Bilateral renal agenesis

Summary

Bilateral renal agenesis (MONDO:0015986) is a disease with 7 cohort genes and 1 clinical trial. The dominant Reactome pathway is Formation of the ureteric bud (4 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 7
• ClinVar variants: 4
• Phenotypes (HPO): 18
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

17 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1.7	Europe	Validated
Prevalence at birth	1-9 / 100 000	4.5	France	Validated
Prevalence at birth	1-9 / 100 000	5.8	Germany	Validated
Prevalence at birth	1-9 / 100 000	1.4	Italy	Validated
Prevalence at birth	1-9 / 100 000	5.7	Netherlands	Validated
Prevalence at birth	1-5 / 10 000	10.8	Ireland	Validated
Prevalence at birth	1-9 / 100 000	3.2	Norway	Validated
Prevalence at birth	1-9 / 100 000	1.2	Poland	Validated
Prevalence at birth	1-9 / 1 000 000	0.6	Spain	Validated
Prevalence at birth	1-9 / 100 000	2.2	Hungary	Validated
Prevalence at birth	1-5 / 10 000	19	Denmark	Validated
Prevalence at birth	1-9 / 100 000	9.7	Austria	Validated
Prevalence at birth	1-9 / 100 000	3	Belgium	Validated
Prevalence at birth	1-5 / 10 000	13.6	Croatia	Validated
Prevalence at birth	1-5 / 10 000	24.1	Malta	Validated
Prevalence at birth	1-9 / 100 000	1.2	United Kingdom	Validated
Prevalence at birth	1-9 / 100 000	3.2	Ukraine	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000104	Renal agenesis	Very frequent (80-99%)
HP:0000286	Epicanthus	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000457	Depressed nasal ridge	Very frequent (80-99%)
HP:0001562	Oligohydramnios	Very frequent (80-99%)
HP:0001958	Nonketotic hypoglycemia	Very frequent (80-99%)
HP:0002089	Pulmonary hypoplasia	Very frequent (80-99%)
HP:0001563	Fetal polyuria	Frequent (30-79%)
HP:0002242	Abnormal intestine morphology	Frequent (30-79%)
HP:0002575	Tracheoesophageal fistula	Frequent (30-79%)
HP:0005107	Abnormal sacrum morphology	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0100589	Urogenital fistula	Frequent (30-79%)
HP:0000008	Abnormal morphology of female internal genitalia	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0010497	Sirenomelia	Occasional (5-29%)
HP:0100335	Non-midline cleft of the upper lip	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	bilateral renal agenesis
Mondo ID	MONDO:0015986
Orphanet	1848
DOID	DOID:0080200
ICD-10-CM	Q60.1
NCIT	C101219
UMLS	C1609433
MedGen	296299
GARD	0016579
NORD	1656
Is cancer (heuristic)	no

Also known as: Renal Agenesis, Bilateral

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

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › renal agenesis › bilateral renal agenesis

Related subtypes (5): renal hypodysplasia/aplasia 2, renal agenesis, unilateral, renal hypodysplasia/aplasia 1, renal hypodysplasia/aplasia 3, renal hypodysplasia/aplasia 4

Subtypes (1): bilateral renal agenesis dominant type

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

4 retrieved; paginated sample, class counts are floors:

3 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1328426	NM_000503.6(EYA1):c.1496_1499del (p.Ile498_Leu499insTer)	EYA1	Pathogenic	criteria provided, single submitter
3774323	NM_001033047.3(NPNT):c.439G>T (p.Gly147Ter)	NPNT	Likely pathogenic	criteria provided, single submitter
996101	NM_002941.4(ROBO1):c.4823C>G (p.Ser1608Ter)	ROBO1	Likely pathogenic	criteria provided, single submitter
996111	NM_002941.4(ROBO1):c.526C>T (p.Pro176Ser)	ROBO1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 34 · Orphanet: 18 · 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
GREB1L	Definitive	Autosomal dominant	renal hypodysplasia/aplasia 3	10
ITGA8	Strong	Autosomal recessive	renal hypodysplasia/aplasia 1	5
FGF20	Moderate	Autosomal recessive	renal hypodysplasia/aplasia 2	3
RET	Supportive	Autosomal recessive	bilateral renal agenesis	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GREB1L	Orphanet:1848	Renal agenesis, bilateral
GREB1L	Orphanet:93100	Renal agenesis, unilateral
FGF20	Orphanet:1848	Renal agenesis, bilateral
ITGA8	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad syndrome
ROBO1	Orphanet:95496	Pituitary stalk interruption syndrome
EYA1	Orphanet:107	BOR syndrome
EYA1	Orphanet:2792	Otofaciocervical syndrome
EYA1	Orphanet:52429	Branchiootic syndrome

