junctional epidermolysis bullosa Herlitz type

Summary

junctional epidermolysis bullosa Herlitz type (MONDO:0009182) is a disease caused by variants in LAMB3, LAMA3, and LAMC2, with 5 cohort genes. The dominant Reactome pathway is MET promotes cell motility (4 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: LAMB3 (GenCC Definitive), LAMA3 (GenCC Strong), LAMC2 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 657
• Phenotypes (HPO): 61

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.17	Worldwide	Validated
Prevalence at birth	<1 / 1 000 000	0.04	United States	Validated
Prevalence at birth	1-9 / 1 000 000	0.4	Netherlands	Validated
Prevalence at birth	<1 / 1 000 000	0.07	Italy	Validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

61 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001030	Fragile skin	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001581	Recurrent skin infections	Very frequent (80-99%)
HP:0001597	Abnormality of the nail	Very frequent (80-99%)
HP:0006297	Enamel hypoplasia	Very frequent (80-99%)
HP:0008066	Abnormal blistering of the skin	Very frequent (80-99%)
HP:0011830	Abnormal oral mucosa morphology	Very frequent (80-99%)
HP:0020117	Hypoplastic dermoepidermal hemidesmosomes	Very frequent (80-99%)
HP:0200035	Skin plaque	Very frequent (80-99%)
HP:0200041	Skin erosion	Very frequent (80-99%)
HP:0001211	Abnormal fingertip morphology	Frequent (30-79%)
HP:0001609	Hoarse voice	Frequent (30-79%)
HP:0001798	Anonychia	Frequent (30-79%)
HP:0001818	Paronychia	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0004395	Malnutrition	Frequent (30-79%)
HP:0010307	Stridor	Frequent (30-79%)
HP:0031446	Erosion of oral mucosa	Frequent (30-79%)
HP:0000003	Multicystic kidney dysplasia	Occasional (5-29%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000014	Abnormality of the bladder	Occasional (5-29%)
HP:0000016	Urinary retention	Occasional (5-29%)
HP:0000070	Ureterocele	Occasional (5-29%)
HP:0000072	Hydroureter	Occasional (5-29%)
HP:0000081	Duplicated collecting system	Occasional (5-29%)
HP:0000107	Renal cyst	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000481	Abnormal cornea morphology	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0000969	Edema	Occasional (5-29%)
HP:0001057	Aplasia cutis congenita	Occasional (5-29%)
HP:0001596	Alopecia	Occasional (5-29%)
HP:0001602	Laryngeal stenosis	Occasional (5-29%)
HP:0001615	Hoarse cry	Occasional (5-29%)
HP:0001644	Dilated cardiomyopathy	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0001955	Unexplained fevers	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002043	Esophageal stricture	Occasional (5-29%)
HP:0002087	Abnormality of the upper respiratory tract	Occasional (5-29%)
HP:0002090	Pneumonia	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002860	Squamous cell carcinoma	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0003111	Abnormal blood ion concentration	Occasional (5-29%)
HP:0004057	Mitten deformity	Occasional (5-29%)
HP:0004386	Gastrointestinal inflammation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	junctional epidermolysis bullosa Herlitz type
Mondo ID	MONDO:0009182
OMIM	226700
Orphanet	79404
DOID	DOID:0060737
ICD-10-CM	Q81.1
SNOMED CT	400140006
UMLS	C0079683
MedGen	36328
GARD	0002153
Is cancer (heuristic)	no

Also known as: epidermolysis bullosa letalis · Herlitz-Pearson type epidermolysis bullosa · Herlitz-Pearson-type epidermolysis bullosa · JEB, generalised severe · JEB, generalized severe · JEB-H · JEB-Herlitz type · junctional epidermolysis bullosa generalisata gravis · junctional epidermolysis bullosa, generalised severe · junctional epidermolysis bullosa, Herlitz type · junctional epidermolysis bullosa, Herlitz-Pearson type

Data availability: 657 ClinVar variants · 12 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 › junctional epidermolysis bullosa › junctional epidermolysis bullosa Herlitz type

