Bladder exstrophy

Summary

Bladder exstrophy (MONDO:0010805) is a disease with 2 cohort genes (33 GWAS associations across 2 studies) and 10 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Spain) [Orphanet-validated]
• Cohort genes: 2
• GWAS associations: 33
• ClinVar variants: 3
• Phenotypes (HPO): 13
• Clinical trials: 10

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	2.8	Spain	Validated
Prevalence at birth	1-9 / 100 000	3.05	Worldwide	Not yet validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated
Prevalence at birth	1-9 / 100 000		Europe	Not yet validated
Prevalence at birth	1-9 / 100 000	2.8	United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000039	Epispadias	Very frequent (80-99%)
HP:0000056	Abnormality of the clitoris	Very frequent (80-99%)
HP:0000076	Vesicoureteral reflux	Very frequent (80-99%)
HP:0001537	Umbilical hernia	Very frequent (80-99%)
HP:0002836	Bladder exstrophy	Very frequent (80-99%)
HP:0004378	Abnormality of the anus	Very frequent (80-99%)
HP:0008736	Hypoplasia of penis	Very frequent (80-99%)
HP:0000010	Recurrent urinary tract infections	Frequent (30-79%)
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000069	Abnormality of the ureter	Frequent (30-79%)
HP:0001539	Omphalocele	Occasional (5-29%)
HP:0002566	Intestinal malrotation	Occasional (5-29%)
HP:0002607	Bowel incontinence	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	bladder exstrophy
Mondo ID	MONDO:0010805
MeSH	D001746
Orphanet	93930
DOID	DOID:0080174
ICD-11	1927556258
NCIT	C123207
SNOMED CT	61758007
UMLS	C0005689
MedGen	2661
GARD	0006398
NORD	860
Is cancer (heuristic)	no

Also known as: bladder exstrophy · bladder exstrophy (disease) · classic exstrophy of the bladder · ectopia vesicae · exstrophy of the bladder

Data availability: 3 ClinVar variants · 33 GWAS associations (2 studies) · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › exstrophy-epispadias complex › bladder exstrophy

Related subtypes (3): cloacal exstrophy, epispadias, bladder exstrophy-epispadias-cloacal exstrophy complex

Genetics & variants

GWAS landscape

33 GWAS associations across 2 studies. Top hits map to 18 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs6874700	6e-24	ISL1 - HMGB1P47	A	1.91
rs80215221	2e-14	LINC01210 - HSPA8P9	G	1.68
rs9291768	2e-12	HMGB1P47 - RNA5SP182	T	2.18
rs1924557	7e-11	ADGRL2	T	2.35
rs4745	4e-10	EFNA1	T	1.5
rs10862001	7e-10	PAWR	A	1.68
rs10853087	1e-09	GOSR2	C	1.47
chr20:55165923	7e-09		G	1.65
chr11:119964758	9e-09		G	1.47
rs12725009	2e-07	MEGF6	A	4.46
rs11580861	3e-07	RNU6-983P - LINC01724	T	3.3
rs62505227	5e-07	SIRLNT - ZMAT4	A	2.23
rs78315000	1e-06	PREX2	G	3.83
rs10119066	1e-06	RPL4P5 - PPIAP33	T	2.51
rs410285	1e-06	PRAMENP, PRAMENP	G	6.45
rs9354654	2e-06	ERVH-3 - LINC02549	C	1.67
rs192378410	2e-06	SMOC2	T	4.11
rs10993625	3e-06	DIRAS2 - OR7E109P	C	1.97
rs2361763	3e-06	LINC02132 - LINC01082	C	1.72
rs5767218	3e-06	CELSR1	C	1.71
rs115650236	5e-06	LINC02494 - LINC02619	G	5.11
rs7689350	5e-06	LINC02562 - LINC02483	C	1.93
rs1222043	6e-06	LINC02790 - RNU1-130P	C	3.41
rs113641325	6e-06	SYT1	C	1.98
rs72748303	6e-06	LINC01717 - LINC01774	A	3.33
rs76754339	7e-06	NUS1 - SLC35F1	G	5.7
rs73077895	7e-06	CREB5	A	5.35
rs12345625	7e-06	LINC01243 - MTATP6P30	T	2.72
rs76239813	7e-06	CCDC15	A	7.44
rs184483498	8e-06	FMO1-AS1, MROH9	A	2.53

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90132313	Mingardo E	2022	628	7,352	A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy.
GCST002807	Draaken M	2015	208	1,703	Genome-wide association study and meta-analysis identify ISL1 as genome-wide significant susceptibility gene for bladder exstrophy.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	32

MAF distribution

Bucket	Variants
common (>=0.05)	17
low_freq (0.01-0.05)	14
rare (<0.01)	0
unknown	2