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GREB1L	HGNC:31042	ENSG00000141449	Q9C091	GREB1-like protein	gencc
FGF20	HGNC:3677	ENSG00000078579	Q9NP95	Fibroblast growth factor 20	gencc
ITGA8	HGNC:6144	ENSG00000077943	P53708	Integrin alpha-8	gencc
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	gencc
ROBO1	HGNC:10249	ENSG00000169855	Q9Y6N7	Roundabout homolog 1	clinvar
NPNT	HGNC:27405	ENSG00000168743	Q6UXI9	Nephronectin	clinvar
EYA1	HGNC:3519	ENSG00000104313	Q99502	Protein phosphatase EYA1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GREB1L	GREB1-like protein	Plays a major role in early metanephros and genital development.
FGF20	Fibroblast growth factor 20	Neurotrophic factor that regulates central nervous development and function.
ITGA8	Integrin alpha-8	Integrin alpha-8/beta-1 functions in the genesis of kidney and probably of other organs by regulating the recruitment of mesenchymal cells into epithelial structures.
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…
ROBO1	Roundabout homolog 1	Receptor for SLIT1 and SLIT2 that mediates cellular responses to molecular guidance cues in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuro…
NPNT	Nephronectin	Functional ligand of integrin alpha-8/beta-1 in kidney development.
EYA1	Protein phosphatase EYA1	Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.43

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	2	8.3×	0.066
Kinase	1	4.0×	0.340
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GREB1L	Other/Unknown	no		GREB1, GREB1_N, GREB1-like_C
FGF20	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
ITGA8	Antibody/Immunoglobulin	yes		Integrin_alpha, FG-GAP, Int_alpha_beta-p
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom
ROBO1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
NPNT	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, MAM_dom
EYA1	Other/Unknown	no		EYA_dom, EYA, EYA_dom_sf

Expression context

Cohort genes with no expression data: 0.

6 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
gastrocnemius	1
male germ line stem cell (sensu Vertebrata) in testis	1
cerebellar cortex	1
cerebellar hemisphere	1
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1
dorsal root ganglion	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
ganglionic eminence	1
tibia	1
ventricular zone	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
choroid plexus epithelium	1
mucosa of paranasal sinus	1
urethra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GREB1L	184	broad	marker	buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis, gastrocnemius
FGF20	119	tissue_specific	yes	buccal mucosa cell, cerebellar cortex, cerebellar hemisphere
ITGA8	246	broad	marker	thoracic aorta, descending thoracic aorta, ascending aorta
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta
ROBO1	287	ubiquitous	marker	ventricular zone, ganglionic eminence, tibia
NPNT	239	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
EYA1	205	broad	marker	choroid plexus epithelium, urethra, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RET	4,203
FGF20	3,798
ROBO1	2,359
EYA1	1,806
ITGA8	1,613
NPNT	735
GREB1L	637

Intra-cohort edges

A	B	Sources
ITGA8	NPNT	biogrid_interaction, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RET	P07949	34
ROBO1	Q9Y6N7	12
FGF20	Q9NP95	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ITGA8	P53708	85.08
GREB1L	Q9C091	72.90
NPNT	Q6UXI9	67.42
EYA1	Q99502	66.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 64. Enrichment computed across 7 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the ureteric bud	4	331.0×	1e-08	NPNT, EYA1, ITGA8, RET
Formation of the nephric duct	2	211.5×	0.001	NPNT, RET
SLIT2:ROBO1 increases RHOA activity	1	475.8×	0.022	ROBO1
Regulation of cortical dendrite branching	1	380.7×	0.022	ROBO1
FGFR3b ligand binding and activation	1	271.9×	0.022	FGF20
Inactivation of CDC42 and RAC1	1	237.9×	0.022	ROBO1
Role of ABL in ROBO-SLIT signaling	1	211.5×	0.022	ROBO1
Signaling by activated point mutants of FGFR1	1	158.6×	0.022	FGF20
Signaling by activated point mutants of FGFR3	1	158.6×	0.022	FGF20
Regulation of commissural axon pathfinding by SLIT and ROBO	1	158.6×	0.022	ROBO1
FGFR3c ligand binding and activation	1	146.4×	0.022	FGF20
FGFR2c ligand binding and activation	1	146.4×	0.022	FGF20
Phospholipase C-mediated cascade; FGFR3	1	146.4×	0.022	FGF20
FGFR4 ligand binding and activation	1	135.9×	0.022	FGF20
Activation of RAC1	1	135.9×	0.022	ROBO1
Kidney development	1	135.9×	0.022	ITGA8
FGFR1c ligand binding and activation	1	126.9×	0.022	FGF20
Phospholipase C-mediated cascade; FGFR4	1	126.9×	0.022	FGF20
Activated point mutants of FGFR2	1	112.0×	0.022	FGF20
Phospholipase C-mediated cascade: FGFR1	1	112.0×	0.022	FGF20
Phospholipase C-mediated cascade; FGFR2	1	105.7×	0.022	FGF20
PI-3K cascade:FGFR3	1	105.7×	0.022	FGF20
SHC-mediated cascade:FGFR3	1	100.2×	0.022	FGF20
PI-3K cascade:FGFR4	1	95.2×	0.022	FGF20
Downstream signaling of activated FGFR1	1	90.6×	0.022	FGF20
FRS-mediated FGFR3 signaling	1	90.6×	0.022	FGF20
SHC-mediated cascade:FGFR4	1	90.6×	0.022	FGF20
PI-3K cascade:FGFR1	1	86.5×	0.022	FGF20
SHC-mediated cascade:FGFR1	1	82.8×	0.022	FGF20
PI-3K cascade:FGFR2	1	82.8×	0.022	FGF20

