Bart-Pumphrey syndrome

Summary

Bart-Pumphrey syndrome (MONDO:0007866) is a disease caused by GJB2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GJB2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 108
• Phenotypes (HPO): 7

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0001820	Leukonychia	Very frequent (80-99%)
HP:0008527	Congenital sensorineural hearing impairment	Very frequent (80-99%)
HP:0032541	Knuckle pad	Very frequent (80-99%)
HP:0000972	Palmoplantar hyperkeratosis	Frequent (30-79%)
HP:0000982	Palmoplantar keratoderma	Frequent (30-79%)
HP:0000410	Mixed hearing impairment	Occasional (5-29%)
HP:0045059	Hyperkeratotic papule	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Bart-Pumphrey syndrome
Mondo ID	MONDO:0007866
MeSH	C537210
OMIM	149200
Orphanet	2698
DOID	DOID:0050658
SNOMED CT	1271009
UMLS	C0266004
MedGen	82727
GARD	0003125
Is cancer (heuristic)	no

Also known as: Bart-Pumphrey syndrome · knuckle pads, leuconychia and sensorineural deafness · knuckle pads, leukonychia, and sensorineural deafness · knuckle pads-leukonychia-sensorineural deafness-palmoplantar keratoderma syndrome

Data availability: 108 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 › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › diffuse palmoplantar keratoderma › Bart-Pumphrey syndrome

Related subtypes (31): autosomal dominant palmoplantar keratoderma and congenital alopecia, dermatopathia pigmentosa reticularis, Clouston syndrome, epidermolytic palmoplantar keratoderma, 1, palmoplantar keratoderma-deafness syndrome, palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome, keratosis palmaris et plantaris-clinodactyly syndrome, Naegeli-Franceschetti-Jadassohn syndrome, palmoplantar keratoderma-sclerodactyly syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, Schöpf-Schulz-Passarge syndrome, hereditary palmoplantar keratoderma, Gamborg-Nielsen type, Papillon-Lefevre disease, Haim-Munk syndrome, mal de Meleda, odonto-onycho-dermal dysplasia, palmoplantar keratoderma, Bothnian type, diffuse nonepidermolytic palmoplantar keratoderma, loricrin keratoderma, skin fragility-woolly hair-palmoplantar keratoderma syndrome, Curly hair - acral keratoderma - caries syndrome, CEDNIK syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, palmoplantar keratoderma, Nagashima type, erythrokeratodermia variabilis, diffuse palmoplantar keratoderma with painful fissures, KID syndrome, diffuse palmoplantar keratoderma - acrocyanosis syndrome, hearing loss with skin disease

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

108 retrieved; paginated sample, class counts are floors:

35 pathogenic, 29 pathogenic/likely pathogenic, 15 uncertain significance, 11 likely pathogenic, 9 conflicting classifications of pathogenicity, 5 benign/likely benign, 2 likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
158607	NM_004004.6(GJB2):c.298C>T (p.His100Tyr)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
158609	NM_004004.6(GJB2):c.647_650del (p.Arg216fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
163514	NM_004004.6(GJB2):c.379C>T (p.Arg127Cys)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17000	NM_004004.6(GJB2):c.101T>C (p.Met34Thr)	GJB2	Pathogenic	reviewed by expert panel
17001	NM_004004.6(GJB2):c.231G>A (p.Trp77Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17002	NM_004004.6(GJB2):c.71G>A (p.Trp24Ter)	GJB2	Pathogenic	reviewed by expert panel
17003	NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17004	NM_004004.6(GJB2):c.35del (p.Gly12fs)	GJB2	Pathogenic	reviewed by expert panel
17005	NM_004004.6(GJB2):c.139G>T (p.Glu47Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17006	NM_004004.6(GJB2):c.355GAG[1] (p.Glu120del)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17007	NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17009	NM_004004.6(GJB2):c.427C>T (p.Arg143Trp)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17010	NM_004004.6(GJB2):c.167del (p.Leu56fs)	GJB2	Pathogenic	reviewed by expert panel
17013	NM_004004.6(GJB2):c.51_62delinsA (p.Thr18fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17014	NM_004004.6(GJB2):c.235del (p.Leu79fs)	GJB2	Pathogenic	reviewed by expert panel
17016	NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17017	NM_004004.6(GJB2):c.428G>A (p.Arg143Gln)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17023	NM_004004.6(GJB2):c.109G>A (p.Val37Ile)	GJB2	Pathogenic	reviewed by expert panel
17029	NM_004004.6(GJB2):c.-23+1G>A	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17030	NM_004004.6(GJB2):c.162C>A (p.Asn54Lys)	GJB2	Pathogenic	no assertion criteria provided
17032	NM_004004.6(GJB2):c.250G>C (p.Val84Leu)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17033	NM_004004.6(GJB2):c.134G>A (p.Gly45Glu)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
177737	NM_004004.6(GJB2):c.269dup (p.Val91fs)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
188756	NM_004004.6(GJB2):c.246C>G (p.Ile82Met)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188758	NM_004004.6(GJB2):c.94C>T (p.Arg32Cys)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
188821	NM_004004.6(GJB2):c.290dup (p.Tyr97Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
188830	NM_004004.6(GJB2):c.131G>A (p.Trp44Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
189051	NM_004004.6(GJB2):c.334_335del (p.Lys112fs)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
189070	NM_004004.6(GJB2):c.508_511dup (p.Ala171fs)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
189176	NM_004004.6(GJB2):c.230G>A (p.Trp77Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 7 · 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
GJB2	Definitive	Autosomal dominant	Bart-Pumphrey syndrome	26

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJB2	Orphanet:166286	Porokeratotic eccrine ostial and dermal duct nevus
GJB2	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
GJB2	Orphanet:2698	Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
GJB2	Orphanet:477	KID syndrome
GJB2	Orphanet:494	Keratoderma hereditarium mutilans
GJB2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	1
gingival epithelium	1
penis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJB2	196	broad	marker	gingival epithelium, gingiva, penis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJB2	1,391

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB2	P29033	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 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
Oligomerization of connexins into connexons	1	3806.7×	5e-04	GJB2
Transport of connexins along the secretory pathway	1	3806.7×	5e-04	GJB2
Transport of connexons to the plasma membrane	1	543.8×	0.002	GJB2
Gap junction assembly	1	292.8×	0.003	GJB2

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
gap junction-mediated intercellular transport	1	2808.7×	0.001	GJB2
gap junction assembly	1	2106.5×	0.001	GJB2
transmembrane transport	1	168.5×	0.010	GJB2
sensory perception of sound	1	100.9×	0.012	GJB2
cell-cell signaling	1	69.6×	0.014	GJB2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
GJB2	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJB2	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GJB2	5	Binding:5

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

1 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)
KANAMYCIN	4	GJB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJB2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.