Functional consequences

Consequence	Count
intron_variant	23
intergenic_variant	7
unknown	2
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs6874700	5	51405916	T>A	0.05	intron_variant	ISL1 - HMGB1P47	6e-24	Tier 4: intronic/intergenic
rs80215221	3	137831578	A>G	0.05	intergenic_variant	LINC01210 - HSPA8P9	2e-14	Tier 4: intronic/intergenic
rs9291768	5	51421959	C>T	0.377	intron_variant	HMGB1P47 - RNA5SP182	2e-12	Tier 4: intronic/intergenic
rs1924557	1	81582249	T>C	0.05	intron_variant	ADGRL2	7e-11	Tier 4: intronic/intergenic
rs4745	1	155133751	A>T	0.05	missense_variant	EFNA1	4e-10	Tier 1: coding
rs10862001	12	79608326	G>A,T	0.05	intron_variant	PAWR	7e-10	Tier 4: intronic/intergenic
rs10853087	17	46928746	C>A,G	0.05	intron_variant	GOSR2	1e-09	Tier 4: intronic/intergenic
chr20:55165923							7e-09	Tier 4: intronic/intergenic
chr11:119964758							9e-09	Tier 4: intronic/intergenic
rs12725009	1	3497433	G>A	0.015	intron_variant	MEGF6	2e-07	Tier 4: intronic/intergenic
rs11580861	1	195026001	C>T	0.031	intergenic_variant	RNU6-983P - LINC01724	3e-07	Tier 4: intronic/intergenic
rs62505227	8	40429730	G>A	0.086	intron_variant	SIRLNT - ZMAT4	5e-07	Tier 4: intronic/intergenic
rs78315000	8	68190823	A>G,T	0.042	intron_variant	PREX2	1e-06	Tier 4: intronic/intergenic
rs10119066	9	7509895	G>C,T	0.057	intergenic_variant	RPL4P5 - PPIAP33	1e-06	Tier 4: intronic/intergenic
rs410285	22	22027370	A>G,T	0.011	intron_variant	PRAMENP, PRAMENP	1e-06	Tier 4: intronic/intergenic
rs9354654	6	68003507	C>A,T	0.375	intergenic_variant	ERVH-3 - LINC02549	2e-06	Tier 4: intronic/intergenic
rs192378410	6	168571878	C>A,T	0.025	intron_variant	SMOC2	2e-06	Tier 4: intronic/intergenic
rs10993625	9	90679923	G>A,C	0.149	intergenic_variant	DIRAS2 - OR7E109P	3e-06	Tier 4: intronic/intergenic
rs2361763	16	85959528	C>G,T	0.494	intergenic_variant	LINC02132 - LINC01082	3e-06	Tier 4: intronic/intergenic
rs5767218	22	46483417	C>A,G,T	0.367	intron_variant	CELSR1	3e-06	Tier 4: intronic/intergenic
rs115650236	4	58802664	A>G,T	0.026	intron_variant	LINC02494 - LINC02619	5e-06	Tier 4: intronic/intergenic
rs7689350	4	75282360	A>C,G,T	0.115	intron_variant	LINC02562 - LINC02483	5e-06	Tier 4: intronic/intergenic
rs1222043	1	96159941	G>C	0.036	intron_variant	LINC02790 - RNU1-130P	6e-06	Tier 4: intronic/intergenic
rs113641325	12	79145979	G>A,C	0.126	intron_variant	SYT1	6e-06	Tier 4: intronic/intergenic
rs72748303	1	208800288	G>A,C	0.023	intron_variant	LINC01717 - LINC01774	6e-06	Tier 4: intronic/intergenic
rs76754339	6	117782973	A>G	0.016	intron_variant	NUS1 - SLC35F1	7e-06	Tier 4: intronic/intergenic
rs73077895	7	28780225	G>A	0.016	intron_variant	CREB5	7e-06	Tier 4: intronic/intergenic
rs12345625	9	31479007	C>G,T	0.03	intergenic_variant	LINC01243 - MTATP6P30	7e-06	Tier 4: intronic/intergenic
rs76239813	11	125039686	T>A	0.016	intron_variant	CCDC15	7e-06	Tier 4: intronic/intergenic
rs184483498	1	170937617	G>A	0.071	intron_variant	FMO1-AS1, MROH9	8e-06	Tier 4: intronic/intergenic

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
267944	46;XY;t(8;9)(p11.2;q13)dn		Uncertain significance	criteria provided, single submitter
548121	NM_006767.4(LZTR1):c.2093C>T (p.Ser698Phe)	LZTR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
548122	NM_006767.4(LZTR1):c.1146G>A (p.Ser382=)	LZTR1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
ISL1	ISL1	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ISL1	Orphanet:93930	Classic bladder exstrophy
LZTR1	Orphanet:251576	Gliosarcoma
LZTR1	Orphanet:251579	Giant cell glioblastoma
LZTR1	Orphanet:2678	Familial isolated café-au-lait macules
LZTR1	Orphanet:648	Noonan syndrome
LZTR1	Orphanet:93921	Full schwannomatosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	1
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ISL1	HGNC:6132	ENSG00000016082	P61371	Insulin gene enhancer protein ISL-1	gwas
LZTR1	HGNC:6742	ENSG00000099949	Q8N653	Leucine-zipper-like transcriptional regulator 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ISL1	Insulin gene enhancer protein ISL-1	DNA-binding transcriptional activator.
LZTR1	Leucine-zipper-like transcriptional regulator 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS).