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
metanephros development	3	218.9×	3e-05	GREB1L, EYA1, ITGA8
branching involved in ureteric bud morphogenesis	3	157.0×	4e-05	NPNT, GREB1L, EYA1
smooth muscle cell differentiation	2	253.4×	0.001	NPNT, ITGA8
positive regulation of transforming growth factor beta receptor signaling pathway	2	150.5×	0.002	NPNT, ITGA8
positive regulation of MAPK cascade	3	34.6×	0.002	ROBO1, FGF20, RET
ureteric bud development	2	130.1×	0.002	NPNT, RET
establishment of protein localization	2	123.5×	0.002	NPNT, ITGA8
outflow tract morphogenesis	2	87.5×	0.003	GREB1L, EYA1
otic vesicle morphogenesis	1	2407.4×	0.006	EYA1
embryonic epithelial tube formation	1	1203.7×	0.007	RET
posterior midgut development	1	1203.7×	0.007	RET
chemorepulsion involved in postnatal olfactory bulb interneuron migration	1	1203.7×	0.007	ROBO1
positive regulation of dopaminergic neuron differentiation	1	1203.7×	0.007	FGF20
cell-matrix adhesion	2	46.8×	0.007	NPNT, ITGA8
transforming growth factor beta receptor signaling pathway	2	45.4×	0.007	NPNT, ITGA8
negative regulation of negative chemotaxis	1	802.5×	0.007	ROBO1
positive regulation of metanephric glomerulus development	1	802.5×	0.007	RET
positive regulation of secondary heart field cardioblast proliferation	1	802.5×	0.007	EYA1
pilomotor reflex	1	802.5×	0.007	NPNT
kidney development	2	40.1×	0.007	GREB1L, ITGA8
homophilic cell-cell adhesion	2	40.1×	0.007	ROBO1, RET
striated muscle tissue development	1	601.9×	0.008	EYA1
ureter maturation	1	601.9×	0.008	RET
Peyer’s patch morphogenesis	1	601.9×	0.008	RET
paramesonephric duct development	1	601.9×	0.008	GREB1L
GDF15-GFRAL signaling pathway	1	601.9×	0.008	RET
extracellular matrix organization	2	34.9×	0.008	NPNT, ITGA8
axon midline choice point recognition	1	481.5×	0.008	ROBO1
negative regulation of mammary gland epithelial cell proliferation	1	481.5×	0.008	ROBO1
regulation of cardiac muscle cell proliferation	1	481.5×	0.008	FGF20

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 2 of 7 evidence-associated genes (29%) 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
RET	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4
GREB1L	0	0
FGF20	0	0
ITGA8	0	0
ROBO1	0	0
NPNT	0	0
EYA1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3
ITGA8	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RET	1,586

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RET
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ROBO1
D	Druggable family + AlphaFold only, no drug	1	ITGA8
E	Difficult family or no structure, no drug	4	GREB1L, FGF20, NPNT, EYA1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GREB1L	0	—
FGF20	0	—
ITGA8	3	—
ROBO1	0	—
NPNT	0	—
EYA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06728228	Not specified	RECRUITING	Amnioinfusion for Fetal Renal Failure