Related subtypes (14): late-onset localized junctional epidermolysis bullosa-intellectual disability syndrome, junctional epidermolysis bullosa, non-Herlitz type, junctional epidermolysis bullosa with pyloric atresia, laryngo-onycho-cutaneous syndrome, epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, junctional epidermolysis bullosa inversa, late-onset junctional epidermolysis bullosa, epidermolysis bullosa, junctional 2A, intermediate, epidermolysis bullosa, junctional 2B, severe, epidermolysis bullosa, junctional 3A, intermediate, epidermolysis bullosa, junctional 3B, severe, epidermolysis bullosa, junctional 4, intermediate, epidermolysis bullosa, junctional 5A, intermediate, epidermolysis bullosa, junctional 6, with pyloric atresia

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:

210 likely pathogenic, 148 uncertain significance, 70 benign, 66 pathogenic, 56 conflicting classifications of pathogenicity, 29 pathogenic/likely pathogenic, 11 likely benign, 10 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1252054	NM_198129.4(LAMA3):c.8302C>T (p.Arg2768Ter)	LAMA3	Pathogenic	criteria provided, single submitter
21264	NM_198129.4(LAMA3):c.6943A>T (p.Arg2315Ter)	LAMA3	Pathogenic	no assertion criteria provided
370076	NM_198129.4(LAMA3):c.8203C>T (p.Arg2735Ter)	LAMA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370424	NM_198129.4(LAMA3):c.6505del (p.Val2169fs)	LAMA3	Pathogenic	criteria provided, single submitter
370688	NM_198129.4(LAMA3):c.5980_5981del (p.Glu1993_Ala1994insTer)	LAMA3	Pathogenic	criteria provided, single submitter
370752	NM_198129.4(LAMA3):c.5049del (p.Cys1684fs)	LAMA3	Pathogenic	criteria provided, multiple submitters, no conflicts
449049	NM_198129.4(LAMA3):c.8941C>T (p.Gln2981Ter)	LAMA3	Pathogenic	criteria provided, multiple submitters, no conflicts
549906	NM_198129.4(LAMA3):c.6041del (p.Gln2014fs)	LAMA3	Pathogenic	criteria provided, single submitter
550430	NM_000227.6(LAMA3):c.108del (p.Leu38fs)	LAMA3	Pathogenic	criteria provided, multiple submitters, no conflicts
551628	NM_198129.4(LAMA3):c.7075C>T (p.Gln2359Ter)	LAMA3	Pathogenic	criteria provided, single submitter
552174	NM_198129.4(LAMA3):c.9511+1G>A	LAMA3	Pathogenic	criteria provided, single submitter
553661	NM_198129.4(LAMA3):c.3376C>T (p.Arg1126Ter)	LAMA3	Pathogenic	criteria provided, single submitter
554567	NM_198129.4(LAMA3):c.8081G>A (p.Trp2694Ter)	LAMA3	Pathogenic	criteria provided, single submitter
555355	NM_198129.4(LAMA3):c.7828C>T (p.Arg2610Ter)	LAMA3	Pathogenic	criteria provided, multiple submitters, no conflicts
555742	NM_198129.4(LAMA3):c.6232_6233del (p.Gln2077_Ser2078insTer)	LAMA3	Pathogenic	criteria provided, multiple submitters, no conflicts
556715	NM_198129.4(LAMA3):c.9114T>G (p.Tyr3038Ter)	LAMA3	Pathogenic	criteria provided, single submitter
556752	NM_198129.4(LAMA3):c.6567del (p.Glu2190fs)	LAMA3	Pathogenic	criteria provided, multiple submitters, no conflicts
557141	NM_198129.4(LAMA3):c.7489C>T (p.Gln2497Ter)	LAMA3	Pathogenic	criteria provided, single submitter
8792	NM_198129.4(LAMA3):c.6808C>T (p.Arg2270Ter)	LAMA3	Pathogenic	criteria provided, multiple submitters, no conflicts
1068583	NM_000228.3(LAMB3):c.1702C>T (p.Gln568Ter)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071051	NM_000228.3(LAMB3):c.823-1G>A	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
1074943	NM_000228.3(LAMB3):c.1676del (p.Gly558_Leu559insTer)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332711	NM_000228.3(LAMB3):c.622del (p.Ile208fs)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339201	NM_000228.3(LAMB3):c.428G>A (p.Trp143Ter)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361158	NM_000228.3(LAMB3):c.435_436del (p.Tyr146fs)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14539	NM_000228.3(LAMB3):c.1903C>T (p.Arg635Ter)	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
14541	NM_000228.3(LAMB3):c.124C>T (p.Arg42Ter)	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
14543	NM_000228.3(LAMB3):c.628G>A (p.Glu210Lys)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14544	NM_000228.3(LAMB3):c.496C>T (p.Gln166Ter)	LAMB3	Pathogenic	criteria provided, single submitter
14545	NM_000228.3(LAMB3):c.1830G>A (p.Trp610Ter)	LAMB3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 54 · Orphanet: 9 · 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
LAMA3	Definitive	Autosomal recessive	junctional epidermolysis bullosa	13
LAMA4	Definitive	Autosomal recessive	junctional epidermolysis bullosa	18
LAMB3	Definitive	Autosomal recessive	junctional epidermolysis bullosa, non-Herlitz type	15
LAMC2	Definitive	Autosomal recessive	junctional epidermolysis bullosa	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAMA3	Orphanet:2407	Laryngo-onycho-cutaneous syndrome
LAMA3	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
LAMA3	Orphanet:79404	Severe generalized junctional epidermolysis bullosa
LAMA4	Orphanet:154	Familial isolated dilated cardiomyopathy
LAMB3	Orphanet:100031	Hypoplastic amelogenesis imperfecta
LAMB3	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
LAMB3	Orphanet:79404	Severe generalized junctional epidermolysis bullosa
LAMC2	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
LAMC2	Orphanet:79404	Severe generalized junctional epidermolysis bullosa