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ISL1	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf
LZTR1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf

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
cervix squamous epithelium	1
islet of Langerhans	1
secondary oocyte	1
adenohypophysis	1
pituitary gland	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ISL1	148	broad	marker	secondary oocyte, cervix squamous epithelium, islet of Langerhans
LZTR1	134	ubiquitous	marker	sural nerve, pituitary gland, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LZTR1	1,562
ISL1	121

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LZTR1	Q8N653	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ISL1	P61371	72.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Incretin synthesis, secretion, and inactivation	1	1038.2×	0.006	ISL1
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	878.5×	0.006	ISL1
Cardiogenesis	1	423.0×	0.008	ISL1
Peptide hormone metabolism	1	271.9×	0.009	ISL1
Signaling by ROBO receptors	1	124.1×	0.016	ISL1
Regulation of expression of SLITs and ROBOs	1	69.2×	0.024	ISL1
Axon guidance	1	45.1×	0.029	ISL1
Nervous system development	1	42.9×	0.029	ISL1
Developmental Biology	1	14.5×	0.077	ISL1
Metabolism of proteins	1	12.4×	0.081	ISL1

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
positive regulation of macrophage colony-stimulating factor production	1	8426.0×	0.004	ISL1
visceral motor neuron differentiation	1	2808.7×	0.004	ISL1
sensory system development	1	2808.7×	0.004	ISL1
regulation of secondary heart field cardioblast proliferation	1	2106.5×	0.004	ISL1
peripheral nervous system neuron axonogenesis	1	2106.5×	0.004	ISL1
cardiac cell fate determination	1	2106.5×	0.004	ISL1
positive regulation of granulocyte colony-stimulating factor production	1	2106.5×	0.004	ISL1
sinoatrial node cell development	1	1404.3×	0.004	ISL1
negative regulation of mesenchymal cell proliferation	1	1404.3×	0.004	ISL1
trigeminal nerve development	1	1203.7×	0.004	ISL1
positive regulation of interleukin-1 alpha production	1	1203.7×	0.004	ISL1
positive regulation of type B pancreatic cell apoptotic process	1	1203.7×	0.004	ISL1
mesenchymal cell differentiation	1	1053.2×	0.005	ISL1
secondary heart field specification	1	766.0×	0.005	ISL1
spinal cord motor neuron cell fate specification	1	766.0×	0.005	ISL1
cardiac right ventricle morphogenesis	1	702.2×	0.005	ISL1
cardiac muscle cell myoblast differentiation	1	702.2×	0.005	ISL1
atrial septum morphogenesis	1	648.1×	0.005	ISL1
axon regeneration	1	561.7×	0.006	ISL1
negative regulation of intracellular estrogen receptor signaling pathway	1	561.7×	0.006	ISL1
positive regulation of granulocyte macrophage colony-stimulating factor production	1	495.6×	0.006	ISL1
spinal cord motor neuron differentiation	1	468.1×	0.006	ISL1
positive regulation of calcium ion import	1	468.1×	0.006	ISL1
innervation	1	443.5×	0.006	ISL1
endocardial cushion morphogenesis	1	421.3×	0.006	ISL1
pharyngeal system development	1	401.2×	0.006	ISL1
retinal ganglion cell axon guidance	1	383.0×	0.006	ISL1
neuron fate specification	1	351.1×	0.006	ISL1
ventricular cardiac muscle tissue morphogenesis	1	351.1×	0.006	ISL1
pancreas development	1	337.0×	0.006	ISL1

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
ISL1	0	0
LZTR1	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	ISL1, LZTR1

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)
ISL1	0	—
LZTR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE1	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01011777	PHASE1	TERMINATED	Muscle Derived Cell Therapy for Bladder Exstrophy Epispadias Induced Incontinence
NCT04626167	EARLY_PHASE1	RECRUITING	Concomitant Renal and Urinary Bladder Allograft Transplantation
NCT03698721	Not specified	NOT_YET_RECRUITING	Urothelium Tissue Engineering Using Biopsies From Transurethral Resection of Prostate
NCT04935918	Not specified	RECRUITING	EVALUATION OF THE SAFETY AND EFFICACY OF ADJUSTABLE CONTINENCE THERAPY BALLOONS IN BLADDER EXSTROPHY AND INCONTINENT EPISPADIAS PATIENTS
NCT06717386	Not specified	NOT_YET_RECRUITING	Pelvic Osteotomy in Bladder Exstrophy
NCT00863070	Not specified	COMPLETED	Biomechanical Assessment of Level Gait in Patient’s Status Post Bladder Exstrophy
NCT01878500	Not specified	COMPLETED	Navigation of the Pelvic Floor in Bladder Exstrophy Using Pre-operative MRI
NCT03061084	Not specified	UNKNOWN	Prospective Cohort of Transitional Urology Patients
NCT04580186	Not specified	UNKNOWN	Outcome Of Classic Bladder Exstrophy Repair, Assiut University Experience
NCT05690594	Not specified	COMPLETED	Long-term Outcomes of Patients Treated for Bladder Exstrophy by Questionnaires.