epidermolysis bullosa simplex 5C, with pyloric atresia

Summary

epidermolysis bullosa simplex 5C, with pyloric atresia (MONDO:0012807) is a disease caused by PLEC (GenCC Strong), with 5 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PLEC (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 5,743
• Phenotypes (HPO): 29

Clinical features

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000079	Abnormality of the urinary system	Frequent (30-79%)
HP:0001030	Fragile skin	Frequent (30-79%)
HP:0001057	Aplasia cutis congenita	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003270	Abdominal distention	Frequent (30-79%)
HP:0003341	Junctional split	Frequent (30-79%)
HP:0004399	Congenital pyloric atresia	Frequent (30-79%)
HP:0007585	Skin fragility with non-scarring blistering	Frequent (30-79%)
HP:0008066	Abnormal blistering of the skin	Frequent (30-79%)
HP:0200041	Skin erosion	Frequent (30-79%)
HP:0200097	Oral mucosal blisters	Frequent (30-79%)
HP:0000070	Ureterocele	Occasional (5-29%)
HP:0000075	Renal duplication	Occasional (5-29%)
HP:0000096	Glomerulosclerosis	Occasional (5-29%)
HP:0000110	Renal dysplasia	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000795	Abnormality of the urethra	Occasional (5-29%)
HP:0001056	Milia	Occasional (5-29%)
HP:0001075	Atrophic scars	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0003560	Muscular dystrophy	Occasional (5-29%)
HP:0004552	Scarring alopecia of scalp	Occasional (5-29%)
HP:0007385	Aplasia cutis congenita of scalp	Occasional (5-29%)
HP:0007589	Aplasia cutis congenita on trunk or limbs	Occasional (5-29%)
HP:0008404	Nail dystrophy	Occasional (5-29%)
HP:0008551	Microtia	Occasional (5-29%)
HP:0010477	Aplasia of the bladder	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolysis bullosa simplex 5C, with pyloric atresia
Mondo ID	MONDO:0012807
MeSH	C567408
OMIM	612138
Orphanet	158684
SNOMED CT	716701004
UMLS	C2677349
MedGen	436922
GARD	0016991
Is cancer (heuristic)	no

Also known as: EBS-PA · EBSPA · epidermolysis bullosa simplex 5C, with pyloric atresia · epidermolysis bullosa simplex with pyloric atresia

Data availability: 5,743 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 5C, with pyloric atresia

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 1D, generalized, intermediate or severe, autosomal recessive, epidermolysis bullosa simplex 7, with nephropathy and deafness, epidermolysis bullosa simplex 2E, with migratory circinate erythema, 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

600 retrieved; paginated sample, class counts are floors:

299 uncertain significance, 221 likely benign, 34 benign, 22 conflicting classifications of pathogenicity, 13 benign/likely benign, 8 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069886	NM_201384.3(PLEC):c.12418C>T (p.Arg4140Ter)	PLEC	Pathogenic	criteria provided, single submitter
1071954	NM_201384.3(PLEC):c.7336G>T (p.Glu2446Ter)	PLEC	Pathogenic	criteria provided, single submitter
1073588	NM_201384.3(PLEC):c.13106C>A (p.Ser4369Ter)	PLEC	Pathogenic	criteria provided, single submitter
1074096	NM_201384.3(PLEC):c.6510del (p.His2170fs)	PLEC	Pathogenic	criteria provided, single submitter
1251951	NM_201378.4(PLEC):c.66C>G (p.Tyr22Ter)	PLEC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1251952	NM_201384.3(PLEC):c.8149C>T (p.Gln2717Ter)	PLEC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1292045	NM_201384.3(PLEC):c.2455G>T (p.Glu819Ter)	PLEC	Pathogenic	no assertion criteria provided
1320041	NM_201384.3(PLEC):c.6970C>T (p.Arg2324Ter)	PLEC	Pathogenic	criteria provided, multiple submitters, no conflicts
1323468	NM_201384.3(PLEC):c.1465_1471del (p.Asn489fs)	PLEC	Pathogenic	criteria provided, multiple submitters, no conflicts
1324937	NM_201384.3(PLEC):c.4468C>T (p.Arg1490Ter)	PLEC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332728	NM_201384.3(PLEC):c.9312del (p.Tyr3105fs)	PLEC	Pathogenic	criteria provided, single submitter
1001872	NM_201384.3(PLEC):c.7634G>A (p.Arg2545Gln)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003332	NM_201384.3(PLEC):c.6427G>A (p.Glu2143Lys)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1004138	NM_201384.3(PLEC):c.9317G>A (p.Arg3106Lys)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006392	NM_201384.3(PLEC):c.8140G>A (p.Ala2714Thr)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007882	NM_201384.3(PLEC):c.5555C>T (p.Ala1852Val)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038192	NM_201384.3(PLEC):c.13529G>T (p.Gly4510Val)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044930	NM_201384.3(PLEC):c.8492G>A (p.Arg2831Gln)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1048028	NM_201384.3(PLEC):c.3850C>T (p.Leu1284Phe)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1058015	NM_201384.3(PLEC):c.9295G>A (p.Glu3099Lys)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1123939	NM_201384.3(PLEC):c.9840C>T (p.Thr3280=)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1124265	NM_201378.4(PLEC):c.70+2T>C	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1141659	NM_201384.3(PLEC):c.5191C>T (p.Leu1731=)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1151961	NM_201384.3(PLEC):c.5241G>A (p.Thr1747=)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1174478	NM_201384.3(PLEC):c.8531C>T (p.Ala2844Val)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1194821	NM_201384.3(PLEC):c.7703G>A (p.Arg2568His)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1195336	NM_201384.3(PLEC):c.5920C>G (p.Gln1974Glu)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1215529	NM_201384.3(PLEC):c.5795C>T (p.Ala1932Val)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1216951	NM_201384.3(PLEC):c.3784G>A (p.Gly1262Ser)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129930	NM_201384.3(PLEC):c.12615C>T (p.Ile4205=)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 10 · 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
ITGB4	Definitive	Autosomal recessive	junctional epidermolysis bullosa with pyloric atresia	14
PLEC	Strong	Autosomal dominant	epidermolysis bullosa simplex 5A, Ogna type	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLEC	Orphanet:1114	Aplasia cutis congenita
PLEC	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia
PLEC	Orphanet:254361	Plectin-related limb-girdle muscular dystrophy R17
PLEC	Orphanet:257	Epidermolysis bullosa simplex with muscular dystrophy
PLEC	Orphanet:79401	PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement
ITGB4	Orphanet:1114	Aplasia cutis congenita
ITGB4	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia
ITGB4	Orphanet:251393	Localized junctional epidermolysis bullosa
ITGB4	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
ITGB4	Orphanet:79403	Junctional epidermolysis bullosa with pyloric atresia

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLEC	HGNC:9069	ENSG00000178209	Q15149	Plectin	gencc,clinvar
ITGB4	HGNC:6158	ENSG00000132470	P16144	Integrin beta-4	gencc
ADCK5	HGNC:21738	ENSG00000173137	Q3MIX3	Uncharacterized aarF domain-containing protein kinase 5	clinvar
MIR661	HGNC:32917	ENSG00000207574		microRNA 661	clinvar
CATSPERQ	HGNC:44155	ENSG00000261587	Q2WGJ8	Cation channel sperm-associated auxiliary subunit theta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLEC	Plectin	Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes.
ITGB4	Integrin beta-4	Integrin alpha-6/beta-4 is a receptor for laminin.
ADCK5	Uncharacterized aarF domain-containing protein kinase 5	The function of this protein is not yet clear.
CATSPERQ	Cation channel sperm-associated auxiliary subunit theta	Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.4

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	5.8×	0.336
Kinase	1	5.5×	0.336
Scaffold/PPI	1	3.5×	0.344
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLEC	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Actinin_actin-bd_CS
ITGB4	Antibody/Immunoglobulin	yes		EGF, Integrin_bsu_VWA, Calx_beta
ADCK5	Kinase	yes		ABC1_dom, Kinase-like_dom_sf, ADCK1_dom
MIR661	Other/Unknown	no
CATSPERQ	Other/Unknown	no		TMEM249

Expression context

Cohort genes with no expression data: 0.

3 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibial nerve	2
hindlimb stylopod muscle	1
sural nerve	1
minor salivary gland	1
skin of leg	1
duodenum	1
mucosa of transverse colon	1
right hemisphere of cerebellum	1
adrenal tissue	1
blood	1
vermiform appendix	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLEC	283	ubiquitous	marker	sural nerve, hindlimb stylopod muscle, tibial nerve
ITGB4	267	broad	marker	tibial nerve, minor salivary gland, skin of leg
ADCK5	136	ubiquitous	marker	mucosa of transverse colon, duodenum, right hemisphere of cerebellum
MIR661	89		yes	adrenal tissue, vermiform appendix, blood
CATSPERQ	123	tissue_specific	yes	right testis, left testis, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLEC	3,529
ITGB4	2,536
ADCK5	978
CATSPERQ	100
MIR661	0

Intra-cohort edges

A	B	Sources
ITGB4	PLEC	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLEC	Q15149	14
ITGB4	P16144	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADCK5	Q3MIX3	82.08
CATSPERQ	Q2WGJ8	79.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 5 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×	1e-05	PLEC, ITGB4
Assembly of collagen fibrils and other multimeric structures	2	200.3×	2e-04	PLEC, ITGB4
Caspase-mediated cleavage of cytoskeletal proteins	1	475.8×	0.009	PLEC
Collagen formation	1	228.4×	0.011	ITGB4
Syndecan interactions	1	211.5×	0.011	ITGB4
Laminin interactions	1	190.3×	0.011	ITGB4
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	139.3×	0.013	ITGB4
Developmental Cell Lineages	1	112.0×	0.014	ITGB4
Cell junction organization	1	93.6×	0.015	ITGB4
Non-integrin membrane-ECM interactions	1	77.2×	0.017	ITGB4
Cell-Cell communication	1	68.8×	0.017	ITGB4
Extracellular matrix organization	1	31.6×	0.034	ITGB4
Developmental Biology	1	7.2×	0.134	ITGB4

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
hemidesmosome assembly	2	2407.4×	7e-06	PLEC, ITGB4
protein-containing complex organization	1	8426.0×	0.002	PLEC
actomyosin contractile ring assembly actin filament organization	1	8426.0×	0.002	PLEC
skeletal myofibril assembly	1	4213.0×	0.002	PLEC
leukocyte migration involved in immune response	1	2808.7×	0.002	PLEC
peripheral nervous system myelin formation	1	2808.7×	0.002	ITGB4
cellular response to hydrostatic pressure	1	2808.7×	0.002	PLEC
tight junction organization	1	1685.2×	0.003	PLEC
nail development	1	1203.7×	0.004	ITGB4
trophoblast cell migration	1	1203.7×	0.004	ITGB4
keratinocyte development	1	766.0×	0.005	PLEC
peripheral nervous system myelin maintenance	1	766.0×	0.005	PLEC
mesodermal cell differentiation	1	766.0×	0.005	ITGB4
skin morphogenesis	1	702.2×	0.005	ITGB4
cellular response to fluid shear stress	1	648.1×	0.005	PLEC
T cell chemotaxis	1	561.7×	0.005	PLEC
regulation of vascular permeability	1	561.7×	0.005	PLEC
intermediate filament cytoskeleton organization	1	468.1×	0.005	PLEC
fibroblast migration	1	421.3×	0.005	PLEC
respiratory electron transport chain	1	421.3×	0.005	PLEC
myoblast differentiation	1	421.3×	0.005	PLEC
cell adhesion mediated by integrin	1	337.0×	0.006	ITGB4
transmission of nerve impulse	1	324.1×	0.006	PLEC
filopodium assembly	1	324.1×	0.006	ITGB4
cardiac muscle cell development	1	312.1×	0.006	PLEC
nucleus organization	1	280.9×	0.006	PLEC
skeletal muscle fiber development	1	271.8×	0.006	PLEC
adherens junction organization	1	255.3×	0.007	PLEC
response to food	1	247.8×	0.007	PLEC
establishment of skin barrier	1	227.7×	0.007	PLEC

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ADCK5	NERATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADCK5	2	4
PLEC	0	0
ITGB4	0	0
MIR661	0	0
CATSPERQ	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NERATINIB	4	ADCK5
LINSITINIB	3	ADCK5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PLEC	12	Binding:12
ITGB4	2	Binding:2
ADCK5	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
NERATINIB	4	ADCK5
LINSITINIB	3	ADCK5

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ADCK5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ITGB4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	PLEC, MIR661, CATSPERQ

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLEC	12	—
ITGB4	2	—
MIR661	0	—
CATSPERQ	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.