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
LAMA3	HGNC:6483	ENSG00000053747	Q16787	Laminin subunit alpha-3	gencc,clinvar
LAMA4	HGNC:6484	ENSG00000112769	Q16363	Laminin subunit alpha-4	gencc,clinvar
LAMB3	HGNC:6490	ENSG00000196878	Q13751	Laminin subunit beta-3	gencc,clinvar
LAMC2	HGNC:6493	ENSG00000058085	Q13753	Laminin subunit gamma-2	gencc,clinvar
MIR4260	HGNC:38179	ENSG00000283876		microRNA 4260	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LAMA3	Laminin subunit alpha-3	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
LAMA4	Laminin subunit alpha-4	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
LAMB3	Laminin subunit beta-3	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
LAMC2	Laminin subunit gamma-2	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 5 · 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	5	1.8×	0.054

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LAMA3	Other/Unknown	no		Laminin_IV, EGF, Laminin_G
LAMA4	Other/Unknown	no		EGF, Laminin_G, LE_dom
LAMB3	Other/Unknown	no		EGF, LE_dom, Laminin_N
LAMC2	Other/Unknown	no		Laminin_IV, EGF, LE_dom
MIR4260	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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
periodontal ligament	2
right lung	1
skin of abdomen	1
skin of leg	1
lower esophagus	1
lower esophagus muscularis layer	1
nerve	1
cartilage tissue	1
gingival epithelium	1
hair follicle	1
islet of Langerhans	1
blood	1
bone marrow	1
olfactory segment of nasal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LAMA3	239	broad	marker	right lung, skin of leg, skin of abdomen
LAMA4	268	ubiquitous	marker	lower esophagus muscularis layer, lower esophagus, nerve
LAMB3	215	ubiquitous	marker	cartilage tissue, periodontal ligament, gingival epithelium
LAMC2	209	broad	marker	islet of Langerhans, hair follicle, periodontal ligament
MIR4260	62		yes	bone marrow, olfactory segment of nasal mucosa, blood

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LAMA4	2,688
LAMA3	2,195
LAMC2	2,061
LAMB3	1,697
MIR4260	0

