1	150.5×	0.010	KRT14
keratinocyte differentiation	1	123.9×	0.010	KRT14
keratinization	1	117.0×	0.010	KRT5
regulation of protein localization	1	102.8×	0.011	KRT5
regulation of cell migration	1	78.8×	0.013	KRT5

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
KRT14	0	0
KRT5	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	KRT14, KRT5

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)
KRT14	0	—
KRT5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.