Intra-cohort edges

A	B	Sources
LAMA3	LAMB3	string_interaction
LAMA3	LAMC2	string_interaction
LAMA4	LAMB3	string_interaction
LAMA4	LAMC2	string_interaction
LAMB3	LAMC2	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 4 · No structure: 1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LAMB3	Q13751	78.55
LAMA4	Q16363	73.75
LAMC2	Q13753	72.89
LAMA3	Q16787

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MET promotes cell motility	4	601.0×	1e-10	LAMA3, LAMA4, LAMB3, LAMC2
Attachment of bacteria to epithelial cells	4	496.5×	1e-10	LAMA3, LAMA4, LAMB3, LAMC2
Laminin interactions	4	380.7×	2e-10	LAMA3, LAMA4, LAMB3, LAMC2
MET activates PTK2 signaling	4	380.7×	2e-10	LAMA3, LAMA4, LAMB3, LAMC2
Signaling by MET	4	317.2×	3e-10	LAMA3, LAMA4, LAMB3, LAMC2
Formation of the dystrophin-glycoprotein complex (DGC)	4	308.6×	3e-10	LAMA3, LAMA4, LAMB3, LAMC2
Developmental Lineage of Pancreatic Ductal Cells	4	228.4×	9e-10	LAMA3, LAMA4, LAMB3, LAMC2
Non-integrin membrane-ECM interactions	4	154.3×	4e-09	LAMA3, LAMA4, LAMB3, LAMC2
Type I hemidesmosome assembly	3	778.6×	6e-09	LAMA3, LAMB3, LAMC2
Anchoring fibril formation	3	571.0×	1e-08	LAMA3, LAMB3, LAMC2
Collagen formation	3	342.6×	6e-08	LAMA3, LAMB3, LAMC2
Extracellular matrix organization	4	63.1×	1e-07	LAMA3, LAMA4, LAMB3, LAMC2
Signaling by Receptor Tyrosine Kinases	4	51.7×	2e-07	LAMA3, LAMA4, LAMB3, LAMC2
Assembly of collagen fibrils and other multimeric structures	3	150.3×	6e-07	LAMA3, LAMB3, LAMC2
Cell junction organization	3	140.4×	7e-07	LAMA3, LAMB3, LAMC2
Cell-Cell communication	3	103.2×	2e-06	LAMA3, LAMB3, LAMC2
Degradation of the extracellular matrix	3	88.3×	3e-06	LAMA3, LAMB3, LAMC2
Signal Transduction	4	10.2×	1e-04	LAMA3, LAMA4, LAMB3, LAMC2
ECM proteoglycans	2	75.1×	3e-04	LAMA3, LAMA4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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	3	158.0×	5e-06	LAMA3, LAMB3, LAMC2
endodermal cell differentiation	2	247.8×	1e-04	LAMA3, LAMB3
regulation of embryonic development	2	165.2×	2e-04	LAMA3, LAMA4
regulation of cell adhesion	2	153.2×	2e-04	LAMA3, LAMA4
cell adhesion	3	28.1×	2e-04	LAMA4, LAMB3, LAMC2
regulation of cell migration	2	78.8×	5e-04	LAMA3, LAMA4
hemidesmosome assembly	1	601.9×	0.003	LAMA3
brown fat cell differentiation	1	108.0×	0.014	LAMB3
negative regulation of cold-induced thermogenesis	1	86.0×	0.015	LAMA4
cell-cell adhesion	1	25.4×	0.047	LAMA3
positive regulation of cell migration	1	15.4×	0.069	LAMC2
positive regulation of cell population proliferation	1	8.4×	0.114	LAMC2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 4 of 5 evidence-associated genes (80%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LAMA3	0	0
LAMA4	0	0
LAMB3	0	0
LAMC2	0	0
MIR4260	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	5	LAMA3, LAMA4, LAMB3, LAMC2, MIR4260

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LAMA3	0	—
LAMA4	0	—
LAMB3	0	—
LAMC2	0	—
MIR4